2002 NEWS 2003 NEWS 2004 NEWS 2005 NEWS 2006 NEWS 2007 NEWS 2008 NEWS
2012 NEWS
DECEMBER
23 - (J Neurol Psychiatry, Dec 2012) Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy
Valeria Ricotti, Deborah A Ridout, Elaine Scott, Ros Quinlivan, Stephanie A Robb, Adnan Y Manzur, Francesco Muntoni, on behalf of the NorthStar Clinical Network - UK
Objective To assess the current use of glucocorticoids (GCs) in Duchenne muscular dystrophy in the UK, and compare the benefits and the adverse events of daily versus intermittent prednisolone regimens.
Design A prospective longitudinal observational study across 17 neuromuscular centres in the UK of 360 boys aged 3–15 years with confirmed Duchenne muscular dystrophy who were treated with daily or intermittent (10days on/10days off) prednisolone for a mean duration of treatment of 4years
Results The median loss of ambulation was 12years in intermittent and 14.5years in daily treatment; the HR for intermittent treatment was 1.57 (95% CI 0.87 to 2.82). A fitted multilevel model comparing the intermittent and daily regiments for the NorthStar Ambulatory Assessment demonstrated a divergence after 7 years of age, with boys on an intermittent regimen declining faster (p<0.001). Moderate to severe side effects were more commonly reported and observed in the daily regimen, including Cushingoid features, adverse behavioural events and hypertension. Body mass index mean z score was higher in the daily regimen (1.99, 95% CI 1.79 to 2.19) than in the intermittent regimen (1.51, 95% CI 1.27 to 1.75). Height restriction was more severe in the daily regimen (mean z score −1.77, 95% CI −1.79 to −2.19) than in the intermittent regimen (mean z score −0.70, 95% CI −0.90 to −0.49).
Conclusions Our study provides a framework for providing information to patients with Duchenne muscular dystrophy and their families when introducing GC therapy. The study also highlights the importance of collecting longitudinal natural history data on patients treated according to standardised protocols, and clearly identifies the benefits and the side-effect profile of two treatment regimens, which will help with informed choices and implementation of targeted surveillance.
14 - (Sci Transl Med 12 December 2012: Vol. 4, Issue 164, p. 164ra160) Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy
, , , , , , , , , , , , and
NOVEMBER
24 -
(Clinical Nutrition, 2012)
Effects of fish oil containing eicosapentaenoic acid and docosahexaenoic acid on
dystrophic mdx mice.
Adriana Fagagnolo Mauricio, Elaine Minatel, Humberto Santo Neto, Maria Julia
Marques - Brazil
Abstract
Background and aims. In Duchenne muscular dystrophy (DMD) and in the mdx
mouse model of DMD, the lack of dystrophin leads to muscle degeneration and
inflammation contributes to progression of the disease. In this study, we
evaluated the effects of
commercially available fish oil containing EPA and docosahexaenoic acid (DHA) on
mdx.
Methods. Mdx mice (14 days old) were treated with fish oil (FDC Vitamins; 0.002 g EPA and 0.001 g DHA) for 16 days by gavage. Control mdx mice received mineral oil (Nujol). Grip strength measurement was used for functional evaluation. The sternomastoid, diaphragm and biceps brachii muscles were removed and processed for histopathology and Western blot analysis.
Results. Fish oil decreased creatine kinase and
myonecrosis. In all muscles studied, the inflammatory area was
significantly reduced after treatment (18.0 ± 3.0% inflammatory area in
untreated mdx mice vs 4.0 ± 1% in treated mdx mice). Fish oil protected against
the loss of muscle strength. Fish oil significantly reduced the levels of TNF-α
and the levels of 4-HNE-protein adducts (30 to 34% reduction for both) in all
muscles studied.
Conclusions. Commercially available fish oil may be potentially useful to ameliorate dystrophic progression of skeletal muscles, deserving further clinical trials in DMD patients.
10 - Sleep disorders in boys with Duchenne muscular dystrophy
10 - Scientific Sessions of American Heart Association 2012
A) Phosphodiesterase Modulation of Cardiomyopathy in Murine and Canine Models of Muscular Dystrophy Treated With Sildenafil and Tadalafil
Chonyang L Albert, Hosp of the Univ of Pennsylvania, Philadelphia, PA; Meg Sleeper, Univ of Pennsylvania Sch of Veterinary Med, Philadelphia, PA; H. Lee Sweeney, Univ of Pennsylvania, Philadelphia, PA
Patients with Duchenne muscular dystrophy (DMD) suffer from a myriad of musculoskeletal, respiratory, and cardiac symptoms.Cardiomyopathy is the second most common cause of death in DMD patients. The development of cardiomyopathy in these patients is often insidious, but untreated, many patients progress to overt heart failure. Current therapies used to treat the cardiomyopathy of DMD have been poorly studied since many of the same medications are used empirically from patients with congestive heart failure, despite the different underlying mechanical causes of heart failure in DMD patients. Using a well-established murine model of DMD, we treated mdx mice with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil or tadalafil) for a duration of 1 month and 8 months. Treatment response was measured by dobutamine stress echocardiography parameters, proteomic expression, and histologic studies. We saw an increase in protein kinase G (PKG) levels in the sildenafil and tadalafil treated mice hearts, afterboth 1 month and 8 months of treatment, which suggests that the PDE-5 inhibitors’ mechanism of action is active in the heart. This was accompanied by a low level of atrial natriuretic peptide in the treated hearts compared to the untreated hearts at 8 months. Our results suggest that PDE-5 inhibition modulates and down-regulates the pro-fibrotic and pro-inflammatory cascade in the dystrophic mdx heart through TGF beta and SMAD2/3 pathways in an ERK-independent manner. Moreover, in a canine study in which dogs affected with golden retriever muscular dystrophy were treated with one of these 2 drugs for one month, both PDE-5 inhibitors resulted in improved left ventricular strain as measured with cardiac magnetic resonance imaging. There are some differences between the effects of the two PDE-5 inhibitors which is likely attributable to differences in the potency and specificity of these two agents at PDE5 inhibition. Further studies will continue to elucidate the role of PDE-5 inhibitors in the treatment of the dilated cardiomyopathy of DMD.
B) Sildenafil Prevents Progressive Hypertrophy and Normalizes the Enhanced Slow Force Response in Dystrophic Myocardium
Peter P Rainer, Kinya Seo, Dong I Lee, Scarlett Hao, Djahida Bedja, David A Kass, Johns Hopkins Sch of Med, Baltimore, MD
Duchenne Muscular Dystrophy (DMD) is a frequent and devastating disease that
affects both skeletal muscle and the heart, resulting in cardiomyopathy in
virtually all patients. Key features include nNOS-dysregulation and excessive
Ca2+ entry upon mechanical stress. A possible source of increased Ca2+ entry are
mechano-sensitive TRPC channels. As TRPC3/6 channels can be suppressed by PKG
phosphorylation, we hypothesized that augmentation of PKG stimulation
ameliorates invivo function coupled to blunting of stretch-activated Ca2+ entry
and the slow force response (SFR).
Methods
Mdx, utrophin+/- mice were treated with sildenafil 200mg/kg/d for 2 months and
followed-up by echocardiography; gene expression was assessed by qRT-PCR and
PDE5 activity by fluorescence polarization. The SFR and Ca2+ transients were
assessed in single cardiomyocytes attached to carbon fibers and papillary muscle
preparations when exposed to stretch.
Results
Mdx, utrophin+/- mice demonstrated marked hypertrophy when compared to WT or
mdx-only mice, with up-regulation of fetal gene expression markers (ANP 4.5±0.8-fold,
BNP 2.5±0.4-fold, bMHC 2.8±0.4-fold, p<0.05) and a trend towards up-regulation
of TRPC6 (3.4±1.5-fold, p=n.s.). Myocardial PDE5 activity was increased 3.5±0.5-fold
over controls (p<0.01). Sildenafil treatment prevented and reversed progressive
myocardial hypertrophy, normalized PDE5 activity, decreased fetal gene and TRPC6
expression (all p<0.05). The morphological and molecular changes were
accompanied by an enhanced SFR in dystrophic cardiomyocytes. Sildenafil
treatment and/or direct TRPC3/6 antagonism using a selective blocker normalized
the myocyte SFR (p<0.05).
Conclusion
PDE5 inhibition is effective in preventing progressive hypertrophy and
normalizing molecular markers of heart failure in dystrophic hearts. The SFR is
enhanced in dystrophic cardiomyocytes and can be normalized by PDE5 inhibition
or acute TRPC antagonism. These data support the involvement of TRPC channels in
excessive Ca2+ entry and the enhanced SFR, offering a rationale for modifying
TRPC Ca2+ entry, either by direct antagonism or by PKG phosphorylation of TRPC
channels.
C) Tadalafil Alleviates Functional Muscle Ischemia in Patients with Becker Muscular Dystrophy
Elizabeth A Martin, Bryan L Scott, Ashley E Walker, Jimmy Johannes, Swaminatha V Gurudevan, Cedars Sinai Medical Ctr, Los Angeles, CA; Francine Anene, Robert M Elashoff, UCLA, Los Angeles, CA; Gail D Thomas, Ronald G Victor, Cedars Sinai Medical Ctr, Los Angeles, CA
Becker muscular dystrophy (BMD) is a progressive, ultimately fatal X-linked
muscle wasting disease for which there is no treatment. BMD is caused by
mutations in the gene encoding dystrophin, a structural cytoskeletal protein
that also targets neuronal nitric oxide synthase (nNOSμ) to the sarcolemma. Our
past work suggests that sarcolemmal nNOSμ normally is activated when muscles are
exercised and the nitric oxide (NO) produced attenuates local alpha-adrenergic
vasoconstriction, thereby optimizing muscle perfusion. We asked if this
protective mechanism (“functional sympatholysis”) is defective, causing
functional ischemia, in BMD patients with dystrophin mutations that disrupt
sarcolemmal targeting of nNOSμ and if the ischemia can be alleviated by boosting
NO-cGMP signaling with a phophodiesterase (PDE5A) inhibitor (tadalafil).
