ccATENÇÃO ESTA PÁGINA CONTÉM INFORMAÇÕES OBTIDAS EM SITES MÉDICOS, DE NOTÍCIAS, DE ENTIDADES DE PESQUISA E LITERATURA MÉDICA ESPECIALIZADA. MUITAS DAS INFORMAÇÕES SE DESTINAM A PROFISSIONAIS DA ÁREA DE SAÚDE OU PESQUISA POR SEREM MUITO ESPECIALIZADAS. AS PESQUISAS AQUI RELATADAS SÃO NA SUA MAIORIA DE PONTA, NÃO PODENDO SER TRANSPOSTAS RAPIDAMENTE PARA O USO CLÍNICO. EM GERAL HÁ UMA DEMORA QUE PODE SER SUPERIOR A 5 ANOS ENTRE UM TRABALHO EXPERIMENTAL PROMISSOR E SEU USO CLÍNICO.
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Canadá - terapia de recrutamento de volume pulmonar diminui taxa de declínio da função pulmonar em doenças neuromusculares, possivelmente devido a limpeza aumentada das vias aéreas , redução da atelectasia ou prevenção de contraturas da parede torácica. Este estudo teve como objetivo determinar se o recrutamento de volume pulmonar mantém a capacidade de insuflação máxima, apesar de declínio da capacidade vital. Foi um estudo retrospectivo (1991-2008) de indivíduos com distrofia muscular de Duchenne em centros terciários pediátricos e adultos. Recrutamento de volume pulmonar foi prescrita duas vezes ao dia, de acordo com o protocolo. Foram avaliadas as alterações ao longo do tempo na capacidade de insuflação máxima, capacidade vital por cento-previsto e sua diferença, máxima pressão inspiratória e expiratória e assistida e não assistida, pico de fluxo da tosse. O estudo demonstrou que a terapia de recrutamento de volume pulmonar foi capaz de manter estável a capacidade máxima de insuflação apesar da perda de capacidade vital. A redução da capacidade vital foi significantemente atenuada e o fluxo de tosse assistida se manteve estável com esta terapia.
Reino Unido - bifosfonatos são drogas utilizadas para tratamento de osteoporose. Neste estudo 52 pacientes com Duchenne em uso de corticóides foram tratados com risedronato oral. Foram acompanhados pela densitometria óssea e dados foram obtidos quanto a tolerabilidade, efeitos colaterais, dor óssea, e frequência de fratura. Os dados foram comparados com os obtidos em 15 pacientes corticóide e sem risedronato.
Os efeitos colaterais ocorreram em 9 pacientes. Trinta e seis pacientes continuaram o tratamento por mais de 12 meses (média de 3,6 anos). Cinco pacientes tratados relataram dor óssea. Três pacientes tratados sofreram uma fratura vertebral, significativamente menor do que no grupo não tratado (5/15). Os resultados da densitometria ficaram estáveis com risedronato e significantemente maiores que no grupo não tratado, demonstrando o efeito positivo desde grupo de drogas em Duchenne.
Itália - neste estudo 5 pacientes com Duchenne receberam doses escalonadas de mesoangioblastos derivadas do doador em artérias dos membros sob terapia imunossupressora (tacrolimus). Quatro infusões consecutivas foram realizadas em intervalos de 2 meses, precedida e seguida por exames clínicos, laboratoriais e análises de ressonância magnética. Dois meses após a última infusão, uma biópsia do músculo foi realizada. Segurança foi o objectivo primário. O estudo foi relativamente seguro: Um paciente desenvolveu um acidente vascular cerebral sem repercussão clínica e cuja correlação com a infusão permaneceu incerta. Ressonância mostrou a progressão da doença em pacientes (4 em 5). Medidas funcionais foram transitoriamente estabilizada em 2/3 pacientes ambulantes, mas não foram observadas melhorias funcionais. Baixo nível de DNA do doador foi detectada em biópsias musculares de pacientes . Transplante intra-arterial de mesoangioblastos de doadores humanos provou ser viável e relativamente seguro. Novos estudos serão necessários para melhorar a eficiência deste tratamento.
Itália - Em pacientes com distrofia muscular de Duchenne eventos inflamatórios secundárias a mutação da distrofina desempenham um papel importante na progressão da doença. Células de Sertoli (SEC) têm sido amplamente utilizadas para proteger enxertos por induzir efeitos tróficos, graças à sua capacidade para secretar fatores tróficos, anti-inflamatórios e imunomoduladores. Neste experimentos as células de Sertoli de porcos recém-nascidos foram encapsuladas e injetadas uma única vez por via intraperitoneal em camundongos com distrofia muscular. Houve melhora das alterações morfológicas e funcionais dos músculos. Análise após cinco meses mostrou que não houve rejeição ao uso das células, com manutenção da eficácia do tratamento. O resumo em inglês pode ser lido abaixo:
(Biomaterials, 2015) Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice
Sara Chiappalupi, Giovanni Luca, Francesca Mancuso, Luca Madaro, Francesca Fallarino, Carmine Nicoletti, Mario Calvitti, Iva Arato, Giulia Falabella, Laura Salvadori, Antonio Di Meo, Antonello Bufalari, Stefano Giovagnoli, Riccardo Calafiore, Rosario Donato, Guglielmo Sorci - Italy
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle degeneration leading to impaired locomotion, respiratory failure and premature death. In DMD patients, inflammatory events secondary to dystrophin mutation play a major role in the progression of the pathology. Sertoli cells (SeC) have been largely used to protect xenogeneic engraftments or induce trophic effects thanks to their ability to secrete trophic, antiinflammatory, and immunomodulatory factors. Here we have purified SeC from specific pathogen-free (SPF)-certified neonatal pigs, and embedded them into clinical grade alginate microcapsules. We show that a single intraperitoneal injection of microencapsulated SPF SeC (SeC-MC) in an experimental model of DMD can rescue muscle morphology and performance in the absence of pharmacologic immunosuppressive treatments. Once i.p. injected, SeC-MC act as a drug delivery system that modulates the inflammatory response in muscle tissue, and upregulates the expression of the dystrophin paralogue, utrophin in muscles through systemic release of heregulin-β1, thus promoting sarcolemma stability. Analyses performed five months after single injection show high biocompatibility and long-term efficacy of SeC-MC. Our results might open new avenues for the treatment of patients with DMD and related diseases.
Austrália - empilhamento de ar melhora a efetividade da tosse e a fraqueza muscular respiratória em pessoas com distrofia muscular de Duchenne (DMD). No entanto, não se sabe se o empilhamento de ar é mais eficaz, através de um ambu ou de um ventilador. Neste estudo com 52 pessoas, 25 utilizaram o ambu e 27 o ventilador. Ambos os métodos conseguiram resultados efetivos, podendo ser utilizados. Como o ambu é mais barato e mais simples de usar seria uma opção melhor para uma parcela maior de pessoas com distrofia muscular de Duchenne. Para ver vídeos com empilhamento de ar com ambu veham os links:
https://www.youtube.com/watch?v=TKh7znrK3AA
https://www.youtube.com/watch?v=HIVM8g1rmkc
Inglaterra - neste congressos encontramos pesquisas inovadoras e sobre novas terapias para as distrofias musculares. Os destaques são as pesquisas experimentais com novas drogas, os estudos em humanos com salto de exon, ataluren, avaliações novas para membros superiores e o risco do uso da codeína em distrofia muscular de Duchenne. Os resumos destas pesquisas selecionados por mim estão a seguir:
1) Audit of DEXA bone density scans in boys with Duchenne muscular dystrophy who have sustained fractures
T. Willis *, N. Emery, R. Kulshrestha Robert Jones and Agnes Hunt Hospital, Muscle Team, Oswestry, UK
Duchenne muscular dystrophy (DMD) is a severe, progressive disease that
affects 1 in 3600–6000 live male births. Those affected can have mildly delayed
motor milestones and the majority are not able to run or jump due to proximal
muscle weakness. Most patients are diagnosed at around 5 years when it
becomes apparent that they are falling behind their peers functionally. Left
untreated, muscle strength deteriorates and boys become non-ambulant by their
teens. In addition to the loss of ambulation; respiratory, orthopaedic and cardiac
complications emerge, and without intervention mean age of death is around 19 years. Glucocorticoids are the only medication available that slows the decline
of muscle strength and function in DMD. However, they have many side effects;
cushingoid features, obesity, growth retardation, behavioural issues, delayed
puberty. Bone demineralisation and its associated increased risk of fracture to
long bones and more notably lumbar vertebrae is a major issue. Bushby et al.
proposed a set of recommendations for the care and management of boys with
DMD. These recommendations were adopted by NICE in 2011. Part of those
recommendations was that bone mineral density needs to be closely monitored.
This would allow interventions to be implemented to preserve bone integrity
and mitigate the risk of fracture. We present retrospective data on our DMD
population; ‘time to first DEXA scan’ and ’12 monthly interval DEXA scans’
as recommended now by the guidelines; 18% did not have a DEXA scan within
6 months of starting glucocorticoids; 100% – 1 occasion of not receiving a
DEXA scan within a 12 month period; 72% – 2 occasions over the 12 month
threshold;18% – 4 occasions over the 12 month threshold; the longest period
between DEXA scans was 4 years and the shortest 1 year and 4 months. These
results will be compared to the non-fractured group pre-guidelines.
2) The evaluation of bone age in patients with Duchenne muscular dystrophy on long-term glucocorticoid treatment
E. Annexstad *,1, J. Westvik 2, A. Myhre 3, J. Bollerslev 4, I. Holm 5,
M. Rasmussen 3
1 Centre for Congenital Neuromuscular Disorders, Department of Neurology,
Oslo, Norway; 2 Oslo University Hospital, Department of Radiology, Oslo,
Norway; 3 Oslo University Hospital, Women and Children’s Division, Oslo,
Norway; 4 Oslo University Hospital, Department of Endocrinology, Oslo,
Norway; 5 Oslo University Hospital, Department of Physical Medicine& Rehabilitation, Oslo, Norway
Long-term treatment with glucocorticoids (GCs) has a well-established
effect on ambulation, prevention of scoliosis and preserved respiratory function
in patients with Duchenne muscular dystrophy (DMD). However, as a new
generation of GC treatedDMDboys growup to become young adults, long-term
side effects of this treatment need to be addressed. A nationwide longitudinal
study of paediatric DMD patients in Norway was set up to assess genotype/
phenotype correlations; growth; puberty; bone health and quality of life. As part
of this study, bone age is assessed. The study is ongoing. So far, 50 boys (62.5%
of 80 known patients under the age of 18), both GC treated and GC naïve boys,
are enrolled in our study. The boys were aged 3–16 years old at the time of
enrolment in 2013. Height, weight, bone age, dual X-ray absorptiometry (DXA)
and biochemical markers of bone metabolism are recorded for most patients on
three occasions of yearly intervals. Bone age is determined on radiographs of the
left hand and wrist, evaluated by a single expert radiologist according to the
Greulich and Pyle atlas. Preliminary analysis of 58 hand radiographs from 42
boys (12 GC naïve, 30 GC treated) yields an unexpected finding of discordance
between the distal and proximal maturity in the hand and wrist in GC treated
boys. Most of the boys have a slightly retarded maturation in the distal part and
marked retarded maturation in the proximal part, including carpal bone and
wrist. To our knowledge, this phenomenon is not previously described in DMD
patients. The questions raised by our results, and the possible implications for
endocrine and bone health evaluation, are discussed.
3) Muscle ultrasound in Duchenne muscular dystrophy: Useful tool to monitor progression of early disease
P. Karachunski *,1, J. Dalton 2, J. Marsh 2 1 University of Minnesota, Minneapolis, USA; 2 University of Minnesota, Department of Neurology, Minneapolis, USA
Development of reliable and sensitive assessment of progression in early
stages of Duchenne muscular dystrophy (DMD) became an important issue in
recent years. Emergence of novel therapies raises necessity for non-invasive
monitoring of disease progression and responses to therapeutic intervention.
We studied a cohort of 12 ambulatory boys, ages of 5 to 13 years old, with
genetically confirmed DMD regarding correlation between functional
assessment and ultrasound of skeletal muscles. In this study functional
assessment of all boys included 6-minute walk, timed functional testing (10-
minute walk, time to raise from the floor, time to take 4-step stair) and North
Star Ambulatory Assessment scale. Functional status of the boys ranged
between early and late ambulatory phases. Sonographic examination of muscle
utilized qualitative and quantitative analyses using Heckmatt scale, crosssectional
area measurement and computerized gray scale analysis. Qualitative
analysis revealed diffuse or heterogeneous patterns of morphological changes
with no specific distribution of various muscle involvement, which is in
contrary to what was reported previously. Measurement of cross-sectional area
of the biceps and rectus femoris muscles showed that loss of muscle mass
correlated with worse function. We conducted gray scale analysis in multiple
muscles in all boys.We showed inverse correlation between mean gray value of
individual muscles, average mean gray value and functional measurements.
Gray scale analysis was superior to semi-quantitative Heckmatt scale in
tracking correlation of function and morphological changes in muscles. Results
of our study suggest that muscle ultrasound can be used to monitor progression
of DMD in ambulatory patients. Being cheap, noninvasive and easily feasible,
the muscle ultrasound can be further developed and standardized to meet
criteria for surrogate marker to monitor DMD progression and response to
novel therapies.
4) Magnetic resonance imaging of the arm and shoulder of boys with DMD
R. Willcocks *,1, S. Forbes 1, W. Triplett 2, D. Lott 1, C. Senesac 1,
T. Nicholson 3, H. Arora 1, G. Walter 2, K. Vandenborne 1
1 University of Florida, Department of Physical Therapy, Gainesville, USA;
2 University of Florida, Department of Physiology and Functional Genomics,
Gainesville, USA; 3 University of Florida, Gainesville, USA
Duchenne muscular dystrophy (DMD) causes progressive weakness and
disability, including the loss of arm function. Magnetic resonance imaging
(MRI) and spectroscopy (MRS) provide insight into the progression of this
disease in the legs and show promise as quantitative biomarkers, but these
methods have not been used to examine the upper arm or shoulder in DMD.
There is a critical need for robust noninvasive biomarkers for nonambulatory as
well as ambulatory boys with DMD to facilitate the inclusion of a wider range
of patients in clinical trials. In this preliminary study, we performed MRI and
MRS examinations as well as strength and functional testing of the arms of 12
boys with DMD (11 ± 3 years, 10 ambulatory) and 5 unaffected controls
(12 ± 3 years). Quantitative measures of muscle quality (fat fraction, MRI
transverse relaxation time (T2) and water T2 measured using MRS) were
significantly altered in DMD, even in boys as young as 7 years. Biceps brachii
water T2 was higher in DMD than control subjects (29.5 ± 2.8 ms vs 25.8 ± 0.9
ms). MRI T2 was elevated in the deltoid (DMD: 44.4 ± 8.7 ms control:
30.9 ± 1.1 ms), biceps brachii (BB, DMD: 48.4 ± 12.1 ms, control: 30.2 ± 2.4
ms), and triceps brachii (DMD: 46.3 ± 8.4 ms, control: 31.4 ± 0.9 ms). Finally,
BB fat fraction (FF) was 0.29 ± 0.11 in DMD and 0.14 ± 0.03 in controls. BB
FF was also significantly correlated with total Performance of Upper Limb test
score (r = 0.89), which measures proximal and distal arm function, in boys with
DMD. These preliminary data suggest that MR measures of muscle quality in
the arms have potential to be used as biomarkers in both ambulatory and
nonambulatory boys with DMD.
5) Cautionary tale in Duchenne muscular dystrophy – Opioids in neuromuscular disorders
C. Marini Bettolo *, M. Guglieri, H. van Ruiten, V. Straub, K. Bushby, H. Lochmüller Newcastle University, Newcastle upon Tyne, UK
We report two severe side effects from opioid drugs in patients with
Duchenne muscular dystrophy (DMD). The first case was a 13 year old child,
not on steroids at the time, non-ambulant, FVC 39% but asymptomatic. He was
admitted acutely to the hospital following a chest infection; he was started on
antibiotics and non-invasive ventilation. During hospitalisation, he was given
codeine phosphate (1 mg/kg) for back pain. A few hours after drug
administration, he complained of feeling nauseous and breathless; he suffered
a respiratory arrest and died. The second case is a 30 year old DMD patient,
non-ambulant and on steroids. He suffered a fall and fractured his femur and
ankle. He was treated acutely with IV morphine followed by tramadol
(100 mg). The following day, he presented with depressed consciousness which
persisted for 48 hours. Codeine phosphate is an opioid drug commonly used for
pain relief in adults and children; it is converted to morphine in the liver by the
CYP2D6 enzyme. Deaths following administration of codeine phosphate have
been previously reported; The Royal College of Paediatrics and Child Health
has recently published guidelines to recommend to avoid codeine in any child
with impaired respiratory drive. Tramadol is structurally related to codeine and
morphine and is considered an opioid drug as it binds to opioid receptors. It has
a minimal risk of respiratory depression, but in combination with morphine
aggravates the risks to patients with breathing problems. Our cases emphasise
that opioid drugs should be used with caution in patients with neuromuscular
conditions with altered respiratory drive, as they have an increased risk of
severe side effects, in particular respiratory depression.
