Pegoraro E.,Neuromuscular Center |
Hoffman E.P.,University of California at Davis |
Piva L.,Neuromuscular Center |
Gavassini B.F.,Neuromuscular Center |
And 18 more authors.
Neurology | Year: 2011
Objective: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. Methods: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. Results: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003). Conclusions: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects. Copyright © 2011 by AAN Enterprises, Inc. All rights reserved.
Narayanaswami P.,Beth Israel Deaconess Medical Center |
Weiss M.,University of Washington |
Selcen D.,Mayo Medical School |
David W.,Harvard University |
And 9 more authors.
Neurology | Year: 2014
Objective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. Results: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. Principal recommendations: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.
Querin G.,Neuromuscular Center |
D'Ascenzo C.,Neuromuscular Center |
Peterle E.,Neuromuscular Center |
Ermani M.,Neuromuscular Center |
And 11 more authors.
Neurology | Year: 2013
Objective: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). Methods: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with theMedical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. Results: Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed. Conclusions: Our findings suggest a positive effect of clenbuterol on SBMA disease progression. Classification of evidence: This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA. © 2013 American Academy of Neurology.
Wang M.,Neuromuscular Center |
Wu B.,Neuromuscular Center |
Tucker J.D.,Neuromuscular Center |
Tucker J.D.,University of North Carolina at Charlotte |
And 3 more authors.
Technical Proceedings of the 2014 NSTI Nanotechnology Conference and Expo, NSTI-Nanotech 2014 | Year: 2014
Series of cationic amphiphlic copolymers constructed from Tween 85 and low molecular weight (Mw) polyethyleneimene (LPEI) were synthesized and evaluated in in vitro and in vivo. They could condense DNA efficiently with particles size below 200 nm at the weight ratio 5 of polymer/pDNA. The introduction of Tween 85 led to a significant increase in transfection efficiency in C2C12 cell line, but without increasing toxicity compared with the parent LPEI, and much lower toxicity than PEI 25k. The best formulation for pDNA delivery give 5, 15-fold compared with PEI 25k at the same dose in vitro and in mdx mice, respectively. There is no obvious muscle damage observed with these new copolymers. These results demonstrated that Tween 85 modified LPEI could be potentially safe and effective polymeric carriers for gene/drug delivery.
Wu B.,Neuromuscular Center |
Lu P.,Neuromuscular Center |
Benrashid E.,Neuromuscular Center |
Malik S.,Neuromuscular Center |
And 3 more authors.
Gene Therapy | Year: 2010
We have earlier shown that antisense morpholino oligomers are able to restore dystrophin expression by systemic delivery in body-wide skeletal muscles of dystrophic mdx mice. However, the levels of dystrophin expression vary considerably and, more importantly, no dystrophin expression has been achieved in cardiac muscle. In this study, we investigate the efficiency of morpholino-induced exon skipping in cardiomyoblasts and myocytes in vitro, and in cardiac muscle in vivo by dose escalation. We showed that morpholino induces targeted exon skipping equally effectively in both skeletal muscle myoblasts and cardiomyoblasts. Effective exon skipping was achieved in cardiomyocytes in culture. In the mdx mice, morpholino rescues dystrophin expression dose dependently in both skeletal and cardiac muscles. Therapeutic levels of dystrophin were achieved in cardiac muscle albeit at higher doses than in skeletal muscles. Up to 50 and 30% normal levels of dystrophin were induced by single systemic delivery of 3 g kg-1 of morpholino in skeletal and cardiac muscles, respectively. High doses of morpholino treatment reduced the serum levels of creatine kinase without clear toxicity. These findings suggest that effective rescue of dystrophin in cardiac muscles can be achieved by morpholino for the treatment of Duchenne muscular dystrophy. © 2010 Macmillan Publishers Limited All rights reserved.