Methods:
We measured reflex vasoconstriction as decreased forearm muscle oxygenation (ΔHbO2)
with near infrared spectroscopy during lower body negative pressure (LBNP, -20
mmHg) at rest and during rhythmic handgrip (HG) at 20% maximum in 10 men with
BMD (age: 37 ± 3 years, mean ± SE) and 7 healthy age-matched male controls. Then,
men with BMD underwent a randomized placebo-controlled double-blind cross-over
trial of single-dose (20 mg) oral tadalafil (clinicaltrials.gov NCT01070511).
Results:
In healthy controls, reflex vasoconstriction was attenuated by 60 ± 8% during HG
(ΔHb02: -18 ± 1% vs. -7 ± 2%, P<.01; rest vs. HG), documenting
functional sympatholysis. In contrast, untreated BMD patients had no reflex
attenuation during HG (ΔHb02: -19 ± 2% vs. -17 ± 2%, P>0.1; rest vs.
HG), indicating functional ischemia. Most importantly, tadalafil fully restored
sympatholysis in patients with BMD: after tadalafil, reflex vasoconstriction was
attenuated by 52 ± 12% during HG (ΔHb02: -17 ± 2% vs. -9 ± 2%, P<0.01;
rest vs. HG) whereas placebo had no effect ([[unable to display character:
∆]]HbO2: -18 ± 2% vs. -17 ± 2%, P>0.1; rest vs. HG).
Conclusion:
These data show that tadalafil alleviates functional muscle ischemia in patients
with BMD and constitute the first-in-man proof-of-concept for PDE5A inhibition
as a putative new treatment strategy for this and possibly other forms of
muscular dystrophy accompanied by loss of sarcolemmal nNOSμ.
D) Phosphodiesterase 5A Inhibition Prevents Functional Muscle Ischemia in the Mdx Mouse Model of Duchenne/Becker Muscular Dystrophy
Liang Li, Ronald G Victor, Gail D Thomas, Cedars-Sinai Medical Ctr, Los Angeles, CA
The fatal muscle-wasting diseases Duchenne and Becker muscular dystrophy (DMD,
BMD) are caused by mutations in the gene encoding dystrophin, a cytoskeletal
protein that provides mechanical support and targets other proteins to the
sarcolemma including the muscle-specific variant of neuronal nitric oxide
synthase (nNOS). Loss of sarcolemmal nNOS impairs the normal paracrine effect of
muscle-derived NO to attenuate α-adrenergic vasoconstriction in exercising
muscle and renders the dystrophin-deficient muscles of boys with DMD and mdx
mice susceptible to ischemia. We hypothesized that treatment with a
phosphodiesterase 5A (PDE5A) inhibitor to reduce cGMP breakdown and enhance the
NO signal from residual cytosolic nNOS would prevent functional muscle ischemia
in mdx mice.
Methods:
Male C57BL6 or mdx mice (10-14 wks old) were anesthetized and instrumented to
measure arterial pressure and femoral artery blood flow responses to
intra-arterial delivery of norepinephrine (NE) into the resting and contracting
hindlimbs. Mdx mice were studied after acute treatment with vehicle or one of
two chemically distinct PDE5A inhibitors: the first generation, short-acting
inhibitor zaprinast (4, 8 mg/kg, ip) or the more potent, long-acting inhibitor
tadalafil (2, 4, 8, 16 mg/kg, po).
Results:
Compared to responses in the resting hindlimbs, NE-mediated vasoconstriction was
appropriately attenuated by 64 ± 6% in the contracting hindlimbs of C57BL6 mice
(n = 8), but was reduced only by 7 ± 10% in the contracting hindlimbs of
vehicle-treated mdx mice (n = 10; P<0.05 vs BL6), indicating functional ischemia.
This NE-induced ischemia in the mdx mice was prevented by PDE5A inhibition:
vasoconstrictor responses in the contracting hindlimbs were attenuated by 76 ±
5% with zaprinast (8 mg/kg; n = 10; P<0.05 vs vehicle) and by 69 ± 9% with
tadalafil (4 mg/kg; n = 6; P<0.05 vs vehicle).
Conclusion:
These data indicate that PDE5A inhibition prevents NE-induced ischemia in the
contracting muscles of mdx mice. A tadalafil dose of 4 mg/kg in the mdx mouse is
equivalent to 20 mg in humans, which is the highest FDA-approved dose used to
treat erectile dysfunction. These findings suggest a novel potential use for
tadalafil to ameliorate functional muscle ischemia in DMD and BMD patients.
E) A Prospective Cohort Study of Left Ventricular Noncompaction in Patients with Duchenne/Becker Muscular Dystrophy
Koichi Kimura, Katsu Takenaka, Aya Ebihara, Kansei Uno, Hiroyuki Morita, The Univ of Tokyo, Tokyo, Japan; Takashi Nakajima, Tetsuo Ozawa, Izumi Aida, Yosuke Yonemochi, Shinya Higuchi, Niigata Natl Hosp, Niigata, Japan; Yasufumi Motoyoshi, Takashi Mikata, Idai Uchida, Shimoshizu Natl Hosp, Chiba, Japan; Tadayuki Ishihara, Tetsuo Komori, Ruriko Kitao, Hakone Natl Hosp, Kanagawa, Japan; Masahiro Terashima, Cardiovascular Imaging Clinic Iidabashi, Tokyo, Japan; Tetsuya Nagata, Shin’ichi Takeda, Natl Ctr of Neurology and Psychiatry, Tokyo, Japan; Yukio Hiroi, Yutaka Yatomi, Kiyoshi Kubota, Ryozo Nagai, The Univ of Tokyo, Tokyo, Japan
Although studies have shown that neuromuscular diseases are most frequently
associated with LV noncompaction (LVNC), the prevalence of LVNC varies widely
and its prognostic impact remains controversial because most studies conducted
to date have been retrospective and lacked adequate controls.
METHODS:
Patients with Duchenne/Becker muscular dystrophy (DMD/BMD) aged 4-64 years
old (n=186) were evaluated by echocardiography at the study entry and
prospectively followed-up their subsequent courses. The study endpoint was
all-cause death and the presence of LVNC was blinded until the end of the study
(median follow-up: 46 months; interquartile range: 41-48 months).
RESULTS:
LVNC was diagnosed in 35 (19%) out of the 186 patients. There were no
significant differences in the baseline distributions of DMD/BMD type, age,
blood pressure, heart rate, medications administered, and follow-up duration
between patients with and without LVNC, with the exception of LV function. A
worse prognosis was observed (Figure) in patients with LVNC (13/35 died) than in
patients without LVNC (22/151 died). Multivariate Cox analysis revealed that
LVNC is an independent prognostic factor (relative hazard 2.7 [95% CI:
1.2-6.0]).
CONCLUSION:
LVNC was prevalent in patients with DMD/BMD. The presence of LVNC was
significantly associated with higher mortality rate. Neurologists and
cardiologists should pay more careful attention to the presence of LVNC.
OCTOBER
28 - (Annual Meeting American Neurological Association 2012) Fetal Stem Cells in Duchenne’s Muscular Dystrophy (DMD)
Nataliia S. Sych, Mariya O. Klunnyk, Olena V. Ivankova and Iryna G. Matiyaschuk; Kiev, Ukraine
Though modern methods can prolong life expectancy of DMD patients, but fetal stem cell therapy (FSCT) can be more promising. Goal of research was to study FSC efficacy in integrated treatment of DMD. Study included 27 male DMD patients aging 4-27. Diagnosis was confirmed clinically and on the basis of test results (high CPK and LDH), EMG, genetic testing, muscle biopsy. Functional capacity of patients was assessed on Total Functional Grade (TFG) scale, quality of life – on SF-36. Patients were examined before stem cell therapy treatment and 6 months after it. All patients underwent transplantation of hematopoietic and non-hematopoietic mesenchymal and ectodermal FSC harvested from germ layers of internal organs of 4-8 weeks old fetuses. FSCT resulted in improvements on TFG – from 8,5760,66 before the treatment to 7,7560,54 after the treatment, p<0,05. 0,5-point improvement was reported in 85,19% cases, 1-point – in 11,11%, and 1,5-point in 3,7%. FSCT also resulted in physical and psychoemotional improvement, higher self-esteem and spiritual realization. FSCT improved functional capacity and life quality of DMD patients, which proves that this method is very promising and should be researched and advanced.
12 - (Muscle Nerve, 46(5): 73-84, 2012) Inflammation in muscular dystrophy and the beneficial effects of non-steroidal anti-inflammatory drugs
Filippo Serra, Marco Quarta, Marta Canato Luana Toniolo Valeria De Arcangelis, Attilio Trotta, Lucia Spath, Lucia Monaco Carlo Reggiani Fabio Naro - Italy
Introduction: Glucocorticoids are the only drugs available for the treatment of Duchenne muscular dystrophy (DMD), but it is unclear whether their efficacy is dependent on their anti-inflammatory activity. Methods: To address this issue, mdx mice were treated daily with methylprednisolone and non-steroidal anti-inflammatory drugs (NSAIDs: aspirin, ibuprofen, parecoxib). Results: NSAID treatment was effective in ameliorating muscle morphology and reducing macrophage infiltration and necrosis. The percentage of regenerating myofibers was not modified by the treatments. The drugs were effective in reducing COX-2 expression and inflammatory cytokines, but they did not affect utrophin levels. The effects of the treatments on contractile performance were analyzed. Isometric tension did not differ in treated and untreated muscle, but the resistance to fatigue was decreased by treatment with methylprednisolone and aspirin. Conclusions: NSAIDs have a beneficial effect on mdx muscle morphology, pointing to a crucial role of inflammation in the progression of DMD.
