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Reino Unido - os autores acompanharam por 4 anos 360 meninos com Duchenne em tratamento com prednisolona comparando o uso de doses diárias da medicação comparando com o uso do esquema intermintente (10 dias com e 10 dias sem). Houve mlehora em ambos os grupos mas o que receberam doses diárias conseguiram deambular por mais tempo mas tiveram maior frequência de efeitos colaterais. Ou seja o uso de corticóides na distrofia muscular de Duchenne é mandatório. O resumo em inglês pode ser lido abaixo:

(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.

USA - dantrole é uma droga usada no tratamento da hipertermia maligna; aplicado por via intramuscular ou venosa em camundongos com distrofia muscular, em conjunto com oligonucleotídeos, a droga causou uma maior quantidade de salto de exons do que o tratamento isolado com oligonucleotídeos. O uso do dantrole em cultura de células resultou em efeito semelhante. O resumo em inglês pode ser lido abaixo:

 (Sci Transl MedVol. 4, Issue 164, p. 164ra160) Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy

Genevieve C. Kendall, Ekaterina I. Mokhonova, Miriana Moran, Natalia E. Sejbuk, Derek W. Wang, Oscar Silva, Richard T. Wang, Leonel Martinez, Qi L. Lu, Robert Damoiseaux, Melissa J. Spencer, Stanley F. Nelson, and M. Carrie Miceli -USA

Duchenne muscular dystrophy (DMD) causes profound and progressive muscle weakness and loss, resulting in early death. DMD is usually caused by frameshifting deletions in the gene DMD, which leads to absence of dystrophin protein. Dystrophin binds to F-actin and components of the dystrophin-associated glycoprotein complex and protects the sarcolemma from contraction-induced injury. Antisense oligonucleotide–mediated exon skipping is a promising therapeutic approach aimed at restoring the DMD reading frame and allowing expression of an intact dystrophin glycoprotein complex. To date, low levels of dystrophin protein have been produced in humans by this method. We performed a small-molecule screen to identify existing drugs that enhance antisense-directed exon skipping. We found that dantrolene, currently used to treat malignant hyperthermia, potentiates antisense oligomer–guided exon skipping to increase exon skipping to restore the mRNA reading frame, the sarcolemmal dystrophin protein, and the dystrophin glycoprotein complex in skeletal muscles of mdx mice when delivered intramuscularly or intravenously. Further, dantrolene synergized with multiple weekly injections of antisense to increase muscle strength and reduce serum creatine kinase in mdx mice. Dantrolene similarly promoted antisense-mediated exon skipping in reprogrammed myotubes from DMD patients. Ryanodine and Rycal S107, which, like dantrolene, targets the ryanodine receptor, also promoted antisense-driven exon skipping, implicating the ryanodine receptor as the critical molecular target.

Brasil -  quatorze camundongos foram tratados por 14 dias por via oral com óleo de peixe. Os  animais tratados apresentaram menor necrose, menor inflamação, menor CK e redução de citocinas inflamatórias.  O resumo em inglês pode ser lido abaixo:

 (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.

 

Brasil - nesta pesquisa células tronco obtidas da gordura humana foram injetadas em cães com distrofia muscular. As células foram injetadas por via venosa e o estudo demonstrou que elas atingem os músculos, que passam a expressar a distrofina por até seis meses após o transplante e sem a necessidade de imunossupressão e sem efeitos colaterais significativos.

Suiça e Irlanda - pacientes com distúrbio do sono foram avaliados por questionário para determinar alterações do sono. Dos 63 pacientes que responderam, 25% apresentavam distúrbios do sono tais como dificuldade em iniciar ou manter o sono, alterações respirátorias e sudorese excessiva.

USA - Deste congresso eu selecionei 5 apresentações envolvendo a distrofia muscular; quatro delas se referem ao uso de inibidores da fosfodiesterase 5 como o sildenafil e tadalafil, drogas comercializadas para tratamento de disfunção erétil. Na distrofia muscular de Duchenne/Becker e nos modelos experimentais inúmeros trabalhos tem demonstrado o benefício cardíaco destas drogas. O quinto trabalho tem uma importância grande pois mostra que uma alteração observada no ecocardiograma de adolescentes com distrofia muscular de Duchenne se relaciona com pior prognóstico cardíaco da doença: a presença de não compactação do ventrículo esquerdo estaria relacionada com pior prognóstico da doença.

