Gene Therapy and Duchenne Muscular Dystrophy

James Radke

The Duchenne Alliance is funding a pilot program to test gene therapy in patients with Duchenne muscular dystrophy.  The gene therapy has been successful in another pilot study involving patients with Becker Muscular Dystrophy. As those studies continue, the Duchenne Alliance is pushing to add the gene therapy to include Duchenne muscular dystrophy, a more severe form of the neuromuscular disease.

The funding - $500,000 in total – will be used by a team lead by Jerry Mendell, MD at Nationwide Children's Hospital (Columbus, Ohio) to test follistatin gene therapy in a trial for Duchenne muscular dystrophy.

The therapy, developed at Nationwide Children's Hospital by Mendell and Brian Kaspar PhD, is based on adeno-associated virus (AAV) delivery of follistatin-344 to increase muscle strength and prevent muscle wasting and fibrosis.

While other treatment options in development for Duchenne muscular dystrophy are focused on the dystrophin gene (ie, exon skipping therapy), the gene therapy for follistatin is not mutation specific but focuses on follistatin’s ability to allow the patient to grow their own muscle mass.  According to Dr. Mendell’s recent review article, follistatin blocks another pathway (myostatin) that is a negative regulator of skeletal muscle growth. This double-negative treatment approach could increase muscle mass and could potentially be used to treat numerous forms of muscular dystrophy since it is not dependent on the type of mutation that limits other treatments in development.

In the Becker muscular dystrophy study that was recently accepted for publication in Medical Therapy, Mendell et al tested two doses of the gene therapy in 6 patients with Becker muscular dystrophy. In both treatment groups, 2 patients showed improvement in the 6-minute walk test while a third did not. No adverse effects were reported In the study and histological analyses showed reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy (especially at the higher dose).

According to Dr. Mendell,"This is the first gene therapy clinical trial to demonstrate functional improvement in any form of muscular dystrophy, and a major advance for those suffering with muscle disease."

Fifteen Non-Profit Groups Involved

The following foundations contributed to the funding
Duchenne Now
Harrison's Fund  
Hope for Gabe
Hope for Gus
JB's Keys
Jett Foundation
Little Hercules Foundation
Michael's Cause
Nash Avery Foundation
Pietro's Fight
Ryan's Quest
Save Our Sons
Team Joseph

In addition to the initial funding, the alliance may provide additional support to Milo Biotechnology for follow-up studies.

About Duchenne Muscular Dystrophy

Duchenne muscular dystrophy is a progressive muscle disorder caused by the lack of functional dystrophin protein. Patients with Duchenne muscular dystrophy lose the ability to walk as early as age 10 and experience life-threatening lung and heart complications in their late teens and twenties.

There are an estimated 35,000 patients with Duchenne in the United States and Europe but the population has many subsets based on mutations of the dystrophin gene.

There are currently no treatments for these patients but several drugs are in late stage clinical development, including Both Sarepta’s eteplirsen and Prosensa’s drisaperson which should be effective in the same 13% of the Duchenne population who would benefit from exon 51 skipping therapy (i.e., those with mutations near exon 51 of the dystrophin gene) and PTC Therapeutics’ ataluren which  should be effective in another 13% subset who have nonsense mutations in the dystrophin gene. Lilly’s tadalafil is also in a phase 3 clinical trial.

Image of gene therapy courtesy wikimedia commons
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