SEPTEMBER
29 - (J Pediatr 2012;161:705-9) Attention Deficit Hyperactivity Disorder and Cognitive Function in Duchenne Muscular Dystrophy: Phenotype-Genotype Correlation
Marika Pane, Maria Elena Lombardo, Paolo Alfieri, Adele D’Amico, Flaviana Bianco, Gessica Vasco, Giorgia Piccini, Maria Mallardi, Domenico M. Romeo, Valeria Ricotti, Alessandra Ferlini, Francesca Gualandi, Stefano Vicari, Enrico Bertini, Angela Berardinelli, and Eugenio Mercuri - Italy
Objectives To assess attention deficit hyperactivity disorder (ADHD) in boys affected by Duchennemuscular dystrophy (DMD) and to explore the relationship with cognitive abilities and genetic findings. Study design Boys with DMD (n = 103; 4-17 years of age, mean: 12.6) were assessed using a cognitive test (Wechsler scales). Assessment of ADHD was based on the Diagnostic Statistical Manual, Fourth Edition, Text Revision criteria and on the long version of the Conners Parents and Teachers Rating Scales. Results ADHD was found in 33 of the 103 boys with DMD. Attention problems together with hyperactivity (17/33) or in isolation (15/33) were more frequent than hyperactivity alone, which was found in 1 patient. Intellectual disability (ID) was found in 27/103 (24.6%). Sixty-two of the 103 boys had no ID and no ADHD, 9 had ID but no ADHD, 14 had ADHD but no ID, and 18 had both. ADHD occurred more frequently in association with mutations predicted to affect Dp140 expression (exon 45-55) and in those withmutations predicted to affect all dystrophin product, including Dp71 (ie, those that have promoter region and specific first exon between exons 62 and 63 but were also relatively frequent). Conclusions Our results suggest that ADHD is a frequent feature in DMD. The risk of ADHD appears to be higher in patients carrying mutations predicted to affect dystrophin isoforms expressed in the brain and are known to be associated with higher risk of cognitive impairment.
14 - (Neuromuscular Disorders, 2012) Growth hormone treatment in boys with Duchenne muscular dystrophy and glucocorticoid-induced growth failure
Meilan M. Rutter, James Collins, Susan R. Rose, Jessica G. Woo, Heidi Sucharew, Hemant Sawnani, Kan N. Hor, Linda H. Cripe, Brenda L. Wong - USA
This study evaluated efficacy and safety of growth hormone treatment in Duchenne muscular dystrophy boys with glucocorticoid-induced growth failure. We reviewed 39 consecutive boys (average age 11.5 years; 32 ambulatory) treated with growth hormone for 1 year during a four-year period. Boys were on long-term daily deflazacort or prednisone (mean duration 5 ± 2.2 years; dosing regimen prednisone 0.75 mg/kg/day equivalent). Primary outcomes were growth velocity and height-for-age z-scores (height SD) at 1 year. Height velocity increased from 1.3 ± 0.2 to 5.2 ± 0.4 cm/year on growth hormone (p < 0.0001). Pre-growth hormone decline in height SD (−0.5 ± 0.2 SD/year) stabilized at height SD −2.9 ± 0.2 on growth hormone (p < 0.0001). The rate of weight gain was unchanged, at 2.8 ± 0.6 kg/year pre-growth hormone and 2.6 ± 0.7 kg/year at 1 year. Motor function decline was similar pre-growth hormone and at 1 year. Cardiopulmonary function was unchanged. Three experienced side effects. In this first comprehensive report of growth hormone in Duchenne muscular dystrophy, growth hormone improved growth at 1 year, without detrimental effects observed on neuromuscular and cardiopulmonary function
2 - Abstracts that will be presented in 17th World Muscle Society Meeting in Australia - October 2012
AUGUST
24 - (Muscle Nerve 46: 400–406, 2012) DOXYCYCLINE AMELIORATES THE DYSTROPHIC PHENOTYPE OF SKELETAL AND CARDIAC MUSCLES IN mdx MICE
JULIANO ALVES PEREIRA, ANA PAULA TIEMI TANIGUTI, CINTIA MATSUMURA, MARIA JULIA MARQUES, HUMBERTO SANTO NETO - Brasil
ABSTRACT: Introduction: We examined whether doxycycline,an
antibiotic member of the tetracycline family, improves the histopathology and
muscle function in mdx mice, the experimental model of DMD. Methods: Doxycycline
was administered for 36 days (starting on postnatal day 0) and for 9 months (starting
at 8 months of age) in drinking water. Histopathological, biochemical (creatine
kinase), and functional (forelimb muscle grip strength) parameters were
evaluated in limb, diaphragm, and cardiac muscle. Results: Doxycycline
significantly minimized the dystrophic phenotype of skeletal and cardiac muscles
and improved forelimb muscle strength. The drug protected muscle fibers against
myonecrosis and reduced inflammation. Furthermore, it slowed the progression of
myocardial fibrosis. Conclusions: This study provides evidence that
doxycycline may be a potential therapeutic agent for DMD.
11 -
Bodywide skipping of exons
45-55 in dystrophic mdx52 mice by systemic antisense delivery
JULY
21 - (Neuromuscular Disorders, 2012) Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy
A.L. Mayo, B.C. Craven, L.C. McAdamc,, W.D. Biggar - Canada
Quality of life in Duchenne Muscular Dystrophy (DMD) has
improved significantly with corticosteroid treatment. However,
corticosteroids decrease bone mass and increase vertebral fragility fracture
risk. We report on bone health in 39 boys with DMD on
long-term deflazacort (0.9 mg/kg/day) therapy. Bone health was defined by lumbar (L1–L4)
bone mineral density (BMD), long-bone
and/or symptomatic vertebral fractures. Lumbar BMD was reported as
height-adjusted Z-scores at initiation of deflazacort (T0) and
1–2 year intervals thereafter. Subcapital body fat percentage and ambulatory
status were recorded. At T0, 39 boys, aged 6.6 ± 1.6 years had height-adjusted
BMD Z-score 0.5 ± 0.8, and 23.5 ± 5.0% body fat. Height-adjusted Z-scores
remained stable with years of deflazacort until loss of ambulation and accrual
of body fat. Nine long-bone fractures occurred in eight ambulating boys, two
before
T0. Seven vertebral fractures occurred in six non-ambulatory boys after >5
years of deflazacort with height-adjusted Z-score
1.8 ± 0.7, and 47.8 ± 12% body fat. Bone health in DMD is influenced by disease
progression, corticosteroids, BMD Z-scores and
fat mass accumulation. Adjustments for short stature must be considered during
BMD interpretation. Percent body fat and ambulatory
status are useful bone health indicators. Routine use of height adjusted
Z-scores is advocated for use in routine clinical practice.
12 - (Clinical Nutrition, 2012) Resveratrol decreases inflammation and increases utrophin gene expression in the mdx mouse model of duchenne muscular dystrophy
Bradley S. Gordon, Diana C. Delgado Díaz , Matthew C. Kostek - USA
Background & aims: Duchenne muscular dystrophy (DMD)
is a lethal genetic disease with no cure. Reducing inflammation or increasing
utrophin expression can alleviate DMD pathology. Resveratrol can reduce inflammation
and activate the utrophin promoter. The aims of this study were to identify an
active dose of resveratrol in mdx mice and examine if this dose decreased inflammation
and increased utrophin expression.
Methods: 5-week old mdx mice were given 0, 10, 100, or 500 mg/kg of
resveratrol everyday for 10 days. Sirt1 was measured by qRT-PCR and used to
determine the most active dose. Muscle inflammation was measured by H&E staining,
CD45 and F4/80 immunohistochemistry. IL-6, TNFa, PGC-1a, and utrophin gene
expression were measured by qRT-PCR. Utrophin, Sirt1, and PGC-1a protein were
quantified by western blot.
Results: The 100 mg/kg dose of resveratrol, the most active dose,
increased Sirt1 mRNA 60 10% (p < 0.01), reduced immune cell infiltration 21 6%
(H&E) and 42 8% (CD45 immunohistochemistry (p < 0.05)), reduced macrophage infiltration
48 10% (F4/80 immunohistochemistry (p < 0.05)), and increased IL-6, PGC-1a, and
utrophin mRNA 247 77%, 27 17%, and 43 23% respectively (p 0.05).Utrophin, Sirt1,
and PGC-1a protein expression did not change.
Conclusions: Resveratrol may be a therapy for DMD by reducing inflammation.