6) Correlation of respiratory function parameters in 10–18 year old patients with Duchenne muscular dystrophy
C. Rummey 1, T. Meier *,2, M. Leinonen 3, C. McDonald 4, G. Buyse 5 1 Pharma, Liestal, Switzerland; 2 Santhera Pharmaceuticals, Liestal, Switzerland; 3 Pharma, Stockholm, Sweden; 4 University of California Davis Medical Center, Sacramento, USA; 5 University Hospitals Leuven, Leuven, Belgium
Respiratory function decline in patients with Duchenne muscular dystrophy
(DMD) is characterized by respiratory muscle weakness and progressive restrictive lung disease. Here we report the correlation of peak expiratory flow
rate (PEF) and measures of lung volume (FVC and FEV1) from cross sectional
and longitudinal data sets. Respiratory function data were collected from 64
DMD patients at age 10–18 (mean 14.3) years participating in the multi-center,
phase III DELOS trial. PEF, FVC and FEV1 were assessed by hospital-based
spirometry following ATS/ETS guidelines. Data were converted to percent
predicted (%p) using standard conversion formulae. Patients had to have
PEF%p < 80 at time of enrollment and received either idebenone (Raxone®,
900 mg/day) or placebo for 52 weeks. At baseline, data for PEF%p, FVC%p
and FEV1%p correlated well as demonstrated by Spearman’s R correlation
coefficients: PEF%p-FVC%p: 0.54; PEF%p-FEV1%p: 0.72; FVC%p-
FEV1%p: 0.91.The within subject coefficients of variation (CV) were 6.95%
for PEF%p, 6.63% for FVC%p and 9.17% for FEV1%p, indicating that these
respiratory function parameters could be more reliably assessed compared to
maximum static airway pressures (MIP%p and MEP%p) for which the CVs
were considerably higher at 18.03% and 15.74%, respectively. PEF and lung
volume parameters also correlated well during a 1-year follow-up period.
Specifically, for the change from baseline to Week 52 the correlation
coefficients were: PEF%p-FVC%p: 0.54; PEF%p-FEV1%p: 0.74; FVC%p-
FEV1%p: 0.66. PEF%p, FVC%p, and FEV1%p are important measures of
pulmonary disease in DMD and are well correlated. Respiratory strength
measured by PEF%p may be more sensitive to treatment intervention, because
lung volumes (measured by FVC) are influenced not only by respiratory muscle
strength but also thoracic wall compliance and thoracic deformities (i.e.
scoliosis).
7) The use of a hand-held device (ASMA-1) for home-based monitoring of
respiratory function changes in pediatric and adolescent patients with
Duchenne muscular dystrophy
T. Meier 1, C. Rummey 2, M. Leinonen 3, T. Voit 4, U. Schara 5, C. Straathof 6, M. D’Angelo 7, G. Bernert 8, J. Cuisset 9, R. Finkel 10, N. Goemans 11, C. McDonald 12, G. Buyse *,13 1 Santhera Pharmaceuticals, Liestal, Switzerland; 2 Pharma, Liestal, Switzerland; 3 Pharma, Stockholm, Sweden; 4 Institut de Myologie, Paris, France; 5 Universitätsklinikum, Essen, Germany; 6 LUMC, Leiden, The Netherlands; 7 IRCCS Eugenio Medea, Lecco, Italy; 8 Gv Preyer’sches Kinderspital, Wien, Austria; 9 CHRU de Lille, Lille, France; 10 Nemours Children’s Hospital, Orlando, USA; 11 University Hospitals Leuven, Leuven, Belgium; 12 UC Davis Medical Center, Sacramento, USA; 13 University Hospitals Leuven, Pediatric Neurology, Leuven, Belgium
Respiratory failure causes morbidity and early mortality in Duchenne
muscular dystrophy (DMD). Standard of care guidelines recommend routine
monitoring of respiratory function. Here we report the use of a hand-held
device for home-based frequent monitoring of respiratory flow and volume
parameters. Respiratory function data were prospectively collected from 64
DMD patients 10–18 (mean 14.3) years participating in the multi-center, phase
III DELOS trial. Standard spirometry was conducted at baseline and 3-monthly
intervals for a period of 52 weeks during hospital visits using a Spirotrac V
device. Patients were also asked to measure peak expiratory flow (PEF) and
forced expiratory volume in 1 second (FEV1) using the portable ASMA-1
device (Vitalograph) once every week at home. Patients were either treated with
idebenone (Raxone, 900 mg/d) or placebo. For each assessment, subjects
recorded several test maneuvers, and the highest value was used for analysis
according to ATS/ETS guidelines. On average patients provided ASMA-1 data
during 41.4 (SD: 14.7) weeks of the 52 week study, corresponding to 79.6%
compliance. PEF, PEF%p, FEV1 and FEV1%p collected during hospital-based
spirometry or by the ASMA-1 device at home correlated well at baseline
(Spearman’s R for PEF: 0.89; PEF%p: 0.80; FEV1: 0.73; FEV1%p: 0.83) and
for the change from baseline toWeek 52 (Spearman’s R for PEF: 0.78; PEF%p:
0.67; FEV1: 0.74 and FEV1%p: 0.60). This is the first demonstration that
frequent, home-based respiratory function testing is possible in young DMD patients. The hand-held ASMA-1 device provides reliable respiratory function
data in pediatric and adolescent patients with DMD. Portable home-based
respiratory function testing could be a valuable tool for routine measuring and
monitoring, especially in patients at risk of respiratory function decline.
8) Impact of three decades of improvement in standards of care for Duchenne
muscular dystrophy
C. Jimenez, Moreno, M. Eagle, A. Mayhew *, M. James, V. Straub, K. Bushby John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle upon Tyne, UK
For three decades, standardized care guidelines have been developed and
practiced for Duchenne muscular dystrophy (DMD) at the Newcastle uponTyne
Hospitals Trust (NUTH), UK, recently designated the John Walton Muscular
Dystrophy Research Centre. These relate to four main interventions: noninvasive
ventilation (NIV), spinal surgery, prophylactic cardiac management
and, since 2002, standardized corticosteroid treatment. A clinical audit was
performed to explore the impact of these interventions. The files of 126
genetically confirmed DMD patients born between 1980 and 2009 were
analyzed and compared to historical records from 119 patients born between
1950 and 1979. Patients were grouped by decade of birth to correlate natural
history and interventions. An additional subgroup was made between steroid treated and naïve patients from the 1990 group. Age at loss of ambulation
showed an improvement from a mean of 9.5 years (95% CI 9–10) in the 1960s
group to a mean of 12.6 years (95% CI 11.9–13.4) in the patients of the 1990s.
73% of patients in the 2000s group are still ambulant at 12 years old. The
incidence of spinal surgery initially increased following standardization of
referral criteria but after the introduction of steroids patients required surgery
less often and later in life, at a mean age of 20 years old (95% CI 19–21.3)
compared to 13.8 years. Survival has also improved from a mean age of
mortality of 19.6 years in the 1950s up to 26.8 years old in the group of the
1990s and currently 65% patients are over their 20s. The combination of
angiotensin-converting-enzyme (ACE) inhibitor with non-selective betablocker
is now standard practice in Newcastle with prophylactic intervention at
a mean age of 13 years. However data are still evolving on the impact of this on
survival and quality of life. In conclusion a series of overlapping interventions
over three decades have significantly improved the age at loss of ambulation and
survival in DMD.
9) High intensity training in patients with facioscapulohumeral muscular dystrophy
A. Buch *,1, G. Andersen 2, K. Borup Heje Pedersen 2, J. Vissing 2
1 Rigshospitalet, University hospital of Copenhagen, Copenhagen
Neuromuscular Center, Rigshopsitalet 2100, Denmark; 2 Rigshospitalet,
Copenhagen Neuromuscular Center, Copenhagen, Denmark
Facioscapulohumeral muscular dystrophy (FSHD) causes an asymmetric
degeneration of the muscles, primarily affecting the face, shoulders, upper arms
and calves. Once, patients with FSHD were advised against exercising, but
studies have shown that aerobic exercise of moderate intensity is a safe and
beneficial treatment. This study aims to evaluate the safety and efficacy of high
intensity training (HIT) in patients with FSHD. In this ongoing study, FSHD patients
with low levels of daily aerobic physical activity are randomized to
either a supervised HIT-program for 8 weeks followed by 8 weeks of optional
training (n = 7; age 26–67 years, 4 males, BMI 22–31 kg m−2, mean FSHD
score 6.3 [1:11]) or to 8 weeks with no intervention followed by 8 weeks of
unsupervised HIT (n = 6; age 30–59 years, 5 males, BMI 20–36 kg m−2, mean
FSHD score 7.25 [5–11]). Age-, sex- and BMI-matched healthy controls (n = 6;
age 27–64 years, 5 males, BMI 22–26 kg m−2) are enrolled to supervised HIT
followed by 8 weeks of optional training. The HIT consists of 2 × 5 min of
interval training on a cycle-ergometer, performed 3 times weekly with one
supervised session or all unsupervised. Preliminary data from participants who
have completed the study period show an increase in VO2max by a mean of
9.5% in FSHD (n = 5, supervised and unsupervised) and 3.1% in the healthy
controls (n = 4) after HIT. VO2max did not change during the 8 weeks without
intervention in patients with FSHD (n = 2). Patients with FSHD all favoured
HIT over training of moderate intensity and continued HIT, maintaining a mean
VO2max by 10.9% above baseline. During the study period, the daily numbers
of steps taken, as monitored by a pedometer and plasma-CK-levels, were
unchanged. Overall the data suggest that HIT is a safe training method, which
improves VO2max in patients with FSHD, and the high motivation seen during
the period of optional training indicates that HIT could be a good alternative to
other training regimes for patients with FSHD.
10) Arm function of boys with Duchenne muscular dystrophy explored by surface electromyography and muscle force measurements
M. Janssen 1, J. Harlaar 2, I. de Groot 1
1 Radboud University Medical Center, Rehabilitation, Nijmegen, The
Netherlands; 2 VU University Medical Center, Rehabilitation, Amsterdam, The
Netherlands
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular
disorder. Since no cure for DMD is available, care is mainly focused on
preserving functional abilities. To improve functionality in the arms, innovative
arm supports are being developed. However, to support this development,
detailed knowledge on arm function in boys and men with DMD is needed.
Therefore the aim of this study was to investigate arm function in boys and men
with DMD in different disease stages and healthy controls by means of surface
electromyography (sEMG) and muscle force measurements. 23 DMD patients
(Brooke 1–5) and 16 healthy subjects between 6 and 23 years have participated
in this study. All participants performed single joint movements of the shoulder,
elbow and wrist, while sEMG signals were recorded. In addition, maximal force
and sEMG amplitude in 7 muscle groups were measured using a fixed force
sensor. This study will compare maximal force and normalized sEMG
amplitudes between DMD patients and controls. The maximal force in all
muscles of controls increases with age, while maximal force of DMD patients
decreases with age. In addition, sEMG amplitude as well as maximal force
levels in DMD patients showed an almost linear decrease with increasing
Brooke scale. Normalized sEMG amplitudes of single joint movements were
much larger in DMD patients compared to controls (40% for shoulder muscles
and 60% for elbow muscles). This study indicates that sEMG and muscle force
reduce, with increasing Brooke scale, which is important knowledge for the
development of new arm supports, as both signals are promising signals for the
control of an arm support. In addition, knowledge on muscle force can be used
to adapt passive arm supports based on the remaining strength in different
muscles. The results are based on preliminary analysis. Final data analysis will
include more subjects and also 3D kinematic data will be discussed.
11) Determinants to predict upper extremity function in boys and men with DMD
M. Janssen *,1, J. Hendriks 2, A. Geurts 1, I. de Groot 3 1 Radboud University Medical Center, Rehabilitation, Nijmegen, The Netherlands; 2 Radboud University Medical Center, Health Evidence, Nijmegen, The Netherlands; 3 Radboud University Medical Center, Reinier Postlaan 2, Nijmegen, The Netherlands
Preserving upper extremity function in Duchenne muscular dystrophy
(DMD) patients is extremely important as it is highly related to quality of life. For
clinical decision making, effective interventions and knowledge on determinants
affecting arm function is necessary. This knowledge, however, is limited.
Therefore, this study aims to gain more insight into determinants and
interventions that could influence upper extremity function in DMD. Data from
a large international web based questionnaire on arm function, in which 211
DMD patients were included, were used. Factor analysis on the questions
regarding armfunction resulted in 6 factors.The sum scores of these factorswere
used as dependent variables in a multiple forward regression analysis. In addition, 28 independent variables regarding medication, therapy, supportive
aids, pain, stiffness and participation were used in this analysis. In total 11
independent variables showed a significant relation with one or more dependent
variables. Variables that had a negative relation with arm function were:
increasing disease stage, the occurrence of scoliosis, increasing age, the use of
splints, increasing age of diagnosis, having physical therapy and increasing
stiffness. In addition, a positive relation with arm function was seen in people
who used corticosteroids, people who went to school or worked and people who
used an arm support. Knowledge on determinants that influence the functional
abilities of the arms is very important for clinical management ofDMDpatients.
The results of this study indicate that corticosteroid use, participating in school
and work related activities and the use of arm supports have a positive effect on
arm function in DMD patients. In addition, reducing stiffness, preventing
scoliosis and early diagnosis could also have a positive effect on arm function.
12) Development of a patient-reported outcome measure for arm and hand function in Duchenne muscular dystrophy (UL-PROM DMD)
K. Klingels 1, A. Mayhew 2, E. Mazzone 3, M. Main 4, V. Decostre 5,
M. van den Hauwe 6, M. Eagle 2, T. Duong 7, I. de Groot 8, V. Ricotti 9,
U. Werlauff 10, G. Campion 11, E. Vroom 12, E. Mercuri 13, N. Goemans *,14
1 University of Leuven, Department of Rehabilitation Sciences, Leuven,
Belgium; 2 Institute of Human Genetics, Newcastle, UK; 3 Policlinico Gemelli,
Department of Paediatric Neurology, Neuropsichiatria Inf, Rome, Italy; 4 Great
Ormond Street Hospital for Children, London, UK; 5 Institut de Myologie,
Paris, France; 6 University Hospitals Leuven, Child Neurology, Leuven,
Belgium; 7 Stanford University, Stanford, USA; 8 Radboud University Medical
Centre, Nijmegen, The Netherlands; 9 University College London, London, UK;
10 Rehabiliterings Center for Muskelsvind, Copenhagen, Denmark;
11 BioMarine Pharmaceutical Inc, Leiden, The Netherlands; 12 Duchenne
Parent Project, Leiden, The Netherlands; 13 Catholic University Rome,
Department of Paediatric Neurology, Neuropsichiatria Inf, Rome, Italy;
14 University Hospitals Leuven, Dept of Paediatric Neurology, Leuven, Belgium
A multidisciplinary international Clinical Outcomes group consisting of
clinicians, scientists, industries, patients and their advocacy groups designed the
Performance of Upper Limb module (PUL) for Duchenne Muscular Dystrophy
(DMD), according to a specific contextual framework of upper limb function in
both ambulant and non-ambulant individuals with DMD. Closely linked to this
motor performance based clinician-reported outcome measure, a parallel
patient-reported outcome measure (UL-PROM) has been developed to evaluate
manual ability related to activities of daily living (ADL) that cannot be observed
in a clinical setting. The developmental process included item generation from
a systematic review of existing tools and expert opinion, based on clinical
relevance and potential to measure the concepts related to quality of life.
Individuals with DMD were involved throughout the iterative process by
offering their opinion on task difficulty and relevance. Also, cultural aspects
affecting ADL were taken into consideration to make this tool applicable to the
broad DMD community. Items were selected in relation to the different domains
of the PUL from proximal to distal performance in order to cover the full range
of upper limb functions. After pilot testing followed by a preliminary Rasch
analysis in 88 boys with DMD, redundant or clinically irrelevant items were
removed. A second Rasch analysis in a larger dataset of 357 boys with DMD
collected within an international multicenter collaboration resulted in further
modifications of the UL-PROM.The questionnaire consists of 32 items covering
four domains of ADL (Food 7 items, Self-care 8 items, Household and
environment 6 items, Leisure and communication 11 items) and is
recommended to be used in boys from 7 years of age. Data are currently
collected to further confirm its suitability to assess the manual abilities of DMD,
relevant to ADL, its psychometric robustness and applicability in clinical trials
13) Reachable workspace and performance of upper limb (PUL) in Duchenne muscular dystrophy
C. McDonald *,1, J. Han 1, E. de Bie 1, A. Nicorici 1, R. Abresch 1, C. Anthonisen 1, R. Bajcsy 2 1 University of California, Davis, Physical Medicine & Rehabilitation, Sacramento, USA; 2 University of California, Berkeley, Electrical Engineering and Computer Science, Berkeley, USA
Introduction: The Kinect-based reachable workspace relative surface area (RSA) is compared with the Performance of Upper Limb (PUL) in Duchenne muscular dystrophy (DMD). Methods: 29 individuals with DMD (ages: 7–23, Brooke: 1–5) underwent both the Kinect-based reachable workspace RSA and the PUL assessments. RSAs were also collected from 24 age-matched controls. Total and quadrant RSAs were compared with the PUL total, shoulder-, middle-, and distal-dimension scores. Results: The total reachable workspace RSA correlated well with the total PUL score (Spearman’s ρ = |0.602|, P < 0.001), and with each of the PUL dimensional scores: shoulder (ρ = |0.624|, P < 0.001), middle (ρ = |0.564|, P = 0.001), and distal (ρ = |0.630|, P < 0.001). With quadrant RSA, reachability in particular quadrant was closely associated with respective PUL dimensional-level function (ipsilateral-upper quadrant for shoulder-, ipsilateral-upper/lower quadrants for middle-, and ipsilateral-lower quadrant for distal-level function). Discussion: This study demonstrates concurrent validity of the reachable workspace outcome measure (RSA) with the DMD-specific upper extremity outcome measure (PUL).