O resumo em inglês destas pesquisas  pode ser lido abaixo:

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.

 

França - 20 crianças com distrofia muscular congênita foram submetidas a polisonografia para determinar as alterações do sono. Despertares, diminuição do tempo de sono e redução do sono REM foram observados. Apnéia do sono estava presente em 65% das crianças. O resultado ressalta a importância da polisonografia no acompanhamento de crianças com distrofia muscular congênita. O resumo em inglês pode ser lido abaixo:

(European Journal of Paediatric Neurology 16 (2012) 619-624) Sleep-disordered breathing in children with congenital muscular dystrophies

Jean-Marc Pinard, Eric Azabou, Nouha Essid, Susana Quijano-Roy, Samir Haddad,Fawzia Cheliout-Héraut

Objective: Most types of neuromuscular diseases are known to be associated with a high risk of sleep-disordered breathing. We performed a prospective study in a well individualized group of muscular disorders, congenital muscular dystrophies (CMD), to characterize the frequency of sleep-disordered breathing and thereby to determine the potential usefulness of sleep studies in such patients.
Methods: Twenty CMD children (12 F, 8 M, aged 4e17 years) were included. Using overnight polysomnography, we determined the following parameters: sleep stages, sleep latency, sleep efficiency index, wake time duration, total sleep time (TST), apnea/hypopnea index (AHI), arterial blood oxygen saturation, and nocturnal paroxysmal EEG activity.
Results: As compared to healthy controls, we detected in our study group frequent awakenings, a decreased TST (mean 448 44.4min) and a decreased REMduration (mean 11.5 3.5% of TST). Significant increase inwake time duration (28e90min) and decrease in REMduration were observed in 12 patients. An apnea/hypopnea syndrome was detected in 13 patients (65%)with central apneas in 8, obstructive apneas in 2 and 3mixed apneas in 3 patients. AHI was >10 in 3 cases, <10> 5 in 4 cases andwere concomitantwith blood oxygen de-saturation in four cases. NPA were detected in 10 patients ranging from10 to 40% of TST.
Interpretation: Our results confirm the high incidence of sleep disordered breathing in children with CMD, and thereby, the usefulness of overnight polysomnography recordings in such patients.
 

Ucrânia - Vinte e sete pacientes com distrofia muscular de Duchenne, com idades variando de 4 a 27 anos  receberam tratamento com um poll de células embrionárias retiradas de fetos sadios. A avaliação realizada 6 meses após o tratamento demosntrou uma melhora funcional e da qualidade de vida destes pacientes. Não há detalhes da qualtidade de células, vias de administração e a avaliação foi feita por um período muito curto, sem demonstrar que as células estavam presentes nos músculos. O resumo em inglês pode ser lido abaixo:

(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.

Itália -  Os autores compararam os efeitos do tratamento com corticóides e com anti-inflamatórios não hormonais (aspirina, ibuprofeno e parecoxib) em camundongos com distrofia muscular. O resultado mostrou que estes anti-inflamatórios reduzem as alterações patológicas dos músculos, reduzem a inflamação e a necrose. O estudo da contratilidade não demonstrou efeito. O resumo em inglês pode ser lido abaixo:

(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.

 

Brasil - agonistas AMPK/PPAR podem controlar o stress oxidativo. Nesta pesquisa os camundongos com distrofia muscular foram tratados com estes agonistas e submetidos a atividade física. Houve melhora do desempenho físico dos animais e redução do stress oxidativo.

 Itália - os autores estudando 103 meninos com Duchenne identificaram 33 pacientes com Distúrbio do Déficit de Atenção e Hiperatividade. Destes 18 apresentavam também deficit intelectual, superior ao encontrado em Duchenne sem defict de atenção e hiperatividade. As mutações envolvendo os exons 45-55 e entre 62 e 63 são as que mais se relacionam ao deficit de atenção e hiperatividade.  O  resumo em inglês pode ser lido abaixo:

(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 Duchenne muscular 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 with mutations 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.