JUNE
23 - (Endocrine Review, 2012, 33) Spine Bone Mineral Density (BMD) in Children with Duchenne Muscular Dystrophy Treated with Corticosteroids
Gisella Viterbo, Cristina Tau, Soledad Monges, Juliana Catagneto, and Alicia Belgorosky - Argentina
Reduced mobility and glucocorticoids as adjunctive therapy may cause osteoporosis and fractures in children with Duchenne muscular dystrophy (DMD). We analyzed in 21 boys (mean age ± SD: 11.6 ±2.7y, weight SDS: -0.27±1.16 (-2.70 to 2.65), and height SDS: -1.77±0.87) DMD after treatment with deflazacort (n=13) or methylprednisone (n=8) during 3.8±2.4 years (range, 0.4-8.75), vitamin D (300 to 2400 IU/day) and calcium supplement (0.13 to 1 g/day) and calcium intake by dairy products of 607±231 mg/day: Lumbar L2-L4 BMD measured by dual-energy X-ray absorptiometry (Lunar, Prodigy), serum calcium (Ca), phosphate (P), alkaline phosphatase (AP), PTH, urinary calcium and D-Pyridoline/creatinine (uD-Pyr). Ten patients were wheelchair-bound (mean age: 13.2 ±2.3 y, immobilization time was 2.04 ±1.9 y) while long bone (n=3) and vertebral crush fractures (n=7) patients were also observed. The cumulative corticosteroid dose was 27.5±19.8 g (range: 4.7-65.7). Mean BMD z score was -2.2±1.5, ranging from -5.9 to 0.4. BMD z score was <-2 in 43%, and between -1 and -2 in 38%. Mean BMD z score was inversely correlated with age (p<0.001), time of immobilization (p<0.001), duration of corticosteroid therapy (p<0.01) and cumulative dose of corticosteroids (p<0.001). Significantly lower BMD z score (-3.78±1.26) was observed in patients with, in comparison with those without vertebral fractures (-1.43±0.62, p<0.005). The number of fractures was positively correlated with cumulative corticosteroids dose. Ca, P, AP and PTH were within the normal range. Urinary calcium and uD-Pyr were increased in 38 % and 56 % of the patients, respectively. In conclusion long-term immobilization and treatment with high corticoid doses affect bone mineralization in children with DMD and might worsen the outcome of the disease.
23 - (Endocrine Review, 2012, 33) Low Bone Density and Effects of Alendronate Therapy in Patients with Duchenne Muscular Dystrophy
Caroline Houston, and Amal Shibli-Rahhal - USA
Background: Duchenne Muscular Dystrophy (DMD) is characterized by progressive muscle weakness that leads to loss of mobility by age 10 and death by age 20. Glucocorticoids are the mainstay of treatment, as they have been shown to slow disease progression. DMD patients develop low bone density as a result of glucocorticoid use and loss of mobility; however, little data exists to guide efforts towards screening for and treating low bone density in this population. We examined changes in bone density and the effects of alendronate therapy in DMD patients treated at the University of Iowa in the last decade.Methods: We conducted a retrospective cohort study of 39 patients with DMD for whom bone density data was available between December 2000 and September 2011. We examined baseline patient characteristics and bone density. We then assessed changes in bone density with alendronate therapy.Results: The mean patient age at the time of diagnosis was 3.5 years. Mean follow-up was 15.1 years. Ninety percent became wheelchair bound at a mean age of 10.6 years. Seventy-four percent were treated with glucocorticoids for an average period of 8.4 years. Seventy-two percent were treated with alendronate for an average period of 3.8 years.Patients received their first DXA scan an average of 8.5 years after diagnosis. Their bone density was low for their age, and the mean z-score was lower at the hip than at the lumbar spine (-3.27 versus -1.84, p < 0.0001). Patients treated with glucocorticoids received their first DXA scan sooner after diagnosis (7.7 versus 10.9 years), yet had lower z-scores at the lumbar spine (-2.04 versus -1.12, p = 0.0014). Among 8 patients who received multiple DXA scans prior to starting alendronate, the mean z-score at the hip declined from -2.85 to -3.04 (p = 0.70) over an average of 4.0 years. Among 18 patients treated with alendronate for an average of 3.0 years, mean z-scores increased at the hip (-3.31 to -3.25, p = 0.836) and lumbar spine (-2.09 to -1.80, p = 0.523).Conclusions: Patients with DMD develop low bone density that is more severe at the hip than the lumbar spine. Our patients were found to have low bone density 8.5 years after diagnosis and may have benefitted from earlier screening. Z-scores at the hip tended to decline with time prior to alendronate therapy. Z-scores at the hip and lumbar spine tended to improve with alendronate therapy. These trends were non-significant, likely due to small sample size.
23 - (Endocrine Review, 2012, 33) Preliminary Observations about Statin Therapy in Heart Transplant Recipients with Muscular Dystrophy
Ekta Singh, Sudhir Kushwaha, Walter K Kremers, and Yogish C Kudva - USA
Background: Statin use is standard practice after heart transplantation (HT) to prevent/delay cardiac allograft vasculopathy. HT recipients with muscular dystrophy (MD) represent a special cohort, since statins are generally avoided in myopathies.Methods: We reviewed the HT database at Mayo Clinic Rochester, MN from January 1996 through December 2011, and studied the medical record for documentation of muscle-related complications from statin use in HT recipients with MD.Results: 4 patients (all males) with MD underwent HT between Jan.1996 and Dec. 2011. Two (50%) patients had Becker's MD, one had Emery Dreifuss MD, and one had an unclassifiable, poorly defined MD. The median age at the time of HT was 29.5 years (25-36). All patients had minimal myopathic symptoms, and were fully functional prior to HT.All patients received pravastatin post-HT with the dose titrated to achieve an LDL-C goal of 100 mg/dL. The mean dose was 45 mg (20-80). One patient was changed to Simvastatin 40 mg due to suboptimal LDL-C control. The patients tolerated pravastatin well, without any functional impairment for a median duration of 54 months (13-96). The median LDL-C during therapy was 84 mg/dL (70-119).One patient developed progressive weakness 7 years after HT, and 1 year after changing treatment to simvastatin, prompting statin discontinuation, that was followed by mild improvement in symptoms. One patient experienced myalgias 2 years after HT, after pravastatin dose was increased to 40 mg. One patient reported myalgias on pravastatin 40 mg 8 years after HT, prompting its discontinuation that did not result in any symptomatic improvement. One patient reported no adverse events 1 yr after HT, on pravastatin 20 mg. There were no serious adverse effects, including rhabdomyolysis. EMG was not performed on any patient. Creatine kinase levels fluctuated widely, and did not correlate with patients' muscular symptoms.With the exception of 1 case of mild subclinical hypothyroidism, all patients had normal thyroid function. Three patients were on Sirolimus, and one on Tacrolimus-based immunosuppression. There was no reported use of medications interfering with statin metabolism. Conclusion: Long-term, medium-dose pravastatin therapy is well tolerated by patients with MD undergoing HT. Creatine kinase is not a reliable predictor of adverse muscle-related events. Since these patients are rare, a multi-center effort is required to study them.
16 - (Am J Cardiol 2012;110:98–102) Effects of Angiotensin-Converting Enzyme Inhibitors and/or Beta Blockers on the Cardiomyopathy in Duchenne Muscular Dystrophy
Laurence Viollet, Philip T. Thrush, Kevin M. Flanigan, Jerry R. Mendell, Hugh D. Allen - USA
Cardiomyopathy is a consequence of Duchenne muscular
dystrophy (DMD). Suggested treatments include angiotensin-converting enzyme (ACE)
inhibitors and/or blockers (BBs), but few large series have been reported. We
present 42 patients with DMD and
cardiomyopathy treated with an ACE inhibitor or an ACE inhibitor plus a BB.
Serial echocardiograms were recorded. Adequate ejection fractions (EFs) were
obtained at initiation of therapy (EF <55%). ACE inhibitor dosage adjustments
were made if a continued decrease in EF was noted. BB therapy was initiated when
average heart rate on Holter monitoring exceeded 100 beats/min. Data were
analyzed using paired t test and linear regression. Before ACE inhibition,
patients (n = 22) demonstrated decreased EF over time (r2= 0.23). At
ACE inhibitor therapy initiation, mean age was 14.1 + 4.6 years and mean
EF was 44.2 + 6.8%. BB therapy was used in 24 of 42 patients. Mean age
for the ACE inhibitor BB group was 15.7 + 3.9 years. The 2 groups showed
significant improvement (p <0.0001 for ACE inhibitor and ACE inhibitor plus BB)
compared to the pretherapy group. No significant differences were noted between
treatment groups. Patients with DMD demonstrated a gradual decrease in
myocardial function. Treatment with ACE inhibitor or ACE inhibitor plus BB
resulted in significant improvement compared to pretherapy. No significant
difference occurred in EF improvement between treatment groups. In conclusion,
treatment with ACE inhibitor or ACE inhibitor plus BB can delay progression of
cardiomyopathy.
10 - (American Journal of Pathology, 2012) Long-Term Rescue of Dystrophin Expression and Improvement in Muscle Pathology and Function in Dystrophic mdx Mice by Peptide-Conjugated Morpholino
Bo Wu, Peijuan Lu, Caryn Cloer, Mona Shaban, Snimar Grewal, Stephanie Milazi, Sapana N. Shah, Hong M. Moulton,Qi L. Lu - USA
Exon skipping is capable of correcting frameshift and nonsense mutations in Duchenne musculardystrophy (DMD). Phase 2 clinical trials in the United Kingdom and the Netherlands have reported induction of dystrophin expression in muscle of DMD patients by systemic administration of both phosphorodiamidate morpholino oligomers (PMO) and 2′-O-methyl phosphorothioate. Peptide-conjugated PMO (PPMO) offers significantly higher efficiency than PMO, with the ability to induce near-normal levels of dystrophin, and restores function in both skeletal and cardiac muscle. We examined 1-year systemic efficacy of PPMO targeting exon 23 in dystrophic mdx mice. The LD50 of PPMO was determined to be approximately 85 mg/kg. The half-life of dystrophin expression was approximately 2 months in skeletal muscle, but shorter in cardiac muscle. Biweekly injection of 6 mg/kg PPMO produced >20% dystrophin expression in all skeletal muscles and ≤5% in cardiac muscle, with improvement in muscle function and pathology and reduction in levels of serum creatine kinase. Monthly injections of 30 mg/kg PPMO restored dystrophin to >50% normal levels in skeletal muscle (but 15% in cardiac muscle), which was associated with greatly reduced serum creatine kinase levels, near-normal histology, and functional improvement of skeletal muscle. Our results demonstrate for the first time that regular 1-year administration of PPMO can be safely applied to achieve significant therapeutic effects in an animal model.