14) Identification of novel therapy-responsive protein biomarkers for Duchenne muscular dystrophy by aptamer-based serum proteomics
A. Coenen-Stass *,1, G. McClorey 1, R. Manzano 1, C. Betts 1, A. Blain 2,
A. Saleh 3, M. Gait 3, H. Lochmüller 2, L. Gold 4, M. Wood 1, T. Roberts 5
1 University of Oxford, Department for Physiology, Anatomy and Genetics,
Oxford, UK; 2 Institute of Human Genetics, Newcastle, UK; 3 Medical Research
Council, Laboratory of Molecular Biology, Cambridge, UK; 4 SomaLogic, Inc.,
Boulder, CO, USA; 5 Sanford-Burnham Medical Research Institute, San Diego,
CA, USA
There is currently an urgent need for biomarkers that can be used to monitor
the therapeutic efficacy of experimental therapies for Duchenne muscular
dystrophy (DMD) in clinical trials. Serum protein biomarkers are widely used
for clinical chemistry applications on account of the relative ease with which
they can be measured. However, identification of novel protein biomarkers has
been limited due to the massive complexity of the serum proteome and the
presence of a small number of very highly abundant proteins. Here, we have
performed an aptamer-based proteomics approach to profile 1129 proteins in
the serum of wild-type and mdx (dystrophic) mice using the SOMAscan
platform at SomaLogic, Inc. (Boulder, CO, USA). The serum levels of 53
proteins were found to be significantly altered in mdx mice. Additionally, we
also profiled mdx mice that had been treated with a peptide-antisense
oligonucleotide conjugate designed to induce Dmd exon skipping and thereby
restore dystrophin protein expression. Using this approach we found that the
majority of differentially abundant serum proteins were restored towards wildtype
levels following the rescue of dystrophin protein in dystrophic muscle. The
results for five leading candidate protein biomarkers (Pgam1, Tnni3, Camk2b,
Cycs and Adamts5) were validated by ELISA in the mouse samples.
Furthermore, ADAMTS5 was also found to be up-regulated in DMD patient
sera, supporting its use as a clinical biomarker. Elevated ADAMTS5 was also
observed in Becker muscular dystrophy (BMD) and facioscapulohumeral
muscular dystrophy (FSHD) suggesting that it may be a non-specific marker of
muscle pathology. In conclusion, we have identified multiple novel serum
protein biomarkers of DMD that are partially or fully restored following exonskipping therapy. Future work will investigate these biomarkers in larger patient
cohorts and longitudinal studies to elucidate the basic biology which leads to
their secretion or leakage from dystrophic muscle.
15) Reversible immortalization allows human artificial chromosome-mediated
gene correction of human dystrophic muscle progenitor cells
S. Benedetti 1, H. Hoshiya 1, M. Ragazzi 1, N. Uno 2, Y. Kazuki 2, G. Ferrari 1,
R. Tonlorenzi 3, A. Lombardo 4, V. Mouly 5, L. Naldini 4, G. Messina 6,
M. Oshimura 2, G. Cossu 7, F. Tedesco *,1
1 University College London, Department of Cell and Developmental Biology,
London, UK; 2 Tottori University, Department of Biomedical Science, Yonago,
Japan; 3 San Raffaele Hospital, Divisions of Regenerative Medicine &
Neuroscience, Milan, Italy; 4 San Raffaele Hospital, Telethon Institute of Gene
Therapy, Milan, Italy; 5 Universite Pierre et Marie Curie, Institut de Myologie,
Paris, France; 6 University of Milan, Department of BioSciences, Milan, Italy;
7 University of Manchester, Institute of Inflammation and Repair, Manchester,
UK
Mutations in the dystrophin gene cause Duchenne muscular dystrophy
(DMD), which affects the skeletal muscle, resulting in disability and premature
death. Even though there is no cure, new treatments are under investigation.
Among these, gene and cell therapy is promising but complex, as dystrophin is
the largest gene in nature (2.4 Mb) and skeletal muscle the most abundant
human tissue. Stem/progenitor cells and large capacity vectors such as human
artificial chromosomes (HACs) can overcome these hurdles. We previously
showed amelioration of the dystrophic phenotype of mice transplanted with
murine mesoangioblast progenitor cells, corrected with a HAC containing the
entire dystrophin locus (DYS-HAC). Notably, allogeneic human
mesoangioblasts have recently been transplanted in 5 DMD boys in a first-inhuman
clinical trial. However, translation of the HAC technology for
autologous strategies requires cells with a significant proliferative capacity, able
to withstand expansion into relevant numbers to treat a dystrophic patient. Here
we present a strategy for the generation of HAC-corrected DMD myogenic
progenitors. Reversible immortalization using excisable human telomerase and
Bmi1 cDNAs allowed bypassing of replicative senescence and DYS-HAC
transfer. Immortalized mesoangioblasts maintain a stable karyotype, remaining
myogenic, non-transformed and non-tumorigenic. Extension of DMD
mesoangioblast proliferation allowed HAC transfer and generation of clones
carrying the DYS-HAC. These clones gave rise to dystrophin-positive fibres
upon transplantation into dystrophic mice. Finally, we also provide evidence of
extension of the DYS-HAC platform to other myogenic cells amenable for
clinical transplantation and immortalization, such as human myoblasts. These
results provide the first evidence of translation of HAC technology to linicallyrelevant
muscle progenitors, paving the way for the establishment of an
autologous HAC-based protocol for gene and cell therapy of DMD.
16) miRNAs as serum biomarkers for Duchenne muscular dystrophy:
Correlation analysis in a multicentre study between miRNA levels and
clinical status of DMD patients
A. D’Amico *,1, J. Martone 2, S. Previtali 3, G. Baranello 4, G. D’Angelo 5, A. Berardinelli 6, S. Messina 7, G. Vita 7, M. Pane 8, L. Morandi 4, E. Mercuri 8, M. Catteruccia 1, E. Bertini 1, I. Bozzoni 2 1 Bamino Gesu’ Children’s Hospital, Unit of Neuromuscular and Neurodegenerative Disorders, Rome, Italy; 2 La Sapienza University, Department of Biology and Biotechnology “Charles”, Rome, Italy; 3 IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology (INSPE), Milan, Italy; 4 Fondazione IRCCS Istituto Neurologico “C. Besta”, Developmental Neurology and Neuromuscular Disease, Milan, Italy; 5 IRCCSEugenio Medea, Neurorehabilitation Unit, Bosisio Parini, Italy; 6 Child Neurology and Psychiatry Unit, Pavia, Italy; 7 University of Messina, Department of Neurosciences and Nemo Sud Clinical, Messina, Italy; 8 Catholic University, Department of Paediatrics and Neurology, Rome, Italy
Currently no treatment is available for Duchenne muscular dystrophy
(DMD) but in the last few years several promising experimental strategies are
emerging. One of the main issues in the design of clinical trials is the lack of
non-invasive and reliable biomarkers. Specific muscle dystro-miRNAs have
been proposed as potential non-invasive biomarkers for monitoring the
outcome of therapeutic interventions and disease progression. The objective is
to validate miRNAs as serum biomarkers for DMD. We performed a
multicentre study in order to correlate circulating miRNA levels and clinical
status of DMD.We quantified miR-1, miR-133 and miR-206 in the serum from
ambulant and non-ambulant DMD patients. We performed a correlation with
age, 6 minute walk tests and North Star Ambulatory Assessment scores. We
recruited 84 DMD patients (67 ambulant/17 non-ambulant; age range 4 and 22
years). Sixty patients were on steroid treatment, 24 were steroid free. MiR-1,
miR-133 and miR-206 were upregulated in DMD. Ambulant patients had
higher levels of dystro-miRNAs than non-ambulant patients (p = 0.0001).
miR206 is statistically higher in patient <7 years than in patients older than 7
(p = 0.01). A weak correlation was found with functional motor abilities
assessed by North Star Ambulatory Scale and 6 minute walk test. Patients on
daily steroid therapy had lower levels of dystro-miRNAs than patients without
steroid therapy.We found a clear correlation between dystro-miRNAs, age and
disease severity. We did not found a clear correlation between miRNAs and
motor outcome measures. Longitudinal studies are needed to demonstrate if
dystro-miRNAs can be considered biomarkers for monitoring the disease
progression or predictive biomarkers as indirect representative of the remaining
muscle mass.
17) Nonsense mutation dystrophinopathy: How mutation-specific treatments changed our clinical practice?
D. Ardicli *, B. Konuskan, G. Haliloglu, M. Alikasifoglu, H. Topalog˘lu Hacettepe Children’s Hospital, Ankara, Turkey
Although there are advances in our understanding of molecular background
of DMD, there is still a considerable delay in diagnosis. Current best practice
molecular approach includes MLPA followed by direct sequencing of all exons
at the genomic level, or from cDNA. Herein, we report clinical and genetic
characteristics of 15 patients followed with nonsense mutated-DMD (nm-
DMD) at Hacettepe University Children’s Hospital, Department of Pediatric
Neurology. We reviewed clinical features and diagnostic approach to 15 nm-
DMD patients, including 14 boys aged between 3 and 17 years, and one
manifesting 37-year-old female carrier. The mean age of the patients was 10
years, and the mean age at DMD diagnosis was 4.8 years (20 months–12 years).
Six patients were diagnosed incidentally with high serum creatine kinase (CK)
levels. The remaining patients presented with delay and difficulty in walking
and climbing up the stairs. Motor developmental delay was observed in 8 (53%)
patients. Learning disability (n = 4) and attention deficient hyperactivity
disorder (n = 1) were additional features. Five of the patients (33%) had positive
family history. Multiplex PCR study of the most commonly deleted exons were
negative (n = 8), and muscle biopsy was consistent with dystrophinopathy
(n = 9). The mean age at muscle biopsy was 5.1 years. MLPA in all patients
followed by direct sequencing of all exons at the genomic level revealed
nonsense mutations. Mean age at molecular diagnosis of nm-DMD was 9 years
(20 months–36 years). Two of our patients were sharing the same point age. Genetic approach has been changed over the years depending on advances
and availability of genetic screening tests in different centers. A dynamic
approach for molecular diagnosis is mandatory.
18) Gene expression profiling of blood in patients with Duchenne muscular dystrophy
B.Wong *,1, D. Liu 2, S. Hu 1, P. Morehart 1, B. Stamova 2, B. Ander 2, F. Sharp 2 1 Cincinnati Children’s Hospital Medical Center, Division of Pediatric Neurology, Cincinnati, OH, USA; 2 M.I.N.D. Institute, UC at Davis, Neurology, Sacramento, CA, USA
This study aims to (1) determine the blood transcriptomic profile of nonglucocorticoid
(GC) treated early and late stage DMD patients and (2) gene
expression profiles of early stage DMD patients after GC treatment. The finding
of a molecular signature in the blood of DMD patients would facilitate the use
of a non-invasive biomarker in clinical trials and monitor biological processes.
Prospective study of DMD patients and healthy age-matched male controls
(HC) with 2 blood samples from young DMD-Y patients (pre-GC and 6 months
post-GC) and 1 from older, non-GC DMD patients and HC. Sixty-six DMD
patients (49 ages 3–10, 17 ages 11–20), 46 HC (28 ages 3–10, 18 ages 11–20)
were studied. There are 4 groups: DMD Young (DMD-Y); DMD Old (DMDO);
Control Young (CTRL-Y) and Control Old (CTRL-O). DMD-Y subjects
had DMD-YpreTx and DMD-YpostTx. One hundred and one mRNAs
(FDR1.2) were differentially expressed in DMD-YpreTx compared to CTRL-Y.
A number of genes that encode ribosomal proteins (RPS29, RPS27, RPL39,
RPL41 and RPS24) in the EIF2 signalling pathway are upregulated. The two
groups are largely segregated on the corresponding heatmap. Eighty mRNAs
(FDR1.2) were differentially expressed in DMD-YpostTx compared to DMDYpreTx.
Three genes (MMP8, SERPINB10 and DEFA3) were found to overlap
between the above 2 lists of differentially expressed genes. Differential
expression of mRNA was not noted in DMD-O compared to CTRL-O.
Functional analysis revealed 6 overlapped biofunctions among the top 10
categories from the 2 lists of altered genes: immunological disease; connective
tissue disorders; inflammatory disease; skeletal and muscular disorders; cellto-
cell signalling and interaction; and inflammatory response. However there
were no overlapped canonical pathways. We found a blood gene expression
signature that characterizes young untreated DMD patients and alteration of the
blood gene expression profile with GC treatment.
19) Development of Rimeporide, a sodium-hydrogen exchanger (NHE-1) inhibitor, for patients with Duchenne muscular dystrophy
F. Porte-Thomé *,1, K. Nagaraju 2, Q. Yu 3, K. Tatem 3, G. Bkaily 4,W. Scholz 5,
A. Slade 6, N. Bot 6, C. Kant 6
1 EspeRare, R&D, Plan les ouates, Geneva, Switzerland; 2 Children National
Medical Center, R&D, Washington, DC, USA; 3 Children National Medical
Center, Washington, DC, USA; 4 University of Medicine, Sherbrooke, Canada;
5 Merck Serono, Darmstadt, Germany; 6 EspeRare, Plan les ouates, Geneva,
Switzerland
NHE-1 is a key membrane transporter regulating the intracellular pH, Na+
concentration and catalysing the electroneutral counter transport of Na+ and H+
through the plasma membrane. A significantly higher influx of Ca2+, partly
triggered via intracellular Na+ concentrations driving the Na+/Ca2+ exchanger
(NCX) into reverse mode, has been seen in dystrophic versus healthy muscle.
Intracellular pH and Ca2+ overload is known to play a key role in DMD
pathophysiology, including cardiomyopathy. Rimeporide is a potent and
selective NHE-1 inhibitor which has been shown to be safe and well tolerated
in Phase I trials. Blocking NHE-1 activity has been shown to decrease
intracellular Na+ and Ca2+ overload and pH and rimeporide represents a new
therapeutic option for DMD. When tested in mdx mice, rimeporide prevented
both nflammation and the accumulation of fibrosis in the skeletal muscle and
in the heart. It also had positive effects on myofibre size and oedema. In the
cardiomyopathic hamster, rimeporide prevented hypertrophy, thrombosis and
necrosis in the heart. Its cardio-protective effect is most clearly demonstrated by
a significant increase in overall survival of treated animals. Rimeporide is
expected to act as a muscle-sparing agent and its mode of action means that it
is mutation independent and could therefore be used to treat a broad population
of patients with DMD. Given the complexity of DMD, it is unlikely a single
agent will be effective over the entire course of disease and in all patients.
Rimeporide’s potential to address skeletal muscle inflammation and fibrosis
and cardiomyopathy makes it an ideal complement to other treatments designed
to augment or replace dystrophin. Rimeporide has an ODD in Europe and a
Phase Ib clinical study in patients with DMD is ongoing. Data from this study,including those from novel biomarkers will set the scene for the pivotal clinical development of rimeporide as new therapeutic option for the treatment of patients with DMD
20) Therapeutic potential of adiponectin and adipoRon in Duchenne muscular
dystrophy
Lecompte *, M. Abou-Samra, R. Boursereau, L. Noel, S. Brichard Univeristé Catholique de Louvain, IREC/EDIN, Bruxelles, Belgium
Persistent and severe inflammation exacerbates disease progression in
Duchenne muscular dystrophy (DMD). Adiponectin (ApN) is a hormone
abundantly secreted by adipocytes, which exhibits insulin-sensitizing, fatburning
and anti-inflammatory properties.We have previously shown that ApN
potently protects muscle against inflammation and injury in mdx mice, a model
of DMD. As every peptide, ApN has to be injected, while AdipoRon, a recently
discovered synthetic small-molecule, which is an agonist of ApN receptors may
be given orally. Here we investigated whetherApN retains its anti-inflammatory
properties in human DMD myotubes and whether this action may be
reproduced by AdipoRon. Primary cultures of myotubes from DMD patients
and age- and sex-matched controls were performed (n = 7 independent cultures
from 4 different patients for each group; myoblasts were obtained from the
French Telethon Myobank-AFM). These myotubes were challenged by an
inflammatory stimulus (to mimic the DMD inflammatory status) and treated or
not by ApN/AdipoRon. ApN downregulated gene expression of TNFα, a proinflammatory
cytokine (p < 0.01) and of Iκb, an inhibitor of NF-κB (p < 0.05)
while upregulating mRNA abundance of Il-6, an anti-inflammatory cytokine
(p < 0.05) in control as well as in DMD myotubes. Silencing selected genes
further indicated that these anti-inflammatory effects were mediated by
AdipoR1, the most abundant ApN receptor in the muscle and by the AMPK– SIRT1–PGC-1α signalling pathway in control and DMD myotubes; PGC-1α is
a transcriptional coactivator, which regulates energy metabolism and
suppresses inflammation. Eventually, AdipoRon reduced TNFα mRNAs
(p < 0.05) and increased Il-6 mRNAs (p < 0.001) in both DMD and control
myotubes challenged by an inflammatory stimulus. ApN retains its antiinflammatory
effects in human myotubes obtained from DMD patients.