 

Canadá - sonolência diurna é uma das manifestações mais frequentes da distrofia miotônica. Vinte e quatro pacientes foram incluídos nestes estudo utilizando 20 mg de metilfenidato. Houve uma significativa melhora da sonolência diurna. A medicação tem efeitos colaterais conhecidos que também foram vistos neste estudo tais como palpitação, náuseas, vômitos e perda do apetite. Em alguns casos os efeitos colaterais como diarréa, nervosismo e irritabilidade levou a suspensão do medicamento. Apesar disto a droga foi considerada eficaz e uma boa alternativa para tratamento da sonolência diurna n distrofia miotônica do tipo 1.

Brasil  - camundongos tratados com células tronco injetadas diretamente no músculo apresentaram menor fadiga e melhora da força muscular. Além disso as alterações patológicas foram diminuídas. Os pesquisadores identificaram menor quantidade de mediadores de inflamação e maior capacidade de formar novos vasos sanguíneos nos animais tratados com estas células originárias do tecido adiposo.

USA - adolescentes com distrofia muscular de Duchenne em uso de corticóides apresentam retardo do crescimento. Neste estudo 39 adolescentes receberam por um ano o tratamento com hormônio do crescimento. Houve um significativo aumento do crescimento neste tratamento. Não houve alteração do peso, da força muscular e da função cardíaca e respiratória. Não ocorreram efeitos colaterais. O resumo em inglês pode ser lido abaixo:

 (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

Suiça - a droga losartana, inibidora da angiotensina II já demostrou efeito em modelos experimentais de distrofia muscular. Nesta pesquisa foram utilizados camundongos com distrofia muscular congênita que foram tratados com L 158809, semelhante a losartana.  Adroga diminui a formação de citocina inflamatória diminuindo as alterações patologicas dos músculos. Portanto neste modelo de distrofia experimental os inibidores da angiotensina II também são úteis.

Autralia - neste congresso de especialistas em doenças neuromusculares que se realizará em Peth, Australia, serão apresentados mais de 300 pesquisas envolvendo diagnóstico, epidemiologia e tratamento clínico e experimental em doenças neuromusculares. Os resumos aqui incluídos são os principais relacionados com tratamento.

Brasil -  os autores utilizaram a doxiciclina, um antibiótico da família da tetraciclina em camundongos com distrofia muscular; houve melhora das alterações patológicas do músculo cardíaco e músculos esqueléticos e aumento da força muscular nos animais tratados. O resumo em inglês pode ser lido abaixo:

(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.

 

Japão - os oligonucleotídeos para salto de exon já estão sendo usados em  pacientes mas eles são específicos para cada mutação. Nesta pesquisa os autores desenvolveram uma solução de oligonucleotídeos para salto de 10 exons, do 45 ao 55. Teoricamente este tratamento poderia ser útil para 60% dos pacientes. Os resultados obtidos em camundongos demonstraram expressão da distrofina em até 15%, aumento da força muscular e das alterações patológicas, sem efeitos colaterais expressivos.

Canadá - esta pesquisa foi realizada pelo grupo que mais experiência tem com o uso de corticóides em distrofia muscular. Trinta e nove meninos com Duchenne foram tratados com deflazacort diariamente por longo prazo. A densitometria óssea foi obtida no início e ao longo do tratamento. Nove fraturas em ossos longos foram observadas em 8 pacientes, duas delas antes do tratamento. Sete fraturas de ossos vertebrais foram observadas em 6 pacientes após 5 anos ou mais do uso dos corticóides. Os valores de densitometria óssea foram corrigidos para a altura e porcentagem de massa gorda e permaneceram estáveis por longo tempo do tratamento.  A saúde óssea é influenciada pela doença, pelos corticóides, pela deambulação e pela massa gorda e estes parâmetros devem ser considerados na análise dos resultados. O resumo em inglês pode ser lido abaixo:

(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.

USA -  resveratrol é uma proteína presenta na casca da uva e que tem sido muito pesquisada como anti-oxidante na prevenção de doença cardiovascular. Nesta pesquisa os camundongos tratados com doses elevadas desta substância apresentaram redução da inflamação nos músculos e aumento da expressão da utrofina, proteína que pode exercer funções semelhantes a distrofina. Os autores sugerem que o resveratrol pode ser um tratamento auxiliar na distrofia muscular para reduzir a inflamação. O resumo em inglês pode ser lido abaixo:

(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.
 