10 - (American Journal of Pathology, 2012) AMPK Activation Stimulates Autophagy and Ameliorates Muscular Dystrophy in the mdx Mouse Diaphragm
Marion Pauly, Frederic Daussin, Yan Burelle, Tong Li, Richard Godin, Jeremy Fauconnier, Christelle Koechlin-Ramonatxo, Gerald Hugon, Alain Lacampagne, Marjorie Quivy, Feng Liang, Sabah Hussain, Stefan Matecki, Basil J. Petrof - Canada
Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy). We hypothesized that pharmacological activation of AMP-activated protein kinase (AMPK), a master metabolic sensor in cells and on-switch for the autophagy-mitophagy pathway, would be beneficial in the mdx mouse model of DMD. Treatment of mdx mice for 4 weeks with an established AMPK agonist, AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside), potently triggered autophagy in the mdx diaphragm without inducing muscle fiber atrophy. In AICAR-treated mdx mice, the exaggerated sensitivity of mdx diaphragm mitochondria to calcium-induced permeability transition pore opening was restored to normal levels. There were associated improvements in mdx diaphragm histopathology and in maximal force-generating capacity, which were not linked to increased mitochondrial biogenesis or up-regulated utrophin expression. These findings suggest that agonists of AMPK and other inducers of the autophagy-mitophagy pathway can help to promote the elimination of defective mitochondria and may thus serve as useful therapeutic agents in DMD.
MAY
26 - (Clinical Neuropathology, 2012;123(6):e64) Improvements in muscle function and accidental falling in ataluren-treated patients with nonsense mutation dystrophinopathy (Duchenne/Becker musculardystrophy)
J. Barth, C.M. McDonald, E. Henricson, T. Abresch, A. Reha, G. Elfring, S. Peltz - USAIntroduction: Duchenne and Becker muscular dystrophy (DBMD) patients progressively lose muscle function and become susceptible to accidental falling. Ataluren is an investigational drug designed to overcome the deleterious effects of nonsense mutations, which are responsible for 13% of DBMD cases. In a pivotal trial in nonsense mutation DBMD (nmDBMD), ataluren 10, 10, 20 mg/kg provided clinical benefit as demonstrated by the primary endpoint of change in 6-min walk distance (6MWD), a measure of global patient function and endurance (p = 0.0584; post hoc analysis).
Objectives: Assess secondary endpoints including timed function tests and patient/caregiver-reported accidental falling, which are discrete measures of patient function.
Methods: Males (5 years old) with nmDBMD were randomized 1:1:1 to placebo; ataluren 10, 10, 20 mg/kg; or ataluren 20, 20, 40 mg/kg orally three times a day and evaluated every 6 weeks for 48 weeks.
Results: The study enrolled 174 subjects (median age 8 years, range 5–20 years; corticosteroid use 123/174 [71%]; median baseline 6MWD 360 m, range 75–554 m). Favorable trends in mean changes from baseline to week 48 for ataluren 10, 10, 20 mg/kg versus placebo were −2.40 s for stair ascend, −1.62 s for stair descend, and −1.35 s for 10-m walk/run. Over 48 weeks, accidental falling declined in the ataluren 10, 10, 20 mg/kg arm relative to placebo (odds ratio = 0.37, p = 0.0239; post hoc analysis). Data from all treatment arms will be presented.
Conclusion: Ataluren 10, 10, 20 mg/kg slowed the loss of muscle function and decreased the frequency of accidental falling relative to placebo. These important findings support the primary endpoint results showing a positive treatment effect for ataluren 10, 10, 20 mg/kg in this population.
20 - Corticosteroids and duchenne muscular dystrophy: Does earlier treatment really matter?
14 - (Muscle & Nerve, 2012) EARLY CORTICOSTEROID TREATMENT IN 4 DUCHENNE MUSCULAR DYSTROPHY PATIENTS: 14-YEAR FOLLOW-UP
LUCIANO MERLINI, MONIA GENNARI, ELISABETTA MALASPINA, ILARIA
CECCONI, ANNARITA ARMAROLI,
SAVERIO GNUDI, BERIL TALIM, ALESSANDRA FERLINI, ALESSANDRO CICOGNANI, EMILIO
FRANZONI - Italy
ABSTRACT: Introduction: Corticosteroid treatment is the standard of care in Duchenne muscular dystrophy (DMD), but the optimal age to initiate treatment and dosage pattern remain a matter of discussion. Methods: We performed a long-term study of alternate-day corticosteroids in five 2- to 4-year-old DMD patients. The primary outcome measure was prolongation of the ability to walk. Results: One patient lost ambulation at age 10. Four patients, aged 16 to 18 were fully ambulant, and 3 of them could still climb stairs. Respiratory function was moderately reduced in 2. Left ventricular ejection fraction was > 45%. Short stature and delayed puberty were the most relevant side effects. Although the negative impact of corticosteroid treatment on growth rate remained their major concern, parents and patients stated that they preferred corticosteroid therapy. Conclusions: Long-term corticosteroid treatment is effective in prolonging function but not in recovering lost function, and its early use seems appropriate.
6 - (Cardiovasc Res, May 2012) Bradykinin restores left ventricular function, sarcomeric protein phosphorylation and e/nNOs levels in dogs with Duchenne muscular dystrophy cardiomyopathy
Jin Bo Su, Olivier Cazorla, Stéphane Blot, Nicolas Blanchard-Gutton, Younss Ait Mou, Inès Barthélémy, Lucien Sambin, Carolina Carlos Sampedrano, Vassiliki Gouni, Yves Unterfinger, Pablo Aguilar, Jean-Laurent Thibaud, Alain Bizé, Jean-Louis Pouchelon, Hubert Dabiré, Bijan Ghaleh, Alain Berdeaux, Valérie Chetboul, Alain Lacampagne, and Luc Hittinger - France
Aims Cardiomyopathy is a lethal result of Duchenne muscular dystrophy (DMD) but its characteristics remain elusive. The golden retriever muscular dystrophy (GRMD) dogs produce DMD pathology and mirror DMD patient’s symptoms including cardiomyopathy. We previously showed that bradykinin slows the development of pacing-induced heart failure. Therefore, the goals of this research were to characterize dystrophin-deficiency cardiomyopathy and to examine cardiac effects of bradykinin in GRMD dogs
Methods and results At baseline, adult GRMD dogs had reduced fractional shortening (28±2% vs 38±2% in control dogs, p<0.001) and left ventricular (LV) subendocardial dysfunction leading to impaired endo-epicardial gradient of radial systolic velocity (1.3±0.1 cm/s vs 3.8±0.2 cm/s in control dogs, p<0.001) measured by echocardiography. These changes were normalized by bradykinin infusion (1 µg/min, 4 weeks). In isolated permeabilized LV subendocardial cells of GRMD dogs, tension-calcium relationships were shifted downward and force-generating capacity and transmural gradient of myofilament length-dependent activation were impaired compared with control dogs. Concomitantly, phosphorylation of sarcomeric regulatory proteins and levels of endothelial and neuronal nitric oxide synthase in LV myocardium were significantly altered in GRMD dogs. All these abnormalities were normalized in bradykinin-treated GRMD dogs
Conclusions Cardiomyopathy in GRMD dogs is characterized by profound LV subendocardial dysfunction, abnormal sarcomeric protein phosphorylation and impaired endothelial and neuronal nitric oxide synthase, which can be normalized by bradykinin treatment. These data provide new insights into pathophysiological mechanisms accounting for DMD cardiomyopathy and open new therapeutic perspectives.
6 - (Cell Stem Cell, Volume 10, Issue 5, 4 May 2012, Pages 610–619) Human ES- and iPS-Derived Myogenic Progenitors Restore DYSTROPHIN and Improve Contractility upon Transplantation in Dystrophic Mice
Radbod Darabi, Robert W. Arpke, Stefan Irion, John T. Dimos, Marica Grskovic, Michael Kyba,Rita C.R. Perlingeiro - USA
A major obstacle in the application of cell-based therapies for the treatment of neuromuscular disorders is obtaining the appropriate number of stem/progenitor cells to produce effective engraftment. The use of embryonic stem (ES) or induced pluripotent stem (iPS) cells could overcome this hurdle. However, to date, derivation of engraftable skeletal muscle precursors that can restore muscle function from human pluripotent cells has not been achieved. Here we applied conditional expression of PAX7 in human ES/iPS cells to successfully derive large quantities of myogenic precursors, which, upon transplantation into dystrophic muscle, are able to engraft efficiently, producing abundant human-derived DYSTROPHIN-positive myofibers that exhibit superior strength. Importantly, transplanted cells also seed the muscle satellite cell compartment, and engraftment is present over 11 months posttransplant. This study provides the proof of principle for the derivation of functional skeletal myogenic progenitors from human ES/iPS cells and highlights their potential for future therapeutic application in muscular dystrophies.
6- (B47 INTENSIVE CARE UNIT PHYSIOTHERAPY AND WEANING: MIND OVER MUSCLE?) Audit Of The Cardiac Management Of Patients With Duchenne Muscular Dystrophy On Ventilatory Support
L. O'Brien , M. Avendano , R. Goldstein , R. A.
Evans - Canada
Introduction. The life expectancy of patients with Duchenne Muscular
Dystrophy (DMD) has increased, from the 2 decade to the 5 decade, in part due to
improved ventilatory support. However, cardiomyopathy is common and is projected
to increase as a cause of death. Current international guidelines recommend an
annual assessment of cardiac function in adult patients with DMD and initiation
of appropriate pharmacological treatment (1). We conducted an audit of the
current cardiac management of patients with DMD with respiratory failure under
the care of West Park Healthcare Centre, Toronto, Canada.