AdipoRon reproduces this protection. These results could open new
perspectives in the management of muscular diseases.
21)
Utrophin modulators to treat Duchenne muscular dystrophy (DMD):
Results from a Phase 1b Clinical Trial of SMT C1100
J. Tinsley *,1, F. Muntoni 2, S. Spinty 3, H. Roper 4, I. Hughes 5, R. Ricotti 2, B. Tejura 6, G. Layton 7, K. Davies 8 1 Summit Therapeutics, Abingdon, UK; 2 UCL Institute of Child Health, Dubowitz Neuromuscular Centre, London, UK; 3 Alder Hey Children’s NHS Foundation Trust, Liverpool, UK; 4 Birmingham Heartlands Hospital, Birmingham, UK; 5 Royal Manchester Children’s Hospital, Manchester, UK; 6 Summit Therapeutics, Cambridge, USA; 7 Paramstat, Ash, UK; 8 University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK
In DMD, skeletal muscle is lost due to an inability to produce dystrophin.
During foetal muscle development utrophin takes the functional role of
dystrophin. Continuous muscle expression of utrophin could functionally
replace dystrophin and potentially overcome the dystrophin deficit in DMD. In
dystrophic animal studies, daily SMT C1100 treatment significantly reduced
muscle degeneration leading to improved muscle function. Data from a recently
completed Phase 1b study in DMD subjects suggest that diet is able to influence
absorption of SMT C1100. This study aims to investigate this further. Twelve
boys with DMD were enrolled into this Phase 1b placebo-controlled study of
single and multiple oral doses of SMT C1100. Boys were randomly allocated to
the three treatment sequence groups. Each patient received both doses of SMT
C1100 (1250 mg twice daily (BID) and 2500 mg BID) in a dose escalating
fashion, with placebo in the other study period. A minimum two week washout
was included between each Treatment Period to allow for study drug washout
and safety review. One of the secondary objectives of this study was to evaluate
reductions in creatine phosphokinase (CPK). With 12 patients this study had 80% power of demonstrating a statistically significant reduction in CPK
compared to placebo with a two-sided, 5% confidence level, if SMT C1100
reduced CPK 30% more than placebo. Data from this trial will be presented and
will assist in designing future Phase 2 studies that will include functional and
biomarker endpoints.
22) Small molecule compounds that promote exon skipping in the DMD gene
N. Naryshkin *, A. Dakka, V. Gabbeta, J. Pichardo, P. Vazirani, G. Ryan, M. Woll, A. Turpoff, N. Zhang, S. Zhang, G. Karp, E. Welch PTC Therapeutics, South Plainfield, NJ, USA
Approximately two thirds of the mutations in the dystrophin gene are
deletions in the open reading frame that result in the production of C-terminustruncated
non-functional dystrophin protein. One potential therapeutic
approach to address a subset of the reading frame-altering deletions, located in
the central rod domain, is to cause skipping of an exon downstream of the
deletion thereby restoring the reading frame. The resulting protein, containing
an internal deletion, would be partially functional but expected to lead to a
milder, attenuated disease phenotype. PTC Therapeutics has developed an
Alternative Splicing drug discovery platform technology to identify small
molecule drug candidates that target pre-mRNA splicing. This platform has
been used to discover and develop orally deliverable small molecule modifiers
of SMN2 alternative splicing to treat the genetic disease spinal muscular
atrophy (SMA). The clinical compound is currently being investigated in
human clinical trials in collaboration with Roche and the SMA Foundation.
PTC is applying this drug discovery platform technology to Duchenne muscular
dystrophy.We have designed high throughput screening approaches to identify
compounds that induce targeted exon skipping during DMD pre-mRNA
splicing of exons 44, 45, 51, and 53. For the most advanced program, exon 51
skipping, we have completed a high throughput screen of our compound library
using a minigene construct. Hit molecules are undergoing structural
optimization to improve biological activity and pharmacological and
pharmaceutical properties.
23) Exon 53 skipping of the dystrophin gene in patients with Duchenne
muscular dystrophy by systemic administration of NS-065/NCNP-01: A
phase 1, dose escalation, first-in-human study
H. Komaki *,1, T. Nagata 2, T. Saito 2, S. Masuda 2, E. Takeshita 1,
H. Tachimori 3, M. Sasaki 1, S. Takeda 2
1 National Center of Neurology and Psychiatry, Department of Child
Neurology, Tokyo, Japan; 2 National Center of Neurology and Psychiatry,
Department of Molecular Therapy, Tokyo, Japan; 3 National Center of
Neurology and Psychiatry, Department of Mental Health Policy and
Evaluation, Tokyo, Japan
Antisense oligonucleotide-induced exon skipping, which is being studied
for the treatment of Duchenne muscular dystrophy (DMD), allows synthesis of
partially functional dystrophin. Patients amenable to exon 53 skipping form the
second-largest population after patients amenable to exon 51 skipping.
Therefore, in 2009, the National Center of Neurology and Psychiatry and
Nippon Shinyaku Company collaborated to jointly develop an exon 53-skipping
drug; an investigator-initiated clinical trial was started in June 2013
(NCT02081625) to examine the efficacy of NS-065/NCNP-01, a morpholino based
antisense oligonucleotide that facilitates skipping of exon 53 of the
dystrophin gene. This drug was shown to have potent efficacy and high safety,
as confirmed in preclinical studies. The primary endpoint of the trial was safety,
and the secondary endpoints were pharmacokinetics and dystrophin expression.
A three-dose cohort design (1.25, 5, and 20 mg/kg) was adopted, and all patients were dosed by weekly intravenous infusion for 12 weeks. A total of 10
patients (ages 6–14) who were amenable to exon 53 skipping were recruited and
were randomly allocated to each of three cohorts. In vitro confirmation of
dystrophin recovery and exon 53 skipping in patient-derived cells was one
inclusion criterion. At the end of 2014, dosing to all patients had been
completed. Early stages of analysis detected dystrophin mRNA with the amino
acid reading frame restored by exon 53 skipping in every dose group.
Furthermore, the expression of dystrophin protein, which appeared to have been
translated from the resulting mRNA, was detected in the high-dose group. In
addition, no serious adverse events were observed throughout the study, and no
patients discontinued administration. Anemia and slight effects on renal
function were reported as general adverse events. Based on these results,
NS-065/NCNP-01 is expected to have therapeutic efficacy in patients with
DMD.
24) Idebenone improves respiratory function in pediatric and adolescent
patients with Duchenne muscular dystrophy not using glucocorticoid
steroids
G. Buyse * University Hospitals Leuven, Pediatric Neurology, Leuven, Belgium
Glucocorticoid steroids (GCS) have become a mainstay of DMD therapy
with well documented efficacy on muscle strength and respiratory function.
However, the side effect profile hampers their long-term use, particularly in
non-ambulant patients, and up to 40% of patients 10 years and older are not using
GCS. Idebenone has been investigated for efficacy on respiratory function in
patients not using concomitant GCS. In the randomized, double-blind, placebo
controlled Phase II DELPHI and Phase III DELOS trials a total of 72 patients not
using GCS were enrolled. Patients were treated with idebenone (Raxone®, 450
or 900 mg/day, N = 36) or placebo (N = 36) for a period of 52 weeks and
respiratory function was monitored by spirometry during hospital visits.
Combined data sets from the DELPHI and DELOS trials were analyzed for
changes in peak expiratory flow (PEF), forced vital capacity (FVC) and forced
expiratory volume in 1 second (FEV1) expressed as percentage of predicted
(%p). The average age of patients at baseline was 14.1 years. Baseline values for
PEF%p, FVC%p, FEV1%p were well matched between treatment groups.
Idebenone reduced the decline from baseline to Week 52 seen in the placebo
group in all three respiratory function parameters (treatment difference in
absolute percent predicted: PEF%p 7.9, p = 0.007; FVC%p 3.5, p = 0.054;
FEV1%p 6.0, p = 0.029). Cumulative response plots showed that higher
proportions of patients on idebenone improved in PEF%p (50%), FVC%p
(25%), and FEV1%p (42%) compared to patients on placebo (PEF%p: 22%,
FVC%p: 8%, FEV1%p: 13%). Similar favorable results for idebenone were
obtained for the proportion of patients declining by 10% or less. The combined
analysis of respiratory function data obtained during the DELPHI and DELOS
trials demonstrated consistent and clinically meaningful treatment effects on
respiratory function for idebenone (Raxone®) in patients not using GCS.
25) CAT-1004, an oral agent targeting NF-κB in development for treatment of
Duchenne muscular dystrophy: Phase 1/2 study design
J. Donovan *,1, H. Sweeney 2, K. Vandenborne 3, B. Russman 4, M. Jirousek 5,
R. Finkel 6
1 Catabasis Pharmaceuticals, Inc., 02139, USA; 2 University of Pennsylvania,
Perelman School of Medicine, Philadelphia, USA; 3 University of Florida,
Gainesville, USA; 4 Oregon Health & Science University, Portland, USA;
5 Catabasis Pharmaceuticals, Inc., Cambridge, USA; 6 Nemours Children’s
Hospital, Orlando, USA
In DMD, muscle NF-κB is activated from infancy, driving inflammation,
muscle degeneration and inhibiting muscle regeneration. Steroids inhibit
NF-κB and block inflammation; they clinically delay loss of ambulation and
progression of cardiopulmonary disease, but side effects limit their use. CAT-
1004 is an orally administered small molecule targeted to inhibit activated
NF-κB. In the mdx mouse and Golden Retriever Muscular Dystrophy models
treated for 6 months, improvements in muscle function were seen with CAT-
1004 or a closely related analog. Toxicology studies did not identify dose
limiting toxicities of CAT-1004. In Phase 1 studies of up to 14 days in adults, no
safety signal was observed. Most common adverse events were headaches and
diarrhea. In peripheral blood mononuclear cells (PBMC), gene expression
showed inhibition at multiple downstream points in the NF-κB pathway after
CAT-1004 administration. In an ex vivo LPS stimulation assay in PBMCs, a
single dose of CAT-1004 reduced nuclear p65 binding, a marker of NF-κB
activation, by 70%. Since magnetic resonance imaging (MRI) assessments (T2)
have shown progressive leg muscle degeneration that reverses with initiation of
steroids and generally correlate with functional assessments, a proof-ofconcept
study of CAT-1004 with MRI endpoints has been designed.A Phase 1/2
study will evaluate CAT-1004 in boys 4 to 7 with confirmed DMD, who are not
on glucocorticoid therapy, irrespective of underlying genetic mutation. Safety
and PK of CAT-1004 will be assessed for 7 days at multiple doses (n = 6 each).
Doses will then be selected for a 12-week double-blind, placebo controlled
study of CAT-1004. MRI assessments of lower and upper leg muscles will be
conducted at baseline and after 12 weeks. Timed function tests (10 m walk/run,
time to stand, 4-step climb) will be conducted monthly. CAT-1004 is being
developed to target NF-κB to treat boys with DMD.
26) VISION – DMD: Drug development of VBP15, an experimental
steroid-like drug for DMD
P. Clemens 1, M. Guglieri 2, A. Cnaan 3, J. Damsker 4, H. Gordish-Dressman 3,
L. Morgenroth 3, K. Nagaraju 3, Y. Hathout 3, E. Hoffman 4, K. Bushby 2,
L. Morgenroth Hache *,5
1 University of Pittsburgh School of Medicine, Pittsburgh, USA; 2 Newcastle
University, Newcastle upon Tyne, UK; 3 Children’s National Medical Center,
Washington, DC, USA; 4 ReveraGen BioPharma, Silver Spring, USA;
5 Children’s National Hospital, Washington, DC, USA
VBP15 is a new chemical entity in the class of dissociative steroid.
Uniquely, VBP15 preserves the anti-inflammatory, and improves the muscle
membrane protective characteristics of traditional glucocorticoids (e.g.
prednisone, deflazacort) that are standards of care in Duchenne muscular
dystrophy (DMD). However, VBP15 largely lacks transactivation subproperties
that are thought to be associated with the many deleterious side effects of
glucocorticoids, such as short stature and osteopenia. The ongoing drug
development of VBP15 is supported by robust preclinical testing in multiple
species. The clinical development program of VBP15 is managed by an
international academic team with regulatory consultants. This includes
partnership with the NIH, NCATS and TRND group. Phase I clinical trials of
single ascending and multiple ascending doses of VBP15 in healthy adults
began in January 2015. Safety parameters and pharmacokinetic studies in the
Phase I studies will refine the plan for Phase II clinical testing in patients with
DMD. A Phase IIa, multiple ascending dose study to assess the safety,
tolerability, pharmacokinetics and pharmacodynamics of VBP15 in boys with
DMD (age 4–<7 years, steroid naïve), using 2–6 participants per dose cohort
following the modified toxicity probability interval (mTPI) method will
facilitate dose selection, while requiring the smallest number of patients with
DMD to achieve this. The Phase IIa study will be followed by a Phase IIb
registration trial toward accelerated approval of VBP15 if the drug proves safe
and efficacious. Discovery of drug responsive pharmacodynamic biomarkers
(both safety and efficacy biomarkers) will be conducted throughout the studies.
Development of a pharmacodynamics biomarker panel will aid both the Phase
IIa and Phase IIb trials which will be followed by extension studies. VBP15drug development is supported by an IND from the FDA and is proceeding
under parallel guidance from both the FDA and the EMA.
27) HT-100: Interim safety, pharmacokinetics, and pharmacodynamic data in
DMD boys
D. Escolar *,1, M. Blaustein 1, E. Bush 1, K.Wagner 2, B.Wong 3, K. Flanigan 4, J. Han 5, A. Britton 1, J. Loewy 1, K. Dykstra 6, A. Connolly 7 1 Akashi Rx, Cambridge, MA, USA; 2 Kennedy Krieger Institute, Johns Hopkins School of Medicine, Center for Genetic Muscle Disorders, Baltimore, USA; 3 Cincinnati Children’s Hospital, Neurology, Cincinnati, USA; 4 Nationwide Children’s Hospital, Neurology, Columbus, OH, USA; 5 UC Davis, Department of Rehabilitation Medicine, Sacramento, CA, USA; 6 qPharmetra, LLC, Andover, MA, USA; 7 Washington University, Neurology, St Louis, MO, USA
In DMD, significant endomysial fibrosis directly impairs force transmission
and muscle regeneration, decreases muscle perfusion and is the only
myopathologic parameter correlated with poor motor and cardiorespiratory
outcome. HT-100 is an orally-delivered anti-fibrotic, anti-inflammatory agent
with effects on molecular, pathology, and functional phenotypes of dystrophic
mice, making it a promising candidate for DMD. Studies HALO-DMD-01 and
HALO-DMD-02 are open-label, single and multiple ascending dose and
Extension studies to evaluate the safety, tolerability, PK, and early PD signals of
HT-100 in steroid-treated DMD boys. Total treatment duration is approximately
13 months. Multiple safety, PK and exploratory PD endpoints, including serum
biomarkers of fibrosis and inflammation are being assessed. To date, 19 boys
have been enrolled in 3 Cohorts. The boys were exposed to HT-100 at doses
ranging from 300 g to 1.5 mg/day for up to 278 days. All 3 cohorts have
completed the SAD/MAD phase and rolled into the extension study. There
have been no significant safety signals to date. Biomarker, safety and
pharmacodynamics data for these 3 cohorts after 6 months of continuous
dosing will be presented.