 

Reino Unido - células adultas de camundongos com distrofia tipo cinturas foram transformada em IPS (células tronco com caracteristicas embrionárias). Em laboratório elas foram tratadas para derivar mesangioblastos, um tipo de células tronco de vasos. Em seguidas elas receberam uma terapia gênica para correção do defeito genético. Em seguida elas foram novamente injetadas nos camundongos. Os animais tratados apresentaram melhora das alterações funcionais e patológicas dos músculos, demonstrando a viabilidade deste procedimento.

Reino Unido - neste guia estão relacionados os principais cuidados a serem feitos em pacientes com doenças neuromusculares. Informação fundamental para profissionais que atuam no atendimento respiratório deste pacientes.

Argentina -  o trabalho demonstra mais uma vez que os pacientes com distrofia muscular de Duchenne apresentam redução da densidade óssea na coluna com o tratamento com corticóides, sendo que os valores eram mais baixos nos tratados com corticóides; é justificável o tratamento preventivo desta complicação em pacientes tratados com corticóides. o resumo em inglês pode ser lido abaixo:

(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.

USA - neste estudo os autores demonstram que a osteoporose esta presente na distrofia muscular de Duchenne, que é progressiva. O diagnóstico precoce é benéfico e o uso de alendronato reduz a perda de massa óssea. O resumo em inglês pode ser lido abaixo:

 (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.

USA - as estatinas fazem parte do protocolo de tratamento de pacientes submetidos a transplante cardíaco. Estas drogas podem causar lesão muscular, podendo chegar a rabdomiólise. Nesta pesquisa são relatados poucos casos de pacientes com distrofia muscular submetidos a transplante e tratados com corticóides. O  tratamento foi bem tolerado, não havendo alterações musculares graves. O resumo em inglês pode ser lido abaixo:

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.

 

 

 

 

 

USA - inibidores da enzima de conversão da angiotensina (IECA) e beta bloqueadores são drogas utilizadas no tratamento da cardiomiopatia da distrofia muscular de Duchenne. Esta pesquisa foi com 42 pacientes com Duchenne e queapresentavam cardiomiopatia. Os pacientes tratados com IECA e receberam beta bloqueadores se a frequência cardíaca superava os 100 batimentos por minuto. Houve um significativo aumento da função cardíaca com IECA não havendo diferença significativa entre os que receberam só IECA ou IECA+ beta bloqueadores. O resumo em inglês pode ser lido abaixo:

(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.
 

USA - nesta pesquisa os oligonucleotídeos foram acoplados a uma pequena proteína para aumentar a sua penetração nas células musculares. Os resultados de um ano de tratamento demonstraram que os animais apresentaram um significante aumento da distrofina muscular e cardíaca, superior ao observado com o uso dos oligonucleotídeos convencionais. O resumo em inglês pode ser lido abaixo:

(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.

 

USA - o sildenafil tem sido testado em distrofia muscular experimental há um certo tempo para melhorar a função cardíaca, apesar de ter sido lançado como primeira droga útil para disfunção erétil. Neste estudo, os camundongos tratados por 14 semanas com sildenafil apresentaram melhora da força muscular do músculo diafragma e redução das alterações patológicas deste músculo. Sildenafil inibe a enzima fosfodiesterase 5 e aumenta os níveis de óxido nítrico.

Brasil - camundongos deficientes em LAMA-2 receberam por via sistêmica as células tronco mesenquimais, sem imunossupressão e com o uso concomitante do IGF-1, uma droga estimulante da regeneração muscular. Os animais apresentaram  melhora da força muscular e redução das alterações patológicas da doença.

Santo André - a Faculdade de Medicina do ABC está realizando no seu campus 2 eventos no dia 2 de junho de 2012 relacionados com as doenças neuromusculares, especialmente doença de Pompe e Distrofia Muscular de Duchenne.  A 1a Jornada destina-se a profissionais e estudantes da área de saúde. O segundo evento será destinado a pais, familiares e portadores de doenças neuromusculares. Ambos os eventos são gratuitos e haverá certificado para os participantes.