Methods: We reviewed the medical charts of patients with DMD requiring
ventilatory support. Patients were included if they had respiratory follow up
within the last three years and were alive at the time of the audit. Patient
demographics and ventilatory status were recorded. Cardiac management was
recorded including date of the last documented electrocardiogram (ECG),
echocardiogram (ECHO), cardiology review and pharmacological management. The ECG
and ECHO reports were reviewed.
Results: 32 patients with DMD (31 male, mean [SD] age 31 [7] yrs) met the
inclusion criteria and their medical notes were retrieved. 7/32 patients were
living in a chronic assisted ventilation unit and 25/32 were cared for at home.
18/32 required continuous ventilation and 14/32 required nocturnal ventilation
only. 17/32 patients were ventilated via a tracheostomy. 10/32 and 6/32 patients
had a documented ECG and ECHO respectively, within the last year. 26/32, 22/32,
and19/32 patients had previous documentation of an ECG, ECHO, and had been
assessed by a cardiologist, respectively. Out of the available results, 21/25
patients had an abnormal ECG and 15/20 patients had demonstrable left
ventricular dysfunction (Grade II: 6, Grade III: 7, Grade IV: 2). 16/32 were
prescribed either an Angiotensin Converting Enzyme inhibitor or an Angiotensin
Receptor Blocker, 11/32 were prescribed Beta-Blockers, 4/32 were prescribed
digoxin and 1/32 was prescribed spironolactone.
Conclusions: Although cardiac function had been assessed in over two
thirds of patients with DMD, few were undergoing annual cardiac assessments. A
new policy of closer monitoring is suggested with a repeat audit in two years.
This audit highlights the need for respiratory physicians to refer these
patients for annual cardiology review in line with current guidance.
(1) Bushby K et al. Lancet Neurol 2010; 9(1):77-93
APRIL
22 - RESEARCH THAT WILL BE PRESENTED IN ANNUAL MEETING OF AMERICAN SOCIETY OF GENE THERAPY 2012, MAY 2012
14 - EXERCISE AND DUCHENNE
MUSCULAR DYSTROPHY: WHERE WE HAVE BEEN AND WHERE WE NEED TO GO
6 - UPDATE 2-AVI muscular dystrophy results fail to impress
6 - Treatment hope for muscular dystrophy
4 - (Experimental Biology 2012) Acute phosphodiesterase inhibition improves functional muscle ischemia in patients with Becker muscular dystrophy
Elizabeth Anne Martin1, Ashley E Walker1, Bryan L Scott1, Teresa C Malott1, Nirmal Singh1, Swaminatha V Gurudevan1, Jimmy Johannes1, Robert M Elashoff2, Gail D Thomas1 and Ronald G Victor1
1
The Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA
2
Biomathematics, UCLA, Los Angeles, CA
oss of sarcolemmal nitric oxide synthase (nNOS) engenders ischemia of exercising dystrophin-deficient muscles of mdx mice and boys with Duchenne muscular dystrophy. We tested if muscle ischemia also occurs in Becker muscular dystrophy (BMD), a milder disease often caused by dystrophin mutations involving the nNOS binding site, and is improved by tadalafil, a phosphodiesterase (PDE5A) inhibitor that enhances cGMP/NO signaling. We measured reflex vasoconstriction (decreased forearm muscle oxygenation [Hb02, near infrared spectroscopy] during lower body negative pressure [LBNP]) at rest and during rhythmic handgrip (HG) in 5 male controls (Ctrls) and 10 men with BMD who underwent a placebo-controlled cross-over trial of single-dose (20 mg) tadalafil. At baseline, HG greatly attenuated vasoconstriction in Ctrls (Hb02:–393±89 vs. –91±40 units, p<.01; rest vs. HG) but caused no attenuation in BMD (–381±45 vs. – 374±46). Tadalafil markedly improved ischemia in BMD (Hb02:– 439±70 vs. –230±54, rest vs. HG; p=0.014) whereas placebo had no effect. These data provide the first evidence in man that PDE5A inhibition can improve blood flow regulation in dystrophin-deficient skeletal muscle. Funded by MDA 201149.
4 - (Experimental Biology 2012) Early Anatomical Identification Markers for Duchenne Muscular Dystrophy in a Subadult Subject
Jasmine H. Harris1, Ellen Godwin2 and Samuel Marquez3
1
College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY
2 Department of Orthopaedic Surgery & Rehabilitation Medicine, SUNY
Downstate Medical Center, Brooklyn, NY
3 Department of Cell Biology, SUNY Downstate Medical Center,
Brooklyn, NY
Duchenne Muscular Dystrophy (DMD) readily affects gait and posture in subadult populations afflicted with the disease. This study used instrumented motion analysis (IMA) to identify how gait and posture changes respond to DMD disease. 3-D motion analysis was performed with the Vicon Motion Capture System on a 5-year-old boy suspected with DMD. Thirty-nine reflective markers were placed on specific anatomical landmarks according to the Plug-in-Gait Model used with the Vicon system. The child walked across the 25 feet gait analysis laboratory for 10 trials. A single representative trial was selected for analysis. Kinematic parameters of gait were compared to those of a typically developing child. IMA identified specific changes in joint kinematics in the child with DMD as compared to the typically developing child. Changes include: increase in anterior pelvic tilt and hip flexion in swing, genu recurvatum in stance, plantar flexion on initial contact with ground, and lack of dorsiflexion in swing. These gait deviations are commonly found in boys with DMD. The results show the ability to identify these changes translating in the early diagnosis of DMD as they represent a specific pattern of walking that is related to the progression of weakness observed. Identification of anatomical gait deviations can assist in the development of treatment interventions to assist the child to be ambulant as long as possible.
4 - (Experimental Biology 2012) Resveratrol decreases inflammation and oxidative stress in the mdx mouse model of duchenne muscular dystrophy
Bradley Scott Gordon, Patti Weed, Emily Learner, Drew Schoenling and Matthew C Kostek
Exercise Science, University of South Carolina, Columbia, SC
Duchenne Muscular Dystrophy (DMD) is a genetic disease characterized by muscle damage, oxidative stress, chronic inflammation, and fibrosis. Resveratrol (RES) is an antioxidant and anti-inflammatory. We have shown that RES improves muscle function in the mdx mouse model of DMD, and others have shown resveratrol decreases fibrosis and oxidative stress in older mdx mice. However, its effect on pathology in young mdx mice is unknown. The purpose of this study was to investigate the effect of resveratrol on muscle pathology in young mdx mice. RES (100 mg/kg) or vehicle was administered to 4–5 week old mdx mice everyday for 10 days or every other day for 8 weeks. Muscle fiber integrity, inflammation, and oxidative stress were assessed by H&E staining and 4-HNE content. Total inflammation was reduced 21 ± 6% (p < 0.05) after 10 days of treatment with no change in oxidative stress. After 8 weeks of RES treatment, centrally located nuclei were reduced 12 ± 4% (p < 0.05), oxidative stress measured through 4-HNE content decreased 2 ± 0.13 fold (p < 0.05), and total inflammation and fibrosis did not change. We conclude that RES enhances muscle membrane integrity by reducing inflammation during the peak pathological period and long term oxidative stress. Therefore, resveratrol could be a treatment for boys with DMD. This project was funded by The Center for Alternative Medicine at The University of South Carolina School of Medicine.
4 - (Experimental Biology 2012) Mdx mice have a defect in autophagy that is restored by rapamycin-loaded nanoparticle treatment
Allison Jinquan Li1, Kristin P. Bibee1, Jon N. Marsh1, Conrad C. Weihl2 and Samuel A. Wickline1
1
Department of Medicine, Division of Cardiology, Washington University in St.
Louis, St. Louis, MO
2 Department of Neurology, Washington University in St. Louis, St.
Louis, MO
Duchenne Muscular Dystrophy (DMD) is genetic disorder caused by mutations in dystrophin, a cytoskeletal protein in muscles, leading to progressive muscle wasting and ultimately death in the second or third decade of life. The current standard of care for DMD patients is corticosteroid therapy which slows down the natural progression of the disease but causes unwanted side effects. Our lab’s previous studies of therapeutics in an in vivo DMD model has demonstrated that mdx mice treated with rapamycin-loaded nanoparticles showed an increase in strength that was not observed with oral rapamycin treatment. Because rapamycin is known to induce autophagy, we assayed for autophagy in mdx mice treated with rapamycin-loaded nanoparticles. Western blot analysis of LC3B-II, the processed form of a protein used in autophagy, suggests that there is a previously unknown defect in autophagy in mdx mice, as shown by a lack of LC3 3B-II accumulation after blockade of autophagic flux by colchicine (Fig. 1A). Rapamycin nanoparticle treatment rescues autophagy to levels comparable to the control (Fig. 1B), suggesting that defective autophagy may contribute to the physical manifestations of muscular dystrophy in mdx mice and that restoration to normal levels may lead to the observed strength increase. Supported by NIH grant (R01 AR056223 to S.A.W.)