28) Nonclinical pharmacokinetic evaluation of Eteplirsen, SRP-4045, and
SRP-4053: Three Phosphorodiamidate morpholino oligomers (PMOs) for
the treatment of patients with Duchenne muscular dystrophy (DMD)
P. Sazani *, J. Charleston, C. Shanks, J. Zhang, M. Carver, J. Saoud, E. Kaye
Sarepta Therapeutics, Inc., Cambridge 02142, USA
DMD, a rare, X-linked recessive, degenerative neuromuscular disorder,
results in severe progressive muscle loss, disability, and premature death. The
disease is most commonly caused by frame-shift mutations in the DMD gene
that disrupt the reading frame, resulting in a lack of dystrophin, a protein that
plays a key structural role in muscle fibers. PMOs can direct alternative splicing
of dystrophin pre-mRNA, restore the mRNA reading frame and enable
translation of an internally deleted yet functional dystrophin protein. Eteplirsen,
SRP-4045, and SRP-4053 are investigational PMO drug candidates, designed
to skip exons 51, 45, or 53 respectively, targeting 29% of the total DMD
population. Studies conducted to evaluate in vitro pharmacokinetic properties
of eteplirsen, SRP-4045 and SRP-4053 included analysis of plasma protein
binding and metabolic stability in hepatic microsomes of mice, rats, monkeys,
and humans. Induction and inhibition of cytochrome P450 isoenzymes were
also evaluated. Each exhibited low protein binding in all species, no evidence of
in vitro metabolism by hepatic microsomes, no extensive inhibition of the major
drug-metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2,
CYP2B6, or CYP3A4 at biologically relevant concentrations. The in vitro
pharmacokinetic profiles of eteplirsen, SRP-4045 and SRP-4053 were similar and showed no significant interaction with total serum protein or metabolic
enzymes. In vivo pharmacokinetic profiles for the three PMOs were also
similar. All three compounds showed comparable Cmax, AUC, and clearance,
and displayed similar dose proportionality across the three doses examined in
non-human primates (5, 40, and 320 mg/kg). These combined results suggest
that PMOs represent a well-tolerated therapeutic class with similar
pharmacokinetic profiles that could potentially be used to target all DMD
patients amenable to exon skipping therapy.
29) Eteplirsen, a Phosphorodiamidate morpholino oligomer (PMO) for the
treatment of Duchenne muscular dystrophy (DMD): Clinical update
E. Kaye *,1, J. Mendell 2, L. Rodino-Klapac 2, Z. Sahenk 2, L. Lowes 2,
L. Alfano 2, K. Berry 2, A. Gomez Ramirez 2, S. Lewis 2, K. Flanigan 2,
L. Cripe 2, S. Al-Zaidy 2, P. Duda 1, P. Sazani 1, J. Saoud 1
1 Sarepta Therapeutics, Inc., Cambridge, USA; 2 Nationwide Children’s
Hospital, Columbus, USA
DMD is a rare, degenerative, X-linked recessive genetic disease that results
in progressive muscle loss and premature death, affecting approximately 1:3500
male births. DMD is most often caused by frame-shift mutations in the
dystrophin gene which prevent production of dystrophin protein. Eteplirsen is a
PMO designed to enable functional dystrophin production in boys amenable to
exon 51 skipping, and is being evaluated in on-going clinical trials. Twelve boys
aged 7–13 years with eligible genotypes were randomized 1:1:1 to eteplirsen
30 mg/kg/week, 50 mg/kg/week, or placebo IV for 24 weeks. All patients then
transitioned into an ongoing open-label extension trial with 30 or 50 mg/kg
eteplirsen. Clinical efficacy endpoints included the 6MWT and PFT. Safety
assessments included adverse event recording, EKG, ECHO, hematology, blood
chemistry and urinalysis. A statistically significant treatment benefit of 65.4 m
(p ≤ 0.017) on the 6MWT over 168 weeks was observed for patients in the 30
and 50 mg/kg eteplirsen cohorts who were able to perform the 6MWT
(modified Intent-to-Treat population; n = 6) compared with the placebo/
delayed-treatment cohort (n = 4). PFTs including MIP (+11.1%, p = NS), MEP
(+13.5%, p = NS), and MIP/MEP %-predicted (−2.4% and −6.3%, p = NS)
were stable from Week 1 through 168 in all 12 subjects. No deaths,
discontinuations due to AEs, treatment-related SAEs, immune activation
including infusion reactions, or clinically significant abnormal laboratory
findings were reported. The study population completed ~99% of all possible
doses (n = 12). Eteplirsen’s demonstrated long-term tolerability and
statistically significant clinical benefit suggest that it could be a viable therapy
for DMD boys amenable to exon 51 skipping. Confirmatory studies are
currently ongoing and include a large study in ambulatory patients as well as
studies in boys 4–6 years old and in more advanced patients.
30) A novel clinical trial design to evaluate the efficacy and safety of two exon-skipping PMOs, SRP-4045 and SRP-4053, in patients with Duchenne muscular dystrophy
G. Laforet *, E. Kaye, J. Saoud Sarepta Therapeutics, Inc., Cambridge, USA
DMD, an X-linked myopathy caused by mutations in the DMD gene, results
in the inability to produce functional dystrophin, an essential protein for muscle
fiber function. Exon-skipping phosphorodiamidate morpholino oligomers
(PMOs) direct alternative splicing of dystrophin pre-mRNA, restoring the
mRNA reading frame and enabling translation of an internally truncated
dystrophin protein. SRP-4045 and SRP-4053 are two PMO drug candidates
designed for patients with mutations amenable to exon 45 and 53-skipping,
respectively (16% of total DMD population). A double-blind, placebo-controlled, multi-center, 48-week study will evaluate the effects of the two PMOs
on ambulation, endurance and muscle function measured by the 6-MinuteWalk
Test (6MWT). Secondary endpoints will evaluate restoration of dystrophin in
muscle tissue and respiratory muscle function as measured by pulmonary
function tests (PFT). Patients (n = 99) will be randomized by genotype 2:1 to
active-treatment (SRP-4045 or SRP-4053) or placebo. All patients will undergo
a muscle biopsy at baseline and at eitherWeek 24 or 48. Safety assessments will
include adverse event monitoring, ECG, ECHO, and safety laboratory tests. The
primary analysis of clinical outcomes will be based on the combined population
receiving either drug compared to the placebo population. The study design
highlights a novel approach in combining two exon-skipping drug candidates
(SRP-4045 and SRP-4053) within a single trial. This is important for future exon
skipping therapies in DMD as they will target increasingly smaller patientpopulations,
making it difficult to conduct separate, well-powered clinical trials
for each compound.
31) Lack of estrogens aggravates the pathology in dystrophic mice
E. Gayi *,1, H. Ismail 1, L. Neff 1, O. Patthey-Vuadens 1, T. Saibara 2, K. Toda 2, U. Ruegg 1, L. Scapozza 1, O. Dorchies 1 1 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland; 2 School of Medicine, Kochi University, Nankoku, Japan
Duchenne muscular dystrophy (DMD) is a severe disorder that results in
progressive muscle wasting and causes death in early adulthood. As part of our
search for compounds to treat DMD, we have found that the inexpensive and
safe anticancer drug tamoxifen (TAM) efficaciously counteracted dystrophic
symptoms in the mdx5Cv mouse, a model of DMD. These effects were mimicked
by several selective estrogen receptor modulators (SERMs) structurally related
to TAM. We also found that TAM protection was abolished by fulvestrant, a
pure anti-estrogenic compound. Moreover, female dystrophic mice were more
resistant to muscle fatigue than males. Collectively, our findings point to a
protective role of estrogen agonists in dystrophic muscle and suggest that
enhancement of estrogenic signalling in muscle by SERMs might be a
therapeutic approach to treat DMD. In order to investigate the roles of estrogen
deficiency in dystrophic muscle, we have generated dystrophic (mdx5Cv) mice
lacking aromatase, the rate-limiting enzyme in the biosynthesis of estrogens
from androgens. Longitudinal analysis of mice from 2 months to 20 months of
age revealed that lack of estrogens due to aromatase deficiency greatly
decreased locomotor activity in both male and female dystrophic mice. At 2
years of age, aromatase deficiency aggravated muscle fatigue in dystrophic
males and caused prominent fibrosis in the soleus muscle of dystrophic females.
Other motor and structural features of aromatase deficient dystrophic mice are
being analyzed. These findings highlight the important contribution of
estrogens, not only in female but also in male dystrophic mice and warrant
further investigation of SERMs as adjuvant therapy for DMD
32) Preclinical data for a novel Toll-like receptor antagonist in mdx mice support its clinical development as a potential treatment for disease-related muscle inflammation in Duchenne muscular dystrophy
J. Boehler *,1, K. Nagaraju 1, M. Hurtt 2, S. Agrawal 2 1 Center for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, USA; 2 Idera Pharmaceuticals, Cambridge, MA, USA
Immunologically triggered inflammatory processes play a central role in the
pathogenesis of Duchenne muscular dystrophy (DMD). Toll-like receptors
(TLRs) are key components of the innate immune system involved in regulating
inflammation and adaptive immunity. Data have shown that TLR 7 is
significantly over-expressed in DMD patients at all stages of the disease,
suggesting TLR activation is an early trigger of muscle inflammation. Targeting
of TLRs is a novel therapeutic approach for DMD that has the potential to
reduce chronic muscle inflammation and slow disease progression across a
broad patient population regardless of dystrophin mutation type. IMO-8400 is
a novel oligonucleotide-based antagonist of TLRs 7, 8 and 9 that was generally
well tolerated and demonstrated anti-inflammatory activity in patients with
autoimmune disease. To evaluate in vivo activity in a DMD model, w
conducted multiple studies in mdx mice. Across studies, treated mice received
one of several TLR antagonist regimens by i.p. injection for 5 weeks, and were
assessed on measures of muscle function, muscle histology, biochemical
response, and cytokine gene expression. Treatment resulted in significant
reductions in muscle inflammation, serum creatine kinase, and gene expression
of IL-6. An increase in the specific force of isolated extensor digitorum longus
muscle was also observed. Detailed results from these preclinical studies will
be presented. DMD is a genetic neuromuscular disorder in which
immunologically triggered inflammatory processes play a central role in
disease pathogenesis. TLRs are key drivers of inflammation and are overactivated
in DMD patients at all stages of the disease. A TLR antagonist
improved disease-associated measures in mdx mice. Collectively, these data
support advancing the TLR antagonist drug candidate IMO-8400 into clinical
development as a potential non-steroidal anti-inflammatory treatment for DMD
patients.
33) Vitamin D in corticosteroid treated Duchenne muscular dystrophy: What dose achieves serum 25OH vitamin D sufficiency?
N. Alshaikh *, A. Brunklaus, T. Davis, S. Robb, R. Quinlivan, P. Munot,
A. Sarkozy, F. Muntoni, A. Manzur
Dubowitz Neuromuscular Centre, Great Ormond Street Hospital and UCL
Institute of Child Health, University College, London, UK
Assessment of the efficacy of vitamin D repletion and maintenance doses to
attain sufficiency levels in DMD boys. 25-OH vitamin D levels and concurrent
vitamin D dose were collected from retrospective case-note review of DMD
boys seen at Dubowitz Neuromuscular Centre. Vitamin D levels were stratified
as deficient 75 nmol/l. 617 levels were available from 197 boys (tested 1–7
times). The median age at level estimation was 9.7 years (2–18). 90% levels
were performed whilst on corticosteroid. The vitamin D supplement-naïve
group, comprising 154 samples from 125 boys, showed deficiency in 70%,
insufficiency in 24%, and sufficiency in 6%. The vitamin D supplemented
group, comprising 463 samples from 164 boys, was tested whilst on different
oral maintenance or replenishment doses. A three month replenishment regime
of daily 3000 IU (no = 23 samples from 20 patients) or 6000 IU (no = 37
samples from 32 patients) achieved sufficiency in 52% and 84%, respectively.
22 samples (form 17 boys) collected on maintenance dose of 200 IU/day
showed deficiency in 13 (59%) and insufficiency in 7 (32%). 182 samples (from
121 boys) taken on 400 IU/day revealed deficiency in 104 (57%) and
insufficiency in 67 (37%). 97 samples (from 66 boys) were taken on 800 IU/day,
with deficiency in 19 (20%) and insufficiency in 56 (58%). 81 samples (from 55
boys) were on 1000 IU and 14 samples (from 11 patients) were on 1500 IU,
with sufficiency in 40 (50%) and 9 (64%), respectively. No toxic level was seen
in this cohort (highest level −230 nmol/l). The prevalence of Vitamin D
deficiency and insufficiency in DMD is high. A three month replenishment
regime of 6000 IU was more effective than 3000 IU in achieving Vitamin D
sufficiency. Maintenance daily doses of 200 or 400 IU demonstrated sufficiency
in 14% and 1000 IU daily achieved sufficiency in 50% of samples obtained
from boys treated with this regime. These data have important implications for
optimising vitamin D dosing in DMD.
34) Clinical outcomes in a large cohort of boys and adolescents with Duchenne muscular dystrophy
N. Alshaikh *, A. Brunklaus, S. Robb, R. Quinlivan, P. Munot, A. Sarkozy,
F. Muntoni, A. Manzur
Dubowitz Neuromuscular Centre, Great Ormond Street Hospital and UCL
Institute of Child Health, University College, London, UK
Standards of care including corticosteroid and non-invasive ventilation
(NIV) have significantly changed the course of DMD and improved survival so
that now transition into adult care is common. To describe the morbidity andmortality in a large pediatric DMD population with contemporary care and
identify the milestones of disease progression, the Dubowitz Neuromuscular
Centre offers diagnosis and management of DMD through the childhood years,
with transition to adult teams at age 17 years. Retrospective analysis of this
DMD cohort was undertaken. Patients were identified from existing databases
and disease course, medical interventions, and outcomes were collated. Over
the past 20 years, 310 DMD boys, born between 1989 and 2013 were seen, with
18 ± 6 sequential assessments for the individual patient. Overall, 63% lost
ambulation at a mean age of 11 ± 2.0 years in the corticosteroid treated group,
compared to 9 ± 1.0 in the steroid naïve group. 231/310 were older than 10
years, and in this subgroup, 50% developed scoliosis, 20% use NIV (age at
initiation 14.3 ± 2 years) and 51% have echocardiographic cardiomyopathy
(age at onset 12.3 ± 2.9 years). All patients with cardiomyopathy were treated
with ACE inhibitor ± beta-blocker. 93 patients were transitioned to adult
service. At the time of transition, 57% had FVC <60%, 32% were on NIV, 85%
had cardiomyopathy, and 26% were on corticosteroid treatment. 10/93 were on
tube feeding. 20 patients died at 14.9 ± 2.5 years. Death was cardiac-related in
6, sudden in 2, pneumonia in 5 (3 on NIV), gastrointestinal complications in 2,
and perioperative in 2. Despite the improved survival, there still is significant
mortality in DMD in the childhood years. Cardiomyopathy was the most
frequent cause of death, and gastrointestinal related mortality also plays an
important role. These data will help direct care to reduce mortality and has
implications in development of adult services.
35) Kinesthesia in children with Duchenne muscular dystrophy
B. Akel 1, S. Karayazgan 1, S. Subası 2, N. Bulut *,2, O. Yılmaz 2, A. Karaduman 2 1 Department of Ergotherapy, Hacettepe University, Ankara, Turkey; 2 Faculty of Health Sciences Department of Physiotherapy and Rehabilitation, Hacettepe University, Ankara, Turkey
In DMD, there is evidence of abnormalities in dendrites and loss of
neurones, however less attention was given in sensory situation and its
relation with function. It is aimed to analyze the relation of kinesthesia with
gross and fine motor skills in children with Duchenne Muscular Dystrophy
(DMD). Twenty four children with DMD with the mean age of 8.48 ± 1.96
years participated in the study, however three of the children could not be
evaluated as they could not perform kinesthesia tests. Kinesthesia was
evaluated with kinesthesia subtest of Ayres Sensory Integration Evaluation.
Brooke Scale to test motor functioning, Gross Motor Function Measure
(GMFM) to test gross motor function, and Bruininks–Oseretsky Test of
Motor Proficiency (BOTMP) to test fine motor skills were also performed.
The relation of kinesthesia with other assessments was analyzed with
Spearman correlation coefficient. Kinesthesia was correlated with Visualmotor
control (r = 0.496, p = 0.01) and upper extremity speed and dexterity
(r = 0.462, p = 0.03) parameters of BOMT. There was not significant
relationship between kinesthesia and Brooke Scale, GMFM and gross motor
parameters of BOMT (p > 0.05). Kinesthesia was not correlated with
functional classification of DMD or gross motor function assessments,
however it was in strong relationship with fine motor skills. Therefore,
kinesthesia should be evaluated separately and should be taken into
consideration while doing treatment plan.
36) Physical activity in boys with DMD is lower and less demanding compared to healthy boys
L. Heutinck *, N. van Kampen, M. Jansen, I. de Groot Department of Rehabilitation, Radboud University Medical Centre, Nijmegen, Netherlands
An important aim in the management of Duchenne Muscular Dystrophy
(DMD) is delaying the loss of functional abilities. Physical activity (PA) is
recommended to avoid disuse and complications of inactivity due to the
disease itself. PA levels in boys with DMD are, however, unknown. We aimed
to describe PA levels in boys with DMD compared to healthy controls (HC).
PA was assessed by a questionnaire constructed out of existing PA
questionnaires describing demographics, transportation, therapy, sports,
benefits and barriers of sports and leisure time activities. Three subgroups
were made: ambulant, non-ambulant with relative good arm function (Brooke
score ≤ 4) and non-ambulant with decreased arm function (Brooke score ≥ 5).
Sixty-six boys (15.8 ± 7.7 years) and 86 healthy boys (12.5 ± 2.6 years)
participated. On average, boys with DMD are less physically active as HC.