USA - ataluren ou PTC-124 é uma droga que tem sido testada para tratamento da mutação de ponto, ou mutação sem sentido das doenças genéticas. Estes resultados agora apresentados são um complemento das informações da pesquisa fase 2 que já tinha demonstrado efeito do ataluren em Duchenne/ Becker. A droga causa redução do número de quedas e aumento da forrça muscular em crianças com Duchenne/Becker. O resumo pode ser lido abaixo:

(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 - USA

Introduction: 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.

USA -  trata-se de um editorial que comenta o artigo publicado sobre o uso precoce com corticóides na distrofia muscular de Duchenne e que também faz uma revisão sobre este tratamento. O uso de corticóides é necessário e útil na distrofia muscular de Duchenne.

Itália - o uso de corticóides é o tratamento padrão da distrofia muscular de Duchenne mas ainda não foi estabelecido o momento da introdução da medicação. Neste estudo os autores descrevem o resultado positivo do tratamento com corticoides, iniciado dos 2 aos 4 anos em crianças com Duchenne. Em quatro casos a capacidade de caminhar permaneceu  até os 16 a 18 anos e 3 conseguiam subir escadas. Houve redução da função respiratória em dois pacientes. Os principais efeitos colaterais foram retardo da puberdade e redução da estatura. O que podemos concluir é que o tratamento precoce com corticóides deve ser preconizado. O resumo em inglês pode ser lido abaixo:

(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.

USA - pesquisadores conseguiram obter em cultura quantidade grande de células tronco embrionárias e IPS células (células adultas transformadas em embrionárias) com potencial miogênico. Inoculdas em camundongos com distrofia muscular estes produziram distrofina e estas células ainda foram identificadas nos animais 11 meses após a aplicação. O resumo e o desenho da pesquisa pode ser visto abaixo:

(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.

 

França -  a bradicinina é uma substância endógena com atividade sobre o endotélio dos vasos e sobre as células cardíacas, tendo sido descoberta por um brasileiro. A injeção da bradicinina em cães promoveu uma significativa melhora das alterações cardiovasculares observadas nestes animais. O texto em inglês pode ser lido abaixo:

(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.

Canadá -  mesmo em países de primeiro mundo os protocolos de axompanhamento cardíológico em Duchenne não sao seguidos; recomenda-se pelo uma avaliação cardiológica anual. Numa avaliação no Canadá estudando 32 pacientes com Duchenne apenas 19 haviam passado por esta avaliação e somente 22 haviam feito o ecocardiograma. Provavelmente no Brasil o número de pessoas sem estas avaliações seria maior. O texto em inglës do trabalho pode ser lido abaixo:

(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

Israel -  losartan é uma droga utilizada em hipertensão arterial; estudos com camundongos com modelo de distrofia muscular de Duchenne já demostraram efeito positivo da droga na musculatura esquelética. Nesta pesquisa com camundongos portadores de distrofia muscular congënita houve significativa melhora tanto da força muscular quanto das alterações patológicas e redução dos mediadores de fibrose nos músculos.  

USA - neste encontro serão apresentadas mais de 17 pesquisas que se relacionam com o tratamento das distrofias musculares, sendo todos os experimentos ainda em animais mas com perspectivas de uso em seres humanos.

Itália - a cardiomiopatia da distrofia muscular de Duchenne é ao lado da insuficiência respiratória a principal causa de mortalidade da doença. Neste relato os autores trataram dois pacientes com Duchenne e que apresentaram cardiomiopatia grave com um equipamento de assistëncia da função ventricular esquerda. O equipamento é implantado em paralelo com o coração. O resultado do tratamento a longo prazo foi bom permitindo a manutenção da qualidade de vida e retorno para as atividades diárias.

USA -  trata-se de um artigo de revisão de estudos já realizados em humanos e animais sobre a realização de exercícios físicos na distrofia muscular. A literatura não é concordante sobre o tema. Há benefícios descritos sobre as vantagens dos exercícios mas não há consenso quanto ao tipo e quantidade necessária.