4 - (Experimental Biology 2012) Acute phosphodiesterase inhibition ameliorates functional muscle ischemia in dystrophin-deficient mdx mice
Liang Li, Ronald G Victor and Gail D Thomas
The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
We previously have shown that the loss of sarcolemmal nitric oxide synthase (nNOS) in the dystrophin-deficient muscles of mdx mice and boys with Duchenne muscular dystrophy (DMD) renders the diseased muscles susceptible to ischemia during exercise. We now are extending this finding to men with Becker muscular dystrophy (BMD). We therefore hypothesized that treatment with a phosphodiesterase (PDE) inhibitor to reduce cGMP breakdown and enhance the NO signal from residual nNOS would prevent functional muscle ischemia. To test this, we compared norepinephrine (NE)-mediated vasoconstriction in resting and contracting hindlimbs of mdx mice after acute treatment with vehicle or a PDE inhibitor (tadalafil, 8 mg/kg; zaprinast, 4 mg/kg). In vehicle-treated mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired as shown by similar decreases in femoral vascular conductance in contracting vs resting hindlimbs (attenuation ratio = 0.87 ± 0.11; n = 10). NE-induced ischemia in the contracting hindlimbs was partially reversed in mice treated with the selective PDE5A inhibitor tadalafil (0.61 ± 0.06; n = 6; P < 0.05 vs vehicle) or the nonselective PDE inhibitor zaprinast (0.46 ± 0.10; n = 7; P < 0.05 vs vehicle). The effect of PDE inhibition to ameliorate functional muscle ischemia in mdx mice suggests a novel potential use for the treatment of DMD/BMD patients. Supported by MDA, 201149.
4 - (Experimental Biology 2012) Dietary quercetin supplementation alleviates disease related muscle injury in dystrophic muscle
Katrin Hollinger1, Elizabeth Snella1, R. Andrew Shanely2 and Joshua T. Selsby1
1
Animal Science, Iowa State University, Ames, IA
2 Human Performance Laboratory; North Carolina Research Campus,
Appalachian State University, Kannapolis, NC
Duchenne muscular dystrophy is the most common, fatal, X-linked muscle disease and is modeled by the mdx mouse. Dystrophic muscle shows signs of progressive necrosis and fibrosis leading to a loss of muscle function. Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) up-regulation has been shown to alleviate some aspects of dystrophic pathology. Quercetin (QCN), a natural polyphenolic compound derived from foods such as red apples and red onions, is a potent sirtuin 1 (SIRT1) activator capable of entering muscle cells via oral delivery. SIRT1, in turn, activates PGC-1α by deacetylation. To determine the extent to which a diet containing QCN could alter the progression of disease related muscle injury 3 mo old mdx mice were fed a diet containing 0% or 0.2% QCN for 6 mo, sacrificed, and diaphragms removed. Control and treated mice ate similar amounts of food and grew at a similar rate during the study period. Dietary QCN reduced the number of extracellular nuclei/mm2 by 37% (p<0.05). The number of muscle cells/mm2 was increased by 20% (p<0.05) and muscle cells with centralized nuclei were reduced by 33% (p<0.05) in diaphragms from treated animals compared to control. Fibrosis was similar between groups. These data suggest that dietary QCN is beneficial to dystrophic muscle and warrants greater exploration as a potential therapeutic agent. Partially supported by the Martin Fund.
4 - (Experimental Biology 2012) PCG-1 alpha over-expression rescues dystrophic muscle by modifying gene expression
Katrin Hollinger, Drance Rice, Elizabeth Snella and Joshua T Selsby
Animal Science, Iowa State University, Ames, IA
Duchenne muscular dystrophy is caused by the inability to produce a functional dystrophin protein. Typically, diagnosis is in the preschool years due to locomotor deficits, indicating muscles have already been damaged by the disease. Thus, it is critical that treatments be able to rescue muscle from further deterioration. We have shown that Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) gene transfer rescues dystrophic muscle from disease related decline. To better understand the mechanism underlying the benefits of PGC-1α over expression, 3 wk old mdx mice were injected in one hind limb with null AAV6 (empty capsid) and in the other with an AAV6 driving expression of PGC-1α. At six weeks of age solei were collected. Utrophin protein expression was measured by immunohistochemistry and was increased nearly 3-fold (p<0.05) in PGC-1α over-expressing limbs compared to control limbs. PCR arrays were performed to identify genes regulated by PGC-1α over-expression. In the PGC-1α treated soleus expression of genes associated with the dystrophinglycoprotein complex (DGC) were increased by 40–92% (p<0.05), oxidative metabolism by 35–87% (p<0.05), muscle repair by 56–92% (p<0.05), and structural components by 20–300% (p<0.05). These data indicate that PGC-1α-mediated rescue of dystrophic muscle is accomplished through numerous contributing mechanisms. Partially supported by CIAG.
4 - (Experimental Biology 2012) The effect of N-acetylcysteine on contractile function and protein-thiol oxidation in skeletal muscles of mdx mice
Gavin Jon Pinniger1, Evanna Binti Assan1, Jessica Terrill2 and Peter Arthur3
1
Physiology, University of Western Australia, Crawley, Australia
2 Anatomy and Human Biology, University of Western Australia,
Crawley, Australia
3 Biochemistry, University of Western Australia, Crawley, Australia
Duchenne Muscular Dystrophy (DMD) is a fatal X-linked recessive disease characterized by severe muscle weakness. We hypothesized that oxidation of skeletal muscle proteins such as myosin contributes to dystrophic muscle weakness seen in DMD boys and dystrophic mdx mice and that this muscle weakness will be attenuated by treatment with the antioxidant N-acetylcysteine (NAC). Six week old mdx mice and non-dystrophic, C57 mice were treated with 2% NAC in drinking water for six weeks and compared to untreated mdx and C57 mice. Grip strength and body weight were measured weekly during the treatment period. After six weeks of treatment, the 12 week old mice were anaesthetized (sodium pentobarbitone; 40 mg/kg; IP) and the extensor digitorum longus (EDL) muscles were excised for analysis of contractile function and protein thiol-oxidation. n mdx mice, NAC treatment significantly increased normalized grip strength and maximum specific force in isolated EDL muscles (NAC = 13.1 ± 1.2 N/cm2; Untreated = 9.8 ± 0.8 N/cm2, p<0.05), and significantly reduced myosin protein-thiol oxidation (NAC = 10.6 ± 0.8 %; Untreated = 13.7 ± 0.8 %, p<0.05). In non-dystrophic C57 mice, NAC treatment significantly increased normalized grip strength by 36%, but had no significant effect on maximum specific force or myosin protein-thiol oxidation in EDL muscles.
4 - (Experimental Biology 2012) Treatment with a nitric oxide-donating NSAID counteracts functional muscle ischemia in dystrophin-deficient mdx mice
Gail D Thomas1, Angela Monopoli2, Claudio De Nardi2, Ennio Ongini2 and Ronald G Victor1
1
The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
2 NicOx Research Institute, Bresso, Italy
he dystrophin-deficient muscles of boys with Duchenne muscular dystrophy (DMD) and mdx mice, a model of DMD, are susceptible to ischemia during exercise due to loss of neuronal nitric oxide synthase (nNOS) from the sarcolemma. We hypothesized that treatment with a NO-donating drug would compensate for nNOS deficiency and counteract functional muscle ischemia. We fed mdx mice a standard diet containing 1% soybean oil (vehicle) or a low (15 mg/kg) or high (45 mg/kg) dose of a NO-releasing derivative of the NSAID flurbiprofen (n = 12/group). After 1 month of treatment, we compared vasoconstrictor responses to intra-arterial norepinephrine (NE) in resting and contracting hindlimbs. In vehicle-treated mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired as shown by similar decreases in femoral vascular conductance in contracting vs resting hindlimbs (attenuation ratio = 0.88 ± 0.03). NE-induced ischemia was also seen in the contracting hindlimbs of mice treated with low dose drug (0.92 ± 0.04; P > 0.05 vs vehicle), but was markedly attenuated in mice treated with high dose drug (0.22 ± 0.03; P < 0.05 vs vehicle or low dose). The beneficial effect of the high dose was maintained with treatment up to 3 months. These data demonstrate a robust anti-ischemic effect of a NO-donating drug in mdx mice and suggest a potential use in the treatment of DMD patients. Supported by NicOx, 801130.
4 - (Experimental Biology 2012) Administration of recombinant adeno-associated virus vector to the diaphragm through direct intramuscular injection
Ashley J Smuder1, Darin J Falk2, W Bradley Nelson1 and Scott K Powers1
1
Department of Applied Physiology and Kinesiology, University of Florida,
Gainesville, FL
2 Department of Pediatrics, University of Florida, Gainesville, FL
Ventilatory insufficiency due to impaired diaphragm function is the leading cause of morbidity and mortality in many conditions (e.g. muscular dystrophy). Currently, pharmacological inhibitors and genetically modified animals are used to study many diseases affecting the diaphragm. However, these methodologies are problematic due to the occurrence of off-target effects and possible consequences of life-long genetic alterations. Further, conventional approaches to gene transfection (i.e., plasmid injection and electroporation) are not possible due to the size and location of the diaphragm and thus alternative methods are needed to alter gene expression. Therefore, we have developed a method for the delivery of recombinant adeno-associated virus vectors (rAAV) to the rat diaphragm via direct intramuscular injection. We hypothesized that by directly injecting rAAV we could selectively target diaphragm muscle fibers and establish a novel animal model for studying signaling pathways and also provide a strategy for effectively using gene therapy to rescue the diaphragm in disease states. Our results demonstrate that the morphology of the rat diaphragm is sufficient to allow direct injection and provide support for the use of rAAV as an intervention to study the diaphragm during conditions that promote diaphragm dysfunction.
MARCH
24 - (Annals of Neurology, 2012) Evidence Based Path to Newborn Screening for Duchenne Muscular Dystrophy
Jerry R Mendell, Chris Shilling, Nancy D. Leslie, Kevin
M Flanigan, Roula al-Dahhak, Julie Gastier-Foster, Kelley
Kneile, Diane M. Dunn, Brett Duval, Alexander Aoyagi, Cindy Hamil, Maha
Mahmoud, Kandice Roush, Lauren Bird,
Chelsea Rankin, Heather Lilly, Natalie Street, MS, Ram Chandrasekar,
Robert B. Weiss - USA
Background: Creatine kinase (CK) levels are increased
on dried blood spots in newborns related to the birthing process. As a marker
for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in
false-positive testing. In this report we introduced a two-tier system using the
dried blood spot to first assess CK with follow up DMD gene testing.