Daily activities such as transportation to school are passive for the majority of
boys with DMD (87%), whereas most HC use active transport (74%). Boys
with DMD play less sports than HC (62% vs. 86%). The type of sport in
DMD is physically low demanding, while HC engage in more strenuous
sports. Benefits of PA in DMD are having fun and improving physical health,
although this decreases when boys grow older. Barriers are lack of sport
facilities and insufficient health. Boys with DMD spend significantly more
time on screen time activities than HC, which indicates more sedentary
behaviour. Screen time increases as boys become non-ambulant and as arm
function is declining. Boys with DMD have an average of 1.0–1.5 hour
physical therapy per week. Therapy time decreases when boys get older (15%
of non-ambulant boys had no therapy at all). The results showed major lower
PA levels in boys with DMD than their healthy peers. PA levels decrease as
boys become wheelchair dependent and as arm function declines. Exercise needs to be stimulated and facilitated, especially in non-ambulant boys with
decreased arm abilities.
37) Mastication problems in Duchenne muscular dystrophy caused by dystrophic changes of the masseter muscle and abnormal dental characteristics
L. van den Engel-Hoek 1, H. Hijdra 1, S. de Groot 1, L. Sie 2, C. Erasmus 2,
I. de Groot *,1
1 Rehabilitation, Radboud UMC, Nijmegen, Netherlands; 2 Neurology,
Radboud UMC, Nijmegen, Netherlands
Duchenne muscular dystrophy (DMD) also affects oral muscles and
influences negatively the oral preparatory and pharyngeal phase of swallowing.
We performed a cross sectional study to (a) describe the clinical course of
mastication problems in consecutive stages of DMD, and (b) to determine the
underlying mechanisms of mastication problems. To this end complaints on
chewing, dental characteristics and mastication muscle structures were
assessed. Seventy two patients with DMD (from 4.3 to 28.0 years) participated,
divided into early ambulatory stage (EAS, N = 13), late ambulatory stage
(LAS, N = 17), early non-ambulatory stage (ENAS, N = 26), and late nonambulatory
stage (LNAS, N = 16). Quantitative muscle ultrasound of masticatory muscles was used to describe thickness and echo intensity (EI) of
the temporal and masseter muscles. The data were compared with normal
values and described as Z-scores. Problems with mastication with the need to
modify chewable food were reported already in the EAS and increased in the
other stages. High percentages of posterior cross-bite were reported in the
ENAS and LNAS. Anterior open bite was present in almost 50% in all stages.
Posterior open bite was frequently seen in the late stages. The mean EI of the
masseter muscles was only normal in the EAS (Z-score 3 in the ENAS and
LNAS indicating infiltration of fat and fibrosis). The EI values of the temporal
muscle were <2 in all stages. Mastication problems in DMD are caused by the
involvement of the disease in the masseter muscle early in the disease, in
combination with anterior and posterior open bites (the loss of occlusal
contacts). Attention for mastication problems in early stages is already needed.
38) Ankle-foot orthoses in Duchenne muscular dystrophy
A. Mattiello-Sverzut *,1, M. Souza 2, C. Baptista 2, M. Figueiredo 2,
R. Avades 3
1 Department of Biomechanics, Medicine and Rehabilitation of Locomotor
Apparatus, Medical School of Ribeirão Preto – University of São Paulo, São
Paulo, Brazil; 2 Medical School of Ribeirão Preto, University of São Paulo,
Ribeirão Preto, Brazil; 3 Clinical Hospital of Ribeirão Preto, Ribeirão Preto,
Brazil
The orthoses are indicated to prevent muscle contracture and to prolong the
ambulation in patients with Duchenne muscular dystrophy (DMD). This study
aimed to assess the effect of day and night use of ankle-foot orthosis (AFO) on
kinematic, kinetic and spatial-temporal gait parameters of patients with DMD.
Twenty patients (4–12 years) were grouped according to the orthoses use: no
orthosis (NO; n = 7), night orthosis (NiO; n = 7), day orthosis (DO; n = 6; with
2 subgroups analyzed, wearing orthosis: DOw; without orthosis: DOno). All
subjects underwent initial evaluations (Ev1) and five were re-evaluated (Ev2)
five to seven months after Ev1. Anthropometric data, motor function, range of
motion, isometric muscle strength, body composition and biomechanics of the
gait were investigated. ANOVA tests were used in cross-sectional statistical
analyses; descriptive analysis was used in longitudinal data. In comparison to
NO, DOw presented the highest peak dorsiflexion angle and dorsiflexor
moment, and a smaller plantarflexion angle and lower ankle joint power
generation (p < 0.05). The DOw group presented a lower peak hip flexion angle,
hip power absorption, plantarflexion angle and a greater peak dorsiflexion
moment than NiO (p < 0.05). In comparison to NO, NiO group obtained greater
peak knee flexion angles and hip power absorption (p < 0.05). Longitudinal
analysis revealed that the two patients who had begun night AFO use early on
displayed greater velocity, peak hip extension angle, hip extensor moment,
plantarflexor moment and ankle joint power generation. Therefore, among the
analyzed patients, day use of AFO generated positive changes in gait,
minimizing typical compensations of DMD, as did night use of AFO when
begun early on. Thus, early and continuous day and night use of AFO in DMD
patients is recommended.
39) Natural history of respiratory function changes in patients with Duchenne
muscular dystrophy not using glucocorticoid steroids
G. Buyse *,1, T. Voit 2, U. Schara 3, C. Straathof 4, M. D’Angelo 5, G. Bernert 6,
J. Cuisset 7, R. Finkel 8, N. Goemans 1, C. McDonald 9, C. Rummey 10,
T. Meier 11
1 Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium; 2 Institut
de Myologie, Paris, France; 3 Universitätsklinikum, Essen, Germany; 4 LUMC,
Leiden, Netherlands; 5 IRCCS Eugenio Medea, Lecco, Italy; 6 Gv Preyer’sches
Kinderspital, Wien, Australia; 7 CHRU de Lille, Lille, France; 8 Nemours
Children Hospital, Orlando, USA; 9 UC Davis Medical Center, Sacramento,
USA; 10 4 Pharma, Liestal, Switzerland; 11 Santhera Pharmaceuticals, Liestal,
Switzerland
Reliable natural history data of respiratory function changes in patients
with DMD are still limited and available data sets are frequently confounded
by heterogeneity in the use of glucocorticoid steroids (GCS). Here we report
respiratory function data prospectively collected from 33 patients, 10–18
(mean 15.0, SD 2.5) years of age, enrolled in the placebo group of the multicenter,
phase III DELOS trial. Patients had stopped taking GCS at least 12
months prior to enrollment and during the 52 week follow up time.
Spirometry was conducted at baseline and 3-monthly intervals during hospital
visits. Data for peak expiratory flow (PEF) and lung volumes (FVC and
FEV1) were converted to corresponding percent of predicted (%p) by
standard formulae. DELOS eligible patients had to have a PEF%p of <80 at
baseline. Baseline values for PEF%p, FEV%p and FEV1%p were comparable
at 54.2 (SD: 13.2), 50.4 (20.0) and 49.7 (18.3) respectively. The annual rate
of change was −8.84 (SE 1.95; p < 0.001) for PEF%p, −8.95 (SE 1.26;
p < 0.001) for FVC%p and −10.68 (SE 2.56; p < 0.001) for FEV1%p. In
patients who previously had taken GCS but stopped on average 4.3 (SD: 2.2)
years prior to enrollment, the annual rate of decline in all respiratory function
data was slightly less than in GCS-naïve patients (previous GCS users:
PEF%p: −7.95, FVC%p: −8.72, FEV1%p: −10.17; GCS naïve: PEF%p: −9.95, FVC%p: −9.09, FEV1%p: −12.37). Baseline values for all respiratory
function parameters were higher in the subgroup of patients below the median
(≤14 years) compared to patients > 14 years and the annual rate of decline
was slightly higher in the subgroup of younger patients. Our findings provide
a set of natural history data for respiratory function in a well-defined group
of DMD patients not using GCS.
40)Dissociation between motor and cognitive skills in patients with Duchenne muscular dystrophy
M. Voos *,1, F. Favero 2, K. Dias 2, M. Artiheiro 1, A. Oliveira 1, F. Caromano 1 1 Physical Therapy, Speech Therapy and Occupational, Universidade de São Paulo, São Paulo, Brazil; 2 Neurology, Federal University of São Paulo, São Paulo, Brazil
Patients with Duchenne Muscular Dystrophy (DMD) may have cognitive
impairments, such as difficulties in visuospatial abilities, language, working
memory and phonological processes. This study aimed to describe motor and
cognitive impairments and investigate possible relationships between them in
a group of patients with DMD. Patients between 10 and 30 years were
included. Each patient underwent a protocol of five tests: 1. Mini Mental
State Examination (MMSE), 2. clock drawing, 3. verbal fluency, 4. digit
order, 5. brief battery of cognitive screening. Patients were also assessed with
Motor Function Measure (MFM) and Vignos scales. Spearman correlation
tests were run to investigate possible relationships between cognitive and
motor variables. There were only correlations motor vs. motor and cognitive
vs. cognitive variables, but not motor vs. cognitive variables. MFM and
Vignos were correlated (r = 0.70; p < 0.05), MMSE and education (r = 0.75;
p < 0.05); MMSE and clock drawing (r = 0.83, p < 0.05); MMSE and digits– direct order (r = 0.76, p < 0.05) and digits – reverse order (r = 0.75, p < 0.05).
Also, correlations between clock drawing and digits – reverse order (r = 0.75,
p < 0.05) and between digits – direct order and digits – reverse order
(r = 0.76, p < 0.05) were found. Conclusion: There was great variability in
cognitive and motor performance of patients with DMD. Correlations were
observed among cognitive variables and between motor variables. However,
there were no significant correlations between cognitive and motor variables
patients with DMD.
41) The frequency and characterisation of cardiac involvement in female
carriers of BMD or DMD: A cross sectional analysis
T. McCaffrey 1, A. Murphy *,2, M. Guglieri 2, K. Bushby 2, J. Bourke 3
1 Medical School, Newcastle University, Newcastle upon Tyne, UK; 2 Institute of
Genetic Medicine, The John Walton Muscular Dystrophy Research Centre,
Newcastle upon Tyne, UK; 3 Academic Cardiology, Newcastle upon Tyne
Hospitals, Newcastle upon Tyne, UK
Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked
inherited disorders resulting from a deletion within the dystrophin gene. Female
carriers often are asymptomatic but at risk of cardiac dystrophinopathy.
Carriers have an estimated 7–18% incidence of dilated cardiomyopathy and it is
recommended that all should be offered cardiac surveillance. The aim was to
determine the incidence and severity of left ventricular (LV) dysfunction as
detected by echocardiogram (ECHO) within a large cohort of female carriers of
DMD/BMD. Following diagnosis of relatives with DMD/BMD, all relevant
family members are offered carrier testing. A registry of all carriers is
maintained by the Neuromuscular Genetics service. All patients are offered
cardiac screening including: symptom review, 12-lead ECG and 2D ECHO. All
patient notes from October 1999 to July 2014 (n = 130) were retrospectively
reviewed for ECHO assessments including measurement of LV end-systolic,
end-diastolic dimensions, wall thicknesses and fractional shortening (FS). LV
ejection fraction was measured in a variety of ways. Some patients had tissue-
Doppler assessments of LV segmental function. Diastolic measures of cardiac
function were measured. No patients had cardiac symptoms. Mean age at
screening was 39 years (range 5–81 years). 12.6% of patients had a FS of less
than normal (<28%), 1.7% of patients had <40% LVEF (corrected) and 33% of
patients had <55% LVEF (uncorrected). 11 patients (8.5%) had wall motion
abnormalities. No correlation was found between age, CK, or muscle
symptoms and LV dysfunction. Incidence of cardiomyopathy is between 1.7%
and 33% depending on definition. ‘Uncorrected’ LVEF is likely to overestimate
systolic dysfunction whereas presence of wall motion abnormalities is most
specific for cardiac dystrophinopathy in carriers without comorbidities. No
correlation is seen between age, CK levels, and LV dysfunction; possibly
suggesting that there may be a trigger to LV dysfunction
42) Epicatechin enhances mitochondrial biogenesis, increases dystrophin and utrophin, increases follistatin while decreasing myostatin, and improves skeletalmuscle exercise response in adults with Becker muscular dystrophy (BMD)
C. McDonald *,1, E. Henricson 1, B. Oskarsson 2, C. Aguilar 1, A. Nicorici 1, N. Joyce 1, D. Reddy 1, A. Wagner 1, E. deBie 1, E. Goude 1, R. Abresch 1, F. Villareal 3, G. Perkins 4, Y. Hathout 5, S. Dugar 6, G. Schreiner 6 1 Physical Medicine and Rehabilitation, University of California Davis, Sacramento, CA, USA; 2 Neurology, University of California Davis, Sacramento, CA, USA; 3 Medicine, University of California San Diego, San Diego, CA, USA; 4 National Center for Microscopy and Imaging Research, University of California San Diego, San Diego, CA, USA; 5 Center for Genetic Medicine, Children’s National Medical Center, Washington, DC, USA; 6 Cardero Therapeutics, Los Altos Hills, CA, USA
Epicatechin is a structural homologue of a family of PGC1-alpha
activating steroid hormones that promote mitochondrial biogenesis and
induce skeletal muscle regeneration. Epicatechin stimulates mitochondrial
biogenesis and improves muscle structure and function in the mdx and
d-sarcoglycan null models. We conducted an open-label pilot study of
epicatechin in ambulatory adults with Becker Muscular Dystrophy (BMD). 7
participants received epicatechin 50 mg b.i.d./8 weeks. Pre- and postassessments
included: biceps biopsy Western blot and EM, blood biomarkers,
metabolic gas exchange/graded exercise testing, tissue saturation index (TSI)
by near-infrared spectroscopy, and muscle strength. Muscle western blot
showed significantly increased dystrophin, utrophin and dysferlin levels. We
observed increased muscle follistatin (p = 0.002) and decreased myostatin
(p = 0.008). Increased markers of muscle regeneration included myogenin,
Myf5, MyoD, myosin and SkM actin alpha 1 (all p < 0.033). Increased
proteins associated with mitochondrial growth included PGC1-alpha
(p = 0.01), AMPK (p = 0.004) and mitofilin (p = 0.007). Plasma Western blot
showed increased follistatin (p = 0.0006), decreased myostatin (p = 0.04) and
increased follistatin:myostatin ratio (p = 0.0004). Muscle EM showed
increased mitochondrial volume and cristae abundance (p = 0.02). Exercise
testing showed decreased VO2/kg (p < 0.0001), lactate (p < 0.0001) and heart
rate (p < 0.00001) at defined workloads. TSI improved in resting (p < 0.008)and post-exercise states (p < 0.001). Epicatechin induces mitochondrial
biogenesis and muscle regeneration in BMD. It is the only oral compound
ever demonstrated to both increase plasma follistatin and decrease plasma
myostatin, whose ratio may comprise a future pharmacodynamic biomarker.
Increased levels of dystrophin and utrophin suggest that stimulation of
bioenergetics and muscle regeneration may be a novel therapeutic strategy for
dystrophinopathies.
43) Simvastatin improves physiological function and protects against muscle
degeneration in mdx mice: A novel therapeutic approach for Duchenne
muscular dystrophy
N. Whitehead *, M. Kim, K. Bible, M. Adams, S. Froehner Department of Physiology and Biophysics, University of Washington, Seattle, USA
Duchenne muscular dystrophy (DMD) is a degenerative muscle disease
that affects 1:5000 males worldwide for which there is currently no effective
treatment. DMD is characterized by chronic inflammation, oxidative stress
and fibrosis. Statins, the most widely used cholesterol lowering drugs,
effectively inhibit these pathogenic processes in cardiovascular and other
tissues. Therefore, statin therapy could potentially improve DMD muscle.
However, statins have never been tested in DMD or other muscular
dystrophies, principally because of the rare, muscle-related side-effects. Here
we show that Simvastatin dramatically reduced muscle damage and enhanced
physiological function of skeletal muscle in dystrophic (mdx) mice. Long term
Simvastatin treatment vastly improved overall muscle health in mdx
mice, reducing plasma CK activity, an established measure of whole-body
muscle damage, to near-normal levels. This was accompanied by significantly
less muscle inflammation, a shift to healthier, more oxidative muscle fibers,
and improved strength of the severely dystrophic diaphragm muscle. There
were no side-effects with long-term Simvastatin administration. Shorter-term
Simvastatin treatment to mdx mice provided resistance from hindlimb muscle
fatigue and dramatically increased specific muscle force by 40%. This
correlated with reduced NADPH Oxidase 2 protein expression, a major
source of oxidative stress and contractile dysfunction in mdx muscle. Finally,
in older, more severely dystrophic mdx mice, Simvastatin decreased plasma
CK activity, improved diaphragm force and halved pre-existing fibrosis, a
major pathological problem in DMD. Together, our findings indicate that
Simvastatin provides considerable improvement to skeletal muscles of
dystrophic mice. While statins are typically avoided in patients with muscle
disease, our data indicate that they should now be considered as a novel,
affordable and readily available therapy for DMD and related neuromuscular
diseases.