USA - neste congresso americano de pesquisas experimentais serão apresentadas mais de 30 trabalhos relacionados com distrofia muscular, sendo que as 10 abaixo são as que tem maior relação com o tratamento da doença. Há pesquisas sobre o uso de suplementos como resveratrol e quercetina, pesquisas com o uso de vetor viral diretamente no diafragma de camundongos, com o uso de antioxidantes como a acetilcisteína, com o uso de anti-inflamatórios doadores de óxido nítrico como o flurbiprofen e com o uso de inibidores da fosfodiesterase (drogas habitualmente usadas na disfunção erétil). O sresumos dos trabalhos em inglês pode ser lido abaixo:

1)   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.

2)  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.

3) 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) 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.)

5)  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.

6) 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.

7) 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.

8) 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.

9) 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.

10)  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.

USA - Eteplirsen  é o oligonucleotídeo desenvolvido pela AVi para salto do exon 51. No estudo parcial de 24 semanas os pesquisadores observaram aumento significante da expressão da distrofina no músculo. No entanto a força muscular não apresentou alteração significativa com o tratamento de 24 semanas. Os estudos prosseguem para avaliação de longo prazo do tratamento.

Australia - pesquisadores indentificaram em camundongos uma proteína HSP72 que contribui para a melhora da distrofia muscular. No experimento os animais receberam a droga BGP-15 que aumenta a HSP72 e os animais apresentaram melhor força muscular, redução das alterações patológicas e aumento da sobrevida.

USA - camundongos deficientes em laminina alfa 2, um modelo experimental de distrofia congênita merosina negativa, foram tratados por via sistêmica com laminina-111. Os animais tratados apresentaram um espetacular aumento da sobrevida, aumento da força muscular e reduçâo das alterações patológicas nos músculos. O resumo em inglês pode ser lido abaixo:

(The American Journal of Pathology, Volume 180, Issue 4, April 2012, Pages 1593-1602) Laminin-111 Protein Therapy Reduces Muscle Pathology and Improves Viability of a Mouse Model of Merosin-Deficient Congenital Muscular Dystrophy

Jachinta E. Rooney, Jolie R. Knapp, Bradley L. Hodges, Ryan D. Wuebbles, Dean J. Burkin

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2–deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm–derived mouse laminin-111 protein could rescue MDC1A in the dyW−/− mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2–deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2–deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dyW−/− mouse model and establish the potential for its use in the treatment of MDC1A.

Canada - 22 pacientes com Duchenne foram submetidos a avaliação da função respiratória por 45 meses após a introdução da manobra do empilhamento de ar; os resultados foram comparados com os resultados obtidos nos 33 meses anteriores ao estudo. A perda de função pulmonar reduziu-se drasticamente com a introdução da manobra de empilhamento de ar.

USA - o teste do pezinho é obrigatório no Brasil parta identificação de algumas doenças genéticas ou congênitas; através de uma amostra seca de sangue faz se uma triagem para várias doenças. Há autores que preconizam a introdução da dosagem da CK para triagem da doença, enquanto outros acham que enquanto não houver tratamento definitivo este diagnóstico precoce não seria desejável. Esta pesquisa envolveu um grande número de recém-nascidos que foram submetidos a dosagem da CK completada com estudo genético quando a CK estava alterada. Em três casos o diagnóstico de distrofia muscular de Duchenne foi realizado e em outros 3 casos o diagnóstico foi de distrofia tipo cinturas. Este estudo demonstra a viabilidade de diagnóstico precoce de distrofias musculares incluindo a dosagem de CK no teste do pezinho. O resumo em inglês pode ser lido abaixo:

(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.

Australia - existem inúmeras pesquisas prévias com o IGF-1 em modelos de distrofia muscular; nesta pesquisa os autores testaram em dois modelos de distrofia o IGF-1 peguilato que tem um efeito mais prolongado; no modelo de distrofia com menor grau de lesão muscular os autores observaram um efeito benéfico que não foi observado nos camundongos com a forma de distrofia mais grave; o seu uso poderia ser útil nas formas iniciais da doença ou quando houvesse algum grau de lesão aguda dos músculos, por trauma por exemplo. O resumo em inglês pode ser lido abaixo:

(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.

 

 

Holanda -  os autores compararam o peso e altura das crianças com distrofia muscular de Duchenne sem tratamento com as tratadas com prednisona no esquema 10 dias com/10 dias sem. O número de crianças tratadas foi pequeno mas os resultados permitiram concluir que este regime de tratamento aparentemente não altera o peso e a altura das crianças tratadas. O resumo em inglês pode ser lido abaixo:

(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.

