ScienceDaily (Nov. 14, 2009)

A study appearing in Science Translational Medicine puts scientists one step closer to clinical trials to test a gene delivery strategy to improve muscle mass and function in patients with certain degenerative muscle disorders.

Severe weakness of the quadriceps is a defining feature of several neuromuscular disorders. Researchers at Nationwide Children's Hospital have shown that a gene delivery strategy that produces follistatin -- a naturally occurring protein that inhibits myostatin, a growth factor expressed specifically in skeletal muscle -- directly to the quadriceps of non-human primates results in long-term gene expression with muscle enhancing effects, including larger muscles with greater strength.

Previously, Nationwide Children's researchers demonstrated follistatin's therapeutic potential using rodent models. This more recent study produced similar results in non-human primates, in a translational study to demonstrate efficacy in safety in a species more closely related to humans. Non-human primates that received the injection of the follistatin transgene experienced pronounced and durable increases in muscle size and strength. Muscle growth occurred for 12 weeks after treatment, after which time the growth rates appeared to stabilize and were well tolerated, with no adverse events noted over the course of the 15-month study.

"Our studies indicate that this relatively non-invasive approach could have long-term effects, involve few risks and could potentially be effective in various types of degenerative muscle disorders including multiple forms of muscular dystrophy," said the study's corresponding author, Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy of The Research Institute at Nationwide Children's Hospital.

Jerry Mendell, MD, principal investigator in the Center for Gene Therapy at Nationwide Children's added, "These findings serve as the basis for testing in patients and give us confidence in moving forward with our translational program of follistatin to enhance muscle mass."

The research team has developed a plan with the Food and Drug Administration and is currently in the process of performing the formal toxicology and biodistribution studies to support initiating a human clinical trial.

The potential use of this strategy for muscle strengthening has important implications for patients with muscle diseases including Duchenne muscular dystrophy -- the most common form of muscular dystrophy -- as well as for the planned first clinical trial for inclusion body myositis. It also may be applicable to other forms of muscular dystrophy, such as facioscapulohumeral muscular dystrophy, in which gene replacement or other types of gene manipulation are not feasible because of the absence of a specific gene defect.

In addition to their roles at Nationwide Children's, Drs. Kaspar and Mendell hold faculty posts at The Ohio State University College of Medicine.