44) Adeno-associated virus vector (AAV) microdystrophin gene therapy
prolongs survival and restores muscle function in the canine model of
Duchenne muscular dystrophy (DMD)
C. Le Guiner *,1, L. Servais 2, M. Montus 3, F. Bodvael 1, B. Gjata 3,
J.Y. Hogrel 4, P. Carlier 5, S. Moullec 6, C. Masurier 3, O. Adjali 7, F. Mingozzi 3,
T. Koo 8, T. Athanasopoulos 9, Y. Cherel 10, F. Mavilio 3, T. Voit 11,
P. Moullier 12, G. Dickson 8
1 INSERM UMR 1089, Atlantic Gene Therapies & Genethon, Nantes, France;
2 Service of Clinical Trials and Databases, Institut de Myologie, Paris, France;
3 Genethon, Evry, France; 4 Neuromuscular Physiology and Evaluation
Laboratory, Institut de Myologie, Paris, France; 5 Laboratoire RMN, AIM& CEA, Institut de Myologie, Paris, France; 6 Centre de Boisbonne, ONIRIS,
Atlantic Gene Therapies, Nantes, France; 7 INSERM UMR 1089, Atlantic Gene
Therapies, Nantes, France; 8 Royal Holloway, University of London, LondonUK; 9 University of Wolverhampton, Wolverhampton, UK; 10 INRA UMR 703,
ONIRIS, Atlantic Gene Therapies, Nantes, France; 11 Groupe Hospitalier
Pitié-Salpêtrière, Institut de Myologie, Université P, Paris, France; 12 Atlantic
Gene Therapies & Department of Molecular Genetics and Microbiology,
INSERM UMR 1089, University of Florida, Nantes, France
Duchenne muscular dystrophy (DMD) is an X-linked inherited musclewasting
disease primarily affecting young boys with a prevalence of 1:5000.
The disease is caused by loss-of-function mutations in the gene encoding for
the Dystrophin protein and is characterised by systemic, progressive,
irreversible and severe loss of muscle function. Among vector systems that
allow efficient in vivo gene transfer, recombinant Adeno Associated Virus
vectors (rAAV) hold great promise and result in particular in very efficient
transduction of skeletal and cardiac muscles. However, full-length dystrophin
cDNA exceeds the packaging capacity for a single rAAV gene-delivery
cassette. Therefore, truncated versions namely micro-dystrophins have been
designed and optimised to contain few clinically important regions of the
dystrophin protein. We have initially tested a rAAV2/8 vector encoding a
sequence optimised canine micro-dystrophin transgene, driven by a musclesynthetic
Spc512 promoter (rAAV2/8-Spc512-Dys) in Golden Retriever
Muscular Dystrophy (GRMD) dogs, the canine model of DMD. Isolated limb
perfusion studies in four 3-month-old animals using a single administration of
1E13vg/kg of the therapeutic vector demonstrated up to 90% dystrophin
positive fibres in the treated limbs at 3 months post-injection and significant
improvement of the local pathological and NMR patterns, as well as an
improvement of the strength of the limb. Similarly, single-dose intravascular
delivery (1E14vg/kg) of the same rAAV2/8-Spc512-Dys vector in five
GRMD dogs, without any immunosuppression, markedly improved severe
widespread muscle weakness and multiple clinical score and gait parameters,
finally prolonging lifespan to more than a year in the absence of toxicity or
deleterious humoral and cell-mediated immune responses. These results
demonstrate the therapeutic efficacy of rAAV-micro-dystrophin mediated
gene therapy in a large animal model of DMD, paving the way for a human
trial in DMD patients.
USA - entidades de pais e especialistas em distrofia muscular de Duchenne publicaram uma revisão com as principais orientações que obrigatoriamente devem ser seguidas no tratamento da doença. Os principais tópicos foram resumidos em um arquivo que eu traduzi para o português com adaptações. O texto resumido em inglês e o artigo na íntegra pode ser lido no link abaixo:
http://currents.plos.org/md/article/imperatives-for-duchenne-md-a-simplified-guide-to-comprehensive-care-for-duchenne-muscular-dystrophy/
USA - O objetivo deste estudo foi realizar um estudo observacional de idade em perda de deambulação independente (LOA) e de efeitos colaterais associados com perfis de diferentes regimes de na distrofia muscular de Duchenne (DMD). Foram estudados 340 participantes sendo que a LoA foi definida como o uso de cadeira de rodas contínua. Os meninos que utilizaram corticóides apresentaram perda da deambulação independente cerca de 3 anos após os que não usavam. Os pacientes que usaram deflazacort apresentaram perda da deambulação mais tardiamente que os que utilizavam prednisona/prednisolona mas apresentram significativamente maior retardo do crescimento, catarata e aparência cushingóide e menor ganho de peso. O estudo demonstra que os corticóides utilizados na distrofia muscular de Duchenne promovem um retardo da perda de deambulação independente, O resumo em inglês pode ser lido abaixo:
(Neurology, 2015) Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study
Luca Bello, Heather Gordish- Dressman, Lauren P. Morgenroth, Erik K. Henricson, Tina Duong, Eric P. Hoffman, Avital Cnaan, Craig M. McDonald, On behalf of the CINRG Investigators
ABSTRACT
Objective: We aimed to perform an observational study of age at loss of independent ambulation
(LoA) and side-effect profiles associated with different glucocorticoid corticosteroid (GC) regimens
in Duchenne muscular dystrophy (DMD).
Methods: We studied 340 participants in the Cooperative International Neuromuscular Research
Group Duchenne Natural History Study (CINRG-DNHS). LoA was defined as continuous wheelchair
use. Effects of prednisone or prednisolone (PRED)/deflazacort (DFZ), administration
frequency, and dose were analyzed by time-varying Cox regression. Side-effect frequencies were
compared using x2 test.
Results: Participants treated $1 year while ambulatory (n 5 252/340) showed a 3-year median
delay in LoA (p , 0.001). Fourteen different regimens were observed. Nondaily treatment was
common for PRED (37%) and rare for DFZ (3%). DFZ was associated with later LoA than PRED
(hazard ratio 0.294 6 0.053 vs 0.490 6 0.08, p 5 0.003; 2-year difference in median LoA with
daily administration, p , 0.001). Average dose was lower for daily PRED (0.56 mg/kg/d, 75% of
recommended) than daily DFZ (0.75 mg/kg/d, 83% of recommended, p , 0.001). DFZ showed
higher frequencies of growth delay (p , 0.001), cushingoid appearance (p 5 0.002), and cataracts
(p , 0.001), but not weight gain.
Conclusions: Use of DFZ was associated with later LoA and increased frequency of side effects.
Differences in standards of care and dosing complicate interpretation of this finding, but stratification
by PRED/DFZ might be considered in clinical trials. This study emphasizes the necessity of
a randomized, blinded trial of GC regimens in DMD.
Classification of evidence: This study provides Class IV evidence that GCs are effective in delaying
LoA in patients with DMD. Neurology® 2015;85:1–8
JULY
Itália - o objetivo deste estudo foi avaliar os efeitos dos corticóides sobre a função dos membros superiores em 91 pacientes não ambulantes com distrofia muscular de Duchenne com idade entre 11 e 26 anos; 48 pacientes estavam em uso de corticóides, 25 pararam com corticóides e 18 nunca usaram corticóides ou usaram por menos de 1 ano. A avaliação da força dos braços demonstrou que os que usavam corticóide apresentaram maior força muscular, superior aos que param com a droga. Os que não usaram corticóides tiveram a menor força muscular. Os achados sugerem que os corticóides continuam a apresentar efeitos benéficos mesmo após a parada da deambulação na distrofia muscular de Duchenne. O resumo em inglês pode ser lido abaixo:
(Neuromuscular Disorders, 2015) Benefits of glucocorticoids in non-ambulant boys/men with duchenne muscular dystrophy: a multicentric longitudinal study using the performance of upper limb test
Highlights
• The paper reports the effect of steroids on upper limb function in non ambulant DMD boys
• Boys continuing steroids after loss of ambulation perform better than those who stopped at the time of loss of ambulation
• The Performance of Upper Limb test can reliably capture change over time and the effect of intervention
Abstract
The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years.
All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year.
At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p<0.001).
The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow level.
Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function.
USA - a distrofia muscular de Duchenne tem sintomas iniciais na infância e as implicações sobre a nutrição são muito importantes, Aspectos como crescimento, composição corporal, necessidades de energia e proteínas, constipação intestinal e dificuldades para engolir são considerações que requerem atenção nutricional.
Alemanha - a ressonância magnética foi realizada em trinta e seis mulheres (idade 44 ± 14 anos) portadoras de Duchene (20) ou Becker (16). Em 22 dessas mulheres pelo menos um parente de primeiro grau do sexo masculino, com diagnóstico de distrofia muscular também foram estudados pela ressonância magnética. A análise dos exames demonstrou que o envolvimento cardíaco é um achado freqüente em mulheres portadoras de Duchenne e menos freqüente em Becker. Nessas mulheres com comprometimento cardíaco demonstram o mesmo padrão de fibrose do miocárdio como os seus homólogos do sexo masculino com doença manifesta. O resumo em inglês pode ser lido abaixo:
26 - (European Heart Journal – Cardiovascular Imaging, 2015) Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study
Aims Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives.
Methods and results Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the ‘MD carrier group’ and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women (‘female MD carrier comparison group’, 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the ‘male MD comparison group’ (n = 24, 6 DMD and 18 BMD). In the total MD carrier group, 17 (47%) MD carriers had at least one pathological CMR finding [5 (14%) with a reduced left ventricular ejection fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P = 0.008)—in spite of being significantly younger (40 ± 11 vs. 50 ± 16 years, P = 0.038). In the male MD comparison group, the same LGE pattern as in female carriers was seen, but with a significantly higher prevalence of cardiac abnormalities compared with their female carrier relatives constituting the female MD comparison group (75 vs. 27%; P = 0.003).
Conclusion Cardiac involvement is a frequent finding in female carriers of DMD, but less frequently observed in carriers of BMD. Those DMDc and BMDc with cardiac involvement demonstrate the same myocardial fibrosis pattern as their male counterparts with overt disease.
Canadá - A terapia celular (CT) é uma abordagem experimental para tratar as distrofias musculares. Os primeiros estudam datam da década de 90 com o transplante de mioblastos. Como não ocorreram efeitos benéficos outras fontes de células foram pesquisadas. Embora o repertório de células propostas para terapia celular das distrofias musculares ter sido ampliado, apenas mioblastos têm atualmente demonstrado de forma inequívoca resultados significantes em seres humanos. Mas ainda há desafios técnicos signifcativos que precisam ser resolvidos para que este tratamento possa estar disponível.
México - este estudo foi feito em 66 pacientes com Duchenne/Becker que não utilizavam corticóides; 68% eram obesos, 48,5% tinham hiperinsulinemia e 36,4% apresentavam resistência a insulina. Pacientes com baixo peso (27,3%) apresentaram hiperinsulinemia e resistência a insulina. Os portadores de deleções em exons 45 e 50 do gene da distrofia apresentaram maior risco para resistência a insulina do que não portadores. Além disso observou-se uma maior coloração de agregados citoplasmáticos para GLUT4 em biópsias musculares do que o tecido muscular saudável.
Japão - embora pacientes com Duchenne têm várias predisposições subjacentes para tromboembolismo venoso (TEV), pouco se sabe sobre sua prevalência e impacto prognóstico. De julho de 2007 a dezembro de 2008, um total de 102 pacientes do sexo masculino com Duchenne em longo prazo (mais de um ano) hospitalização foram inscritos e prospectivamente acompanhados até o final de outubro de 2014. No início do estudo, 24 de 102 pacientes tiveram trombose venosa profunda subclínica. Dois pacientes tinham história anterior de TEV e 1 paciente tinha recebido terapia anticoagulante. Pacientes com trombose venosa profunda tinham significativamente menor peso corporal. Uma tendência para um risco aumentado de trombose venosa profunda foi observada no uso de ventilador e por maior imobilidade.
USA - com a melhora do atendimento das manifestações respiratórias da distrofia muscular de Duchenne as manifestações cardíacas passaram a ser a maior causa de morte na doença. A cardiomiopatia em Duchenne é diferente de outras observadas em pacientes pediátricos. Neste artigo os especialistas foram reunidos para discutir as diretrizes utilizadas para diagnóstico, tratamento e prevenção da doença.
USA - neste congresso são apresentadas diferentes pesquisas em diversas doenças como as distrofias musculares: Duchenne, miotônica,facio escapulo umeral, disferlina, etc. Tem pesquisas com exon skipping, como o primeiro caso de tratamento com salto do exon 53, terapia gênica, células tronco, cromosso artificial,etc
USA - a insuficiência respiratória e cardíaca são as principais causas de óbito na distrofia muscular de Duchenne. Estudos prévios demonstraram que o debenone causa efeitos benéficos na distrofia muscular de Duchenne por melhorar as condições energéticas dos músculos. Neste estudo controlado fase 3 os pacientes foram tratados com idebenone (31 pacientes) (300mg, trës vezes ao dia) ou placebo (33 pacientes) por 52 semanas. A avaliação da função respiratória mostrou que a queda da função pulmonar foi menor nos tratados com idebenone, ficando a função pulmonar intermediária entre os tratados com corticóides e os que não tomaram nem corticóides e nem idebenone. Efeitos colaterais foram raros e a droga foi bem tolerada. O Idebenone reduziu a perda da função respiratória e representa uma nova opção de tratamento para pacientes com distrofia muscular de Duchenne. O resumo em inglês pode ser lido abaixo:
(The Lancet, 2015) Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial
Gunnar M Buyse, Thomas Voit, Ulrike Schara, Chiara S M Straathof, M Grazia D'Angelo, Günther Bernert, Jean-Marie Cuisset, Richard S Finkel, Nathalie Goemans, Craig M McDonald, Christian Rummey, Thomas Meier, for the DELOS Study Group
Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids.
In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10–18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884.
31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (−3·05%p [95% CI −7·08 to 0·97], p=0·134, vs placebo −9·01%p [–13·18 to −4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (−2·57%p [–6·68 to 1·54], p=0·215, vs −8·84%p [–12·73 to −4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients).
Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy.
USA - O uso de corticóides é considerado como único tratamento da distrofia muscular de Duchenne. No entanto seu uso tem sido muito avaliado sobre a função muscular e poucas vezes sobre a função cardíaca. Nesta pesquisa os autores avaliaram a função cardíaca em Duchenne através da ressonância nuclear magnética. Os resultados demonstraram que o grau de fibrose aumenta com a idade e com o uso de corticóides e reflete diretamente com a função cardíaca. Nesta mesma publicação há um editorial que reforça a necessidade de tratamento com corticóides visto que é a única opção de tratamento e discute todas as resalvas com relação a estes resultados. O resumo em inglês e o editorial na íntegra podem ser lidos abaixo:
(Journal of American Heart Association, 2015) Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and Is Associated With Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy
Animesh Tandon, Chet R. Villa, Kan N. Hor, John L. Jefferies, Zhiqian Gao, Jeffrey A. Towbin, Brenda L. Wong, Wojciech Mazur, Robert J. Fleck, Joshua J. Sticka, D. Woodrow Benson, and Michael D. Taylor - USA
Background Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort.
Methods and Results We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with ≥4 cardiac magnetic resonance studies) for left ventricular ejection fraction (LVEF) and presence of late gadolinium enhancement (LGE), a marker for myocardial fibrosis. LVEF was modeled by examining LGE status, myocardial fibrosis burden (as assessed by the number of LGE‐positive left ventricular segments), patient age, and steroid treatment duration. An age‐only model demonstrated that LVEF declined 0.58±0.10% per year. In patients with both LGE‐negative and LGE‐positive studies (n=51), LVEF did not decline significantly over time if LGE was absent but declined 2.2±0.31% per year when LGE was present. Univariate modeling showed significant associations between LVEF and steroid treatment duration, presence of LGE, and number of LGE‐positive left ventricular segments; multivariate modeling showed that LVEF declined by 0.93±0.09% for each LGE‐positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of LGE‐positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age‐related increases
Conclusion Progressive myocardial fibrosis, as detected by LGE, was strongly correlated with the LVEF decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age‐related increase in myocardial fibrosis burden.
Glucocorticoid Therapy for Duchenne Cardiomyopathy: A Hobson's Choice?
Subha V. Raman and Linda H. Cripe
Reino Unido - a cardiomiopatia da distrofia muscular de Duchenne aumenta a mortalidade peri-operatória e a melhro maneira de avaliar o paciente não foi ainda estabelecida. Trinta e cinco pacientes com Duchenne submetidos a cirurgia foram avaliados com o ecocardiograma e ressonância nuclear magnética. Os resultados demonstraram que a ressonância nuclear magnética acrescenta maiores informações sobre a função cardíaca do que o ecocardiograma que pode substimar ou superestimar a função cardíaca, além de freuqentemente apresentar dificuldades técnicas de visualização (janela ruim). O resumo em inglês pode ser lido abaixo:
(European Journal of Paediatric Neurology,2015) The value of cardiac MRI versus Echocardiography in the pre-operative assessment of patients with Duchenne muscular dystrophy
A. Brunklaus, E. Parish, F. Muntoni, S. Scuplak, S.K. Tucker, M. Fenton, M.L. Hughes, A.Y. Manzur - UK
Duchenne Muscular Dystrophy (DMD) related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been systematically evaluated as pre-operative assessment tool for heart function in DMD. Our aim was to establish whether CMR versus echocardiography contributes to pre-operative DMD assessment. Case records were retrospectively reviewed of 35 consecutive DMD boys who underwent evaluation for surgical procedures between 2010-2013. Echocardiography revealed a median left ventricular (LV) shortening fraction (SF) of 29% (range: 7-44). 37% of boys (13/35) had abnormal SF <25%, 66% (23/35) showed hypokinesia and 26% (9/35) had LV dilatation. CMR revealed a median left ventricular ejection fraction (LVEF) of 52% (range: 27-67%). 57% of boys (20/35) had abnormal LVEF <55%, 71% (25/35) had hypokinesia, and 82% late gadolinium enhancement. Extensive versus minimal late gadolinium enhancement was associated with reduced left ventricular ejection fraction (48% vs 58%; p=0.003) suggesting more severe cardiomyopathy. Although echocardiography shortening fraction correlated with CMR ejection fraction (rs=0.67; p<0.001), three-quarter of echocardiography studies had suboptimal scanning windows and in 26% measurements significantly over- or underestimated left-ventricular function compared to CMR.
Our findings clearly demonstrate the added value of CMR versus echocardiography in assessing DMD-cardiomyopathy. Particularly when echocardiographic scanning windows are suboptimal, CMR should be considered to allow accurate pre-operative cardiac assessment.
USA - nesta pesquisa os autores estudaram pacientes com cardiomiopatia na distrofia muscular de Duchenne. Os níveis de ST2 no soro dos pacientes com Duchenne é maior que nas pessoas que não tem a doença. Mas os níveis são significantemente maiores nos pacientes com Duchenne que apresentam cardiomiopatia. O resumo em inglês pode ser lido abaixo:
(ACC, 2015) Elevated ST2 Serum Levels a Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy
Julia Anderson, Haeri Seol, Yetrib Hathout, Christopher Spurney, Children's National Medical Center, Washington, DC, USA
Background: Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein. Nearly 50% of DMD patients now die from cardiac related causes. The purpose of our research was to identify cardiac serum biomarkers associated with DMD cardiomyopathy.
Methods: Serum was collected from 30 participants enrolled in the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History study (clinicaltrials.gov: NCT00468832) from 5 clinical sites. Cardiomyopathy was defined as a reported shortening faction (SF) < 28% and/or ejection faction (EF) < 55%. Serum was analyzed via enzyme-linked immunosorbent assays (R&D Systems; Cloud-Clone Corp.) in duplicate using an xMark spectrometer (Bio-Rad Laboratories). ANOVAs (α < 0.05) were used to determine significance.
Results: There were no significant differences in ages between participants with DMD and cardiomyopathy; those with DMD and normal cardiac function; and normal controls. The DMD cardiomyopathy group had an EF=45±10% (mean±SD) / SF=25±2% and the DMD non-cardiomyopathy group had an EF=58±5% and SF=32±3% (p<0.01). Interleukin 1 receptor-like 1 (ST2) serum protein levels were significantly elevated in the DMD cardiomyopathy group [n=12; 35798±16918 pg/mL; p<0.01] compared to controls (n=4; 9940±6565 pg/mL). The DMD non-cardiomyopathy group also showed a significant 3 fold increase (n=12; 28837±17305 pg/mL; p<0.05) compared to controls. Matrix metallopeptidase 9 (MMP9) levels were significantly increased in both DMD groups compared to controls (p<0.02). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TSP4 levels.
Conclusions: In conclusion, increased ST2 levels were found in serum of DMD patients compared to healthy volunteers and significantly elevated in DMD patients with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for earlier detection and administration of cardioprotective therapies in DMD patients
USA - nesta pesquisa os autores estudaram a inibição dos receptores dos mineralocorticóides que foram associados com espironolactona e lisinopril resultando em um dramático aumento da força muscular e respiratória com menor alterações patológicas dos músculos. O resumo em inglês pode ser lido abaixo:
(Experimental Biology, 2015) Elucidating the Role of Mineralocorticoid Receptors in Skeletal Muscle as a Potential Therapeutic Target for Duchenne Muscular Dystrophy
Jessica Chadwick, James Hauck, Jeovanna Low, Jill Rafael-Fortne - USA
Our lab identified a potential new treatment for Duchenne Muscular Dystrophy using the mineralocorticoid receptor (MR) antagonist spironolactone and ACE inhibitor lisinopril. Drug studies using dystrophic Het (utrn+/-;mdx) mice showed a dramatic improvement in both respiratory and limb muscle force and a reduction of ongoing muscle damage, in addition to preventing cardiomyopathy. We show MR is present in both skeletal muscle tissue and myogenic cultures , supporting a direct affect by MR antagonists on skeletal muscle. Global analysis of gene expression between treated and untreated dystrophic mice identified potential molecular targets to unravel the drugs' mode of action. Preliminary microarray data comparing quadriceps muscle from lisinopril and spironolactone treated het mice to untreated controls revealed changes in the expression of several gene targets with known roles in striated muscle, which have been confirmed using immunofluorescence and western blot analysis. Myogenic cultures treated with MR agonists and antagonists are being used to test whether these potential downstream targets are affected in a cell autologous manner in skeletal muscle and represent bona fide MR gene targets. NIH 1 R01 NS082868; T32 NS077984
USA - A epicatequina foi descoberta para ser uma homóloga estrutural de uma família recém-descoberta de PGC1-alfa ativando hormônios esteróides que promovem biogênese mitocondrial e induzir a regeneração do músculo esquelético. Foi realizado um estudo piloto aberto de epicatequina(50mg duas vezes ao dia por 8 semanas) em adultos ambulatoriais com Distrofia de Becker. A epicatequina induziu biogênese mitocondrial e regeneração muscular. É o único composto oral que pode concomitantemente aumentar a folistatina e diminuir a miostatina. Aumento dos níveis de distrofina e utrofina também foram observados. Houve aumento da força muscular. A epicanterina pode ser uma nova estratégia terapêutica para distrofinopatias. O resumo em inglês pode ser lido abaixo:
(MDA Conference, 2015) Epicatechin enhances mitochondrial biogenesis, increases dystrophin and utrophin, increases follistatin while decreasing myostatin, and improves skeletal muscle exercise response in adults with Becker muscular dystrophy (BMD).
Craig M. McDonald, MD1†*, Erik K. Henricson, MPH1†, Bjorn Oskarsson, MD1, Candace Aguilar, BS1, Alina Nicorici, BS1, Nanette Joyce, DO1, Divya Reddy, MD1, Amy Wagner, MS1, Evan deBie, BS1, Erica Goude, BS1, R. Ted Abresch, MS1, Francisco Villareal, MD2, Guy Perkins, MD2, Yetrib Hathout, PhD3, Sundeep Dugar, PhD4, George Schreiner, MD, PhD4. 1University of California, Davis, Sacramento CA; 2University of California, San Diego, San Diego CA; 3Children’s National Medical Center, Washington, DC; 4Cardero Therapeutics, Los Altos Hills, CA.
Objective: To assess the effect of epicatechin on mitochondrial density and muscle function in Becker muscular dystrophy (BMD).
Background: Epicatechin has been discovered to be a structural homologue of a newly discovered family of PGC1-alpha activating steroid hormones that promote mitochondrial biogenesis and induce skeletal muscle regeneration. Epicatechin has been shown to stimulate mitochondrial biogenesis and improve muscle structure and function in the mdx and delta sarcoglycan null models of muscular dystrophy. We conducted an open-label pilot study of epicatechin in ambulatory adults with BMD.
Design: Seven participants received epicatechin 50 mg b.i.d. for 8 weeks. Pre- and post-assessments included: biceps biopsy Western blot and EM, peripheral blood biomarkers, metabolic gas exchange / graded exercise testing, quadriceps tissue saturation index (TSI) by near-infrared spectroscopy, and quantitative muscle strength.
Results: Muscle western blot showed significantly increased dystrophin, utrophin and dysferlin levels. In addition we observed increased muscle follistatin (p=0.002) and decreased myostatin (p=0.008). Increased markers of muscle regeneration included myogenin, Myf5, MyoD, myosin and SkM actin alpha 1 (all p<0.033). Increased proteins associated with mitochondrial growth included PGC1-alpha (p=0.01), AMPK (p=0.004) and mitofilin (p=0.007). Plasma Western blot showed increased follistatin (p=0.0006), decreased myostatin (p=0.04) and increased follistatin:myostatin ratio (p=0.0004). Muscle EM showed increased mitochondrial volume and cristae abundance (p=0.02). Exercise testing demonstrated decreased VO2/kg (p<0.0001), lactate (p<0.0001) and heart rate (p<0.00001) at defined workloads. TSI improved in resting (p<0.008) and post-exercise states (p<0.001). Performance on 6MWT, cycle test maximal watts and strength increased in a subset of patients.
Conclusion: Epicatechin induces mitochondrial biogenesis and muscle regeneration in BMD. It is the only oral compound ever demonstrated to both increase plasma follistatin and decrease plasma myostatin, whose ratio may comprise a future pharmacodynamic biomarker. Increased levels of dystrophin and utrophin suggest that concurrent stimulation of bioenergetics and muscle regeneration may be a novel therapeutic strategy for dystrophinopathies.
Itália - os autores pesquisaram uma maneira de tratar a distrofia com anti-inflamatórios que tivessem menor quantidade de efeitos colaterais que os corticóides. A interleucina 6 está aumentada em pessoas e camundongos com distrofia muscular de Duchenne. Neste experimento em camundongos utilizaram um bloqueador do receptor da interleucina 6. Os animais tratados apresentaram melhora da força muscular e melhora das alterações patológicas demonstrando um efeito positivo e promissor para tratamento desta forma de distrofia muscular. O resumo em inglês pode ser lido abaixo:
(EBioMedicine, 2015) Functional and morphological improvement of dystrophic muscle by interleukin 6 receptor blockade
Laura Pelosi, Maria Grazia Berardinelli, Loredana De Pasquale, Carmine Nicoletti, Adele D’Amico, Francesco Carvello, Gian Marco Moneta, Angela Catizone, Enrico Bertini, Fabrizio De Benedetti, Antonio Musarò - Italy
The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for Duchenne muscular dystrophy (DMD). However, long-term GC treatment causes muscle atrophy and wasting. Thus, targeting specific mediator of inflammatory response may be more specific, more efficacious, and with fewer side effects. The pro-inflammatory cytokine interleukin (IL) 6 is overproduced in patients with DMD and in the muscle of mdx, the animal model for human DMD. We tested the ability of inhibition of IL6 activity, using an interleukin-6 receptor (Il6r) neutralizing antibody, to ameliorate the dystrophic phenotype. Blockade of endogenous Il6r conferred on dystrophic muscles resistance to degeneration and alleviated both morphological and functional consequences of the primary genetic defect. Pharmacological inhibition of IL6 activity leaded to changes in the dystrophic muscle environment, favoring anti-inflammatory responses and improvement in muscle repair. This resulted in a functional homeostatic maintenance of dystrophic muscle.
These data provide an alternative pharmacological strategy for treatment of DMD and circumvents the major problems associated with conventional therapy.
Holanda - Este estudo foi realizado com 80 adultos (acima de 20 anos) com distrofia muscular de Duchenne. Os sintomas de fadiga (40,5%), dor (73,4%), ansiedade (24%) e depressão (19%) foram frequentemente encontrados. Muitos indivíduos muitas vezes tinha várias condições. Os autores concluem que estes sintomas são muito frequentes e são tratáveis e podem melhorar a qualidade de vida. O resumo em inglês pode ser lido abaixo:
(Archives of Physical Medicine and Rehabilitation,2015) Prevalence of fatigue, pain, anxiety and depression in adults with Duchenne Muscular Dystrophy, and their associations with quality of life
Robert F. Pangalila, Geertrudis AM. van den Bos, Bart Bartels, Michael Bergen, Henk J. Stam, Marij E. Roebroeck - The Netherlands
Design: cross-sectional study
Setting: Home of participants
Participants: 80 adults with Duchenne Muscular Dystrophy
Interventions: Not applicable
Main outcome variables: Fatigue was assessed with the Fatigue Severity Scale; pain with one item of the SF-36 and by interview; and anxiety and depression, using the Hospital Anxiety and Depression Scale. Health-related quality of life was assessed using the World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF). Associations between these conditions and quality of life were assessed by means of univariate and multivariate logistic regression analyses.
Results: Symptoms of fatigue (40.5%), pain (73.4%), anxiety (24%), and depression (19%) were frequently found. Individuals often had multiple conditions. Fatigue was related to overall quality of life, and to the quality of life domains of physical health and environment; anxiety was related to the psychological domain.
Conclusion: Fatigue, pain, anxiety, and depression, potentially treatable symptoms, occur frequently in adults with Duchenne Muscular Dystrophy and significantly influence health-related quality of life.
Canada - pacientes com distrfoia muscular podem apresentar osteoporose e a causa não está totalemnte esclarecida. Nesta pesquisa os autores identificaram uma proteína, a osteoprotegerina, sendo produzida pelo músculo. Ela é responsável pela diferenciação de osteoclastos e remodelamento ósseo. A administração de osteoprotegerina de origem muscular promoveu aumento de força e redução das alterações patológicas dos músculos de camundongos com distrofia muscular. O resumo em inglês pode ser lido abaixo:
(American Journal of Pathology, 2015) Osteoprotegerin Protects against Muscular Dystrophy
Sébastien S. Dufresne, Nicolas A. Dumont, Patrice Bouchard, Éliane Lavergne, Josef M. Penninger, Jérôme Frenette - Canada
Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis.
Alemanha - doenças neuromusculares hereditárias podem causar insuficiência respiratórias com complicações, inclusive fatais. Neste estudo 21 pacientes com doenças neuromusculares com capacidade vital reduzida foram submetidos a exercícios com o cough assist, 10 minutos, duas vezes ao dia. Antes do tratamento os pacientes apresentaram redução da capacidade vital que aumento 28% após os exercícios.
USA - Neste estudo 58 pacientes com distroglicanopatias foram incluidos, comparados com controles. A idade variou de 6 a 50 anos, com predomínio do sexo feminino, Os sintomas urinários foram mais frequentes nos pacientes com distroglicanopatias e a disfagia também. Os sintomas foram progressivamente mais frequentes com a evolução da idade. Estes sintomas pioram a qualidade de vida e podem estar relacionados com a doença. Os autores sugerem que estes sintomas devam ser perguntados e avaliados durante as consultas de pessoas com distroglicanopatias. O resumo em inglês pode ser lido abaixo:
(NEUROLOGY, January 2015) Urologic and gastrointestinal symptoms in the dystroglycanopathies
Cameron D. Crockett, Laura A. Bertrand, Christopher S. Cooper, Riad M. Rahhal, Ke Liu, M. Bridget Zimmerman, Steven A. Moore, and Katherine D. Mathews - USA
Abstract
Objective: To determine the frequency of urologic and gastrointestinal (GI) symptoms in a cohort of individuals with dystroglycanopathy compared with healthy household controls.
Methods: Participants in a North American dystroglycanopathy natural history study (NCT00313677) and other members of their households completed a questionnaire modified from validated instruments and clinical criteria. Urologic and GI symptom frequency, effect on patient life, and medications taken for these symptoms were assessed. Those younger than 4 years or not toilet trained were excluded. Healthy human bladder, esophagus, and duodenum from surgical specimens were immunostained for glycosylated α-dystroglycan.
Results: Thirty of 58 potential participants with dystroglycanopathy (51.7%) and 16 household controls participated. Subjects were aged 6 to 51 years (mean 26.7); 60.0% were female. Controls were aged 7 to 55 years (mean 34.6); 56.3% were female. The dystroglycanopathy cohort had higher frequency of urinary voiding symptoms (p = 0.02), higher urologic symptom scores (p = 0.05), and higher dysphagia symptom scores (p = 0.04). A correlation existed between urologic symptom score and effect on life (r = 0.71; 95% confidence interval 0.46, 0.85; p < 0.0001) and between dysphagia symptom score and effect on life (r = 0.72; 95% confidence interval 0.48, 0.86; p < 0.0001). Glycosylated α-dystroglycan was present in visceral smooth muscle of all normal tissues analyzed.
Conclusions: Urologic symptoms and dysphagia are reported more frequently by individuals with dystroglycanopathies than by household controls. These symptoms can cause a perceived negative effect on patient life. Our results suggest urologic and GI dysfunction may be part of the dystroglycanopathy phenotype, and that questions about these symptoms should be incorporated into routine care because they may influence medical management.
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NOTÍCIAS DO MÊS DE ABRIL DE 2002
NOTÍCIAS DO MÊS DE MARÇO DE 2002
NOTÍCIAS DO MÊS DE FEVEREIRO DE 2002
NOTÍCIAS DO MÊS DE JANEIRO DE 2002
NOTÍCIAS DO MÊS DE DEZEMBRO DE 2001
NOTÍCIAS DO MÊS DE NOVEMBRO DE 2001
NOTÍCIAS DO MÊS DE OUTUBRO DE 2001
NOTÍCIAS DO MÊS DE SETEMBRO DE 2001
NOTÍCIAS DO MÊS DE AGOSTO DE 2001
NOTÍCIAS DO MÊS DE FEVEREIRO AO MÊS DE JULHO DE 2001