USA -  nesta pesquisa realizada em vários centros no mundo, os autores estudaram a pentoxifilina, uma droga que demonstrou efeitos em camundongos. A droga foi usada por 12 meses em meninos com distrofia muscular de Duchenne tratados com corticóides. Os resultados observados não demonstraram efeito da droga sobre a força muscular e na função pulmonar. O resumo em inglês pode ser lido abaixo:

(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

Abstract

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

 

USA -  selecionei 29 pesquisas que serão apresentadas no maior congresso mundial de neurologia. As pesquisas que estão mais avançadas são a da terapia com ACE-031 com resultados preliminares bons em Duchenne (pesquisa 1) e a que demonstra a melhora da função cardíaca em pacientes com Duchenne tratados com drogas cardioprotetoras como os inibidores da ECA e os beta bloqueadores (pesquisa 5)

Suécia - pacientes com distrofia muscular de Duchenne e Becker podem apresentar osteoporose, mesmo sem o uso de corticóides. Neste estudo de seguimento da densitometria óssea por 4 anos os pesquisadores encontraram densidade óssea maior nos pacientes com Becker e uma progressiva redução nos pacientes com Duchenne, demonstrando uma correlação entre força muscular e osteoporese e a necessidade de prolongar a deambulação em pacientes com Duchenne.  O resumo em inglês pode ser lido abaixo:

(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.

USA - laminina 111 está presente na fase embrionária e não é encontrada na musculatura adulta. Neste experimento a laminina 11 foi administrada a camundongos com distrofia muscular congênita. Os animais tratados por via sistêmica com laminina 111 apresentaram aumento da força muscular e redução das alterações patológicas.

China -  células mesenquimais obtidas da medula óssea de camundongos foram submetidas a terapia gênica com vírus contendo microgene da distrofina. Após o tratamento elas forma inoculdas em camundongos e após 12 semanas observou-se melhora das alterações musculares, mantendo a capacidade de regeneração prolongadamente. O resumo em inglês pode ser lido abaixo:

(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.

 

Brasil -  trata-se de mais um aviso para os pais de crianças com distrofia muscular de Duchenne que ainda deambulam e podem ser beneficiar do salto do exon 51, participando desta pequisa. Se a criança ainda consegue caminhar e não tem o diagnóstico genético ela deve ser submetida ao exame do DNA para identificação da mutação. As mutações que se beneficiam do tratamento podem ser vista aqui.

Itália -  Nesta pesquisa os pacientes, 71 no total, foram tratados com um anti-inflamatório (ibuprofen) e com um doador de óxido nítrico (dinitrato de isosorbitol), medicamento usado para tratamento da angina do peito. Os pacientes tinham distrofia de Duchenne, Becker e cinturas) e foram tratados por um ano. Os medicamentos foram bem tolerados com poucos efeitos colaterais com algum grau de melhora. O resumo em inglês pode ser lido abaixo:

 (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.

 

Alemanha - os corticóides continuam sendo a melhor alternativa terapêutica da distrofia muscular de Duchenne, mas apresentam efeitos colaterais. Nesta pesquisa os autores construiram uma partícula de gordura contendo em seu interior o corticoides com objetivo de manter o efeito prolongado da droga e reduzindo seus efeitos colaterais. Os resultados demonstraram que o corticóide administrado como lipossoma não é superior ao tratamento convencional. O resumo em inglês pode ser lido abaixo:

(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

 

Alemanha - vetores virais contendo um microgene da distrofina  foram injetados por via venosa em camundongos com distrofia muscular. Após 10 meses de tratamento os animais apresentavam melhora ecocardiográfica e histológica demonstrando as possibilidades futuras deste tratamento.

França - trata-se de um estudo preliminar para determinar a segurança e a dose necessária para tratamento da distrofia muscular tipo cinturas 2C. Os pacientes receberam um injeção intramuscular contento um vetor viral que levava o gene da gama sarcoglican.  O seguimento foi de 6 meses e não houve efeitos colaterais graves. Os melhore resultados obtidos foram em pacientes que receberam as doses mais altas de vetores virais. Novos estudos deveram ser feitos para observar resultados da administração do tratamento por via venosa para todos os músculos.

 

 

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