Methods: A fluorometric assay based upon the enzymatic
transphosphorylation of ADP to ATP was used to measure CK activity. Preliminary
studies established a population-based range of CK in newborns using 30,547
de-identified anonymous dried blood spot samples. Mutation analysis used genomic
DNA extracted from the dried blood spot followed by whole genome
amplification with assessment of single/multi-exon deletions/duplications in the
DMD gene using multiplex ligation-dependent probe amplification.
Results: DMD gene mutations (all exonic deletions) were found in six of
37,649 newborn male subjects, all of whom had CK levels > 2000 U/L. In three
newborns with CK >2000 U/L in whom DMD gene abnormalities were not found, we
identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB,
and FKRP.
Conclusions: A two-tier system of analysis for newborn screening for DMD
has been established. This path for newborn screening fits our health care
system, minimizes false%positive testing, and uses predetermined levels of CK on
dried blood spots to predict DMD gene mutations.
24 - Lung Volume Recruitment Slows Pulmonary Function Decline in Duchenne Muscular Dystrophy
18 - (Growth Hormone & IGF Research, 2012) Therapeutic potential of PEGylated insulin-like growth factor I for skeletal muscle disease evaluated in two murine models of muscular dystrophy
Stefan M. Gehrig, Chris van der Poela, Andreas Hoeflich, Timur Naim, Gordon S. Lynch, Friedrich Metzger - Australia
Objective: Duchenne muscular dystrophy (DMD) is a fatal
monogenetic disease with affected males displaying severe and progressive muscle
wasting and weakness eventually leading to premature death. Possible therapeutic
benefits of insulin-like growth factor I (IGF-I) have been studied extensively in
various models of muscle disease and DMD with IGF-I as a mediator of improved
skeletal muscle regeneration by enhancing myoblast proliferation and
differentiation.
Design: We tested the efficacy of a novel IGF-I analogue, a polyethylene glycol
modified IGF-I (PEG-IGF-I), to ameliorate the pathophysiology of muscular
dystrophy in two mouse models of DMD. We used mdx mice which lack dystrophin (as
in DMD) but exhibit only a relatively mild phenotype, and the dko mouse which is
a transgenic model lacking utrophin in addition to dystrophin, and which
exhibits a more severe, lethal phenotype like that in DMD.
Results: In young mdx mice, twice-weekly PEG-IGF-I s.c. injections for 6 weeks
protected the diaphragm muscle against fatigue and the tibialis anterior (TA)
muscle against contraction-induced injury. However, this beneficial effect of
PEG-IGF-I was less pronounced in mdx mice when treatment was initiated later in
adulthood. In severely affected dko mice PEG-IGF-I treatment did not affect
pathophysiological parameters including animal survival.
Conclusions: These data suggest a therapeutic benefit with PEG-IGF-I treatment
only in mild muscle pathologies, since its potential to ameliorate the
pathophysiology in models of severe muscular dystrophies was limited. Treatment
should be initiated only for mild muscle pathologies if functional benefits are
to be realised and therefore may be relevant as a short-term therapy to hasten
the functional repair of otherwise healthy muscles after injury.
10 - (Neuromuscular Disorders, 2012) Normal height and weight in a series of ambulant Duchenne muscular dystrophy patients using the 10 day on/10 day of prednisone regimen
K. ten Dam, I.J.M. de Groot, C. Noordam, N. van Alfen, J.C.M. Hendriks e L.T.L. Sie - The Netherlands
Prednisone treatment delays the progressive course of
Duchenne muscular dystrophy. The aim of this study was to determine the
influence of the 10 day on/10 day of treatment on height and weight. We
retrospectively reviewed the growth and weight charts of Duchenne patients born
between 1988 and 2006 (patients between 4 and 9 years old, being able to walk in
the home situation). Forty-seven patients were eligible for further analysis and
divided into two groups: 33 patients treated with prednisone and 14
non-prednisone treated patients. Results of a median follow-up of 57 months
(range 27–146) are described. By using linear mixed models this study
demonstrates that height and body mass index in prednisone-treated patients with
10/10 regimen are not significantly diferent compared to untreated patients. We
cautiously conclude that the alternating prednisone regimen has no apparent side
effects on weight and height in the ambulatory phase of Duchenne muscular
dystrophy.
10 - (Neurology, 2012) Pentoxifylline as a rescue treatment for DMD. A randomized double-blind clinical trial
D.M. Escolar, A. Zimmerman, T. Bertorini, P.R. Clemens, A.M. Connolly, L. Mesa, K. Gorni, A. Kornberg, H. Kolski, N. Kuntz, Y. Nevo, C. Tesi-Rocha, K. Nagaraju, S. Rayavarapu, L.P. Hache, J.E. Mayhew, J. Florence, F. Hu, A. Arrieta, E. Henricson, R.T. Leshner, and J.K. Mah
Objective: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).
Methods: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (∼20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test
Results: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs
Conclusion: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.
Classification of evidence: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD
3 - Research that will be presented in 2012 Annual Meeting of American Academy of Neurology
3 - (Acta Paediatrica, 2012, 101(4): 424-32) Bone mass development in patients with Duchenne and Becker muscular dystrophies: a 4-year clinical follow-up
Ann-Charlott Söderpalm ([email protected]), Per Magnusson,, Anne-Christine Åhlander, Jón Karlsson, Anna-Karin Kroksmark,Már Tulinius, Diana Swolin-Eide - Sweden
Aim: To investigate the longitudinal development of
bone mass in patients with Duchenne and Becker muscular dystrophies and to study
the impact of muscle strength and motor function on bone mass in these patients.
Methods: Eighteen patients with Duchenne muscular dystrophy (2.3–19.7
years at baseline) and six patients with the milder Becker muscular dystrophy
(10.8–18.9 years at baseline) were followed during a 4-year period with respect
to areal bone mineral density (BMD), motor function and muscle strength.
Results: Greater bone mineral accretion was observed in the Becker
patient group compared with the age-related Duchenne group above 10 years of
age, and the older patients with Duchenne experienced decreased femoral neck BMD
during the study period. In the study group, significant correlations were found
between BMD in the lower extremities and muscle function parameters.
Conclusions: The differences in BMD between patients with Duchenne and
Becker as well as between different bone measurement sites demonstrated in the
present study point out the importance of preserving muscle strength and motor
function in patients with muscular dystrophy. Moreover; it highlights the value
of performing region-specific analysis of the bone quality in these patients.
FEBRUARY
12 - Restoration of dystrophin expression using the Sleeping Beauty transposon
JANUARY
30 - (Biochemical and Biophysical Research Communications, 2012) Restoration of Muscle Fibers and Satellite Cells after Isogenic MSC Transplantation with Microdystrophin Gene Delivery
Shan-wei Feng, , Fei chen, , Jiqing Cao, Ying-yin Liang, Xin-ming Song, Cheng Zhang - China
Duchenne muscular dystrophy is the most prevalent inheritable muscle disease. Transplantation of autologous stem cells with gene direction is an ideal therapeutic approach for the disease. The current study aimed to investigate the restoration of myofibers in mdx mice after mdx bone marrow-derived mesenchymal stem cell (mMSC) transplantation with human microdystrophin delivery. Possible mechanisms of action were also studied. In our research, mMSCs were successfully transduced by retrovirus carrying a functional human microdystrophin gene. Transplantation of transduced mMSCs enabled persistent dystrophin restoration in the skeletal muscle of mdx mice up to the 12th week after transplantation. Simultaneous coexpression of human microdystrophin and desmin showed that implanted mMSCs are capable of long-term survival as muscle satellite cells.
25 - (Pharmacological Research, January 2012) Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: evidence from a safety study with pilot efficacy measures in adult dystrophic patients
Maria Grazia D’Angelo, Sandra Gandossini, Filippo Martinelli Boneschi, Clara Sciorati, Sara Bonato, Erika Brighina, Giacomo Pietro Comi, Anna C. Turconi, Francesca Magri, Giuseppe Stefanoni, Silvia Brunelli, Nereo Bresolin, Dario Cattaneo, Emilio Clementi - Italy
This open-label, single centre pilot study was designed to evaluate safety and tolerability of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a non steroid anti-inflammatory drug, in a cohort of adult dystrophic patients (Duchenne, Becker and Limb-girdle muscular dystrophy). Seventy-one patients were recruited: 35, treated with the drug combination for 12 months, and 36 untreated. Safety and adverse events were assessed by reported signs and symptoms, physical examinations, blood tests, cardiac and respiratory function tests. Exploratory outcomes measure, such as the motor function measure scale, were also applied.
Good safety and tolerability profiles of the long-term co-administration of the drugs were demonstrated. Few and transient side effects (i.e. headache and low blood pressure) were reported. Additionally, exploratory outcomes measures were feasible in all the disease population studied and evidenced a trend towards amelioration that reached statistical significance in one dimension of the MFM scale. Systemic administration of ibuprofen and isosorbide dinitrate provides an adequate safety margin for clinical studies aimed at assessing efficacy.
21 - (Journal of Neuroscience Research, 2012) Motor performance of young dystrophic mdx mice treated with long-circulating prednisolone liposomes
Charlotte Weller, Jana Zschüntzsch, Gregor Makosch, Josbert M. Metselaar, Florian Klinker, Lars Klinge, David Liebetanz and Jens Schmidt - Germany
For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3–6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-β and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases