Medical Professional Publications

Gene Therapy Trial Improves Walking Performance for Becker Muscular Dystrophy

(From the January 2015 Issue of PediatricsOnline)

Becker muscular dystrophy (BMD) is an inherited, degenerative neuromuscular disorder resulting from defects of muscle caused by a mutation in the DMD gene. Although BMD is similar in genotype to Duchenne muscular dystrophy, the only beneficial drug treatment for Duchenne has not proven successful in clinical trials for patients with BMD. But now, gene therapy shows promise as a safe and effective strategy to increase muscle size and strength for patients with BMD, according to the first human clinical trial, led by a team at Nationwide Children’s Hospital.

“Currently, there is no treatment for BMD, and clinical trials using proven treatment for DMD have failed for patients with BMD,” says Jerry Mendell, MD, corresponding author of the study, principal investigator of the trial and the director of the Center for Gene Therapy in The Research Institute at Nationwide Children’s. “But this proof-of-principle clinical trial offers promise for patients with BMD and their families.”

Muscle tissue biopsy from a lab in the Center for Gene Therapy
Analysis of these samples helped assess the efficacy of gene therapy for patients with Becker muscular dystrophy.











The study, which was published in the journal Molecular Therapy, used distance walked on the standard 6-minute walk test (6MWT) as the primary outcome measure following follistatin gene therapy. Follistatin targets myostatin, a protein that inhibits muscle development. Muscle fiber size distribution and hypertrophy in participants were assessed based on muscle biopsy changes.

“Initial research on mice and nonhuman primates showed that inhibition of the myostatin pathway had a clinically meaningful effect on muscle health and strength,” explains Brian Kaspar, PhD, a senior authorof the study and a principal investigator in the Center for Gene Therapy at Nationwide Children’s. “After extensive preclinical studies demonstrated the absence of toxicity, we moved forward with a phase 1/2a clinical trial using an alternatively spliced isoform of follistatin, a potent myostatin antagonist.”

In this single-site study, the follistatin was delivered to six male BMD patients using adeno-associated virus (AAV). Direct, bilateral intramuscular quadriceps injections followed a dose-ascending gene therapy regimen. Participants were divided into two cohorts. Cohort 1 included three ambulatory subjects who received 12 injections per muscle and were followed for a year post-gene delivery.

Researchers observed substantial increases in 6MWT, above those that would be predicted over the course of one year in untreated BMD patients. Pituitary-gonadal hormone levels remained normal throughout the trial. Additionally, patients did not experience any significant adverse effects related to follistatin gene therapy or abnormalities in the liver, kidneys or bone marrow.

Due to the treatment’s safety demonstrated in Cohort 1, an additional three BMD patients were enrolled for Cohort 2 and received treatment according to a similar regimen, but with an increase in dosage. These three patients had been followed for six months at the time of the study’s publication. Two of the three patients in Cohort 2 improved their walking distance, and there was no apparent difference in functional outcomes between the low and high-dose groups. Patients in Cohort 2 also did not experience any adverse events.

Although each type of muscular dystrophy is passed on by a different gene and has a different course of symptom progression, every form of the disease impacts ambulation and muscle strength adversely. This makes all of these conditions targets for research and clinical trials. Because of the safety and efficacy demonstrated in this clinical trial, researchers explain that this same approach — delivery of follistatin using adeno-associated virus — warrants future consideration for the treatment of other dystrophin-deficient muscle diseases, such as Duchenne muscular dystrophy.

“The results of this first human clinical trial are encouraging, but this is a very small study and there are still questions to be answered,” says Dr. Mendell, who is also director of the Neuromuscular Disorders program at Nationwide Children’s and a professor of Pediatrics, Neurology, Pathology, and Physiology and Cell Biology at The Ohio State University College of Medicine. “Moving forward, we have plans to extend the trial to patients with Duchenne muscular dystrophy, changing the protocol to include a wider delivery of vector to multiple muscle groups.”     

Mendell J, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK. A Phase 1/2a follistatin gene therapy trial for Becker muscular dystrophy. Molecular Therapy. 2014 Oct 17. [Epub ahead of print]

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