Development of delivery of a therapeutic gene via the bloodstream to the thigh muscles in people with type 2D limb-girdle muscular dystrophy (LGMD2D) is proceeding on schedule, thanks in part to a new $458,814 grant from MDA to neurologist Jerry Mendell at Nationwide Children's Hospital in Columbus, Ohio.
MDA's Board of Directors approved the new funding, via the Association's translational research/MDA Venture Philanthropy program, on Dec. 4, 2009.
Delivering a therapeutic gene to the thigh muscles via the bloodstream (vasculature), the ultimate goal for this project, has the potential to improve function, such as walking, for people with this disease.
To date, clinical trials of gene therapy in LGMD2D and in Duchenne muscular dystrophy have involved direct injection of a gene into a single muscle. While of crucial importance, these trials have focused on safety and gene activity, not on improving limb function. (See Gene Therapy Trial in MD First to Show Promise Beyond Safety and Gene Transfer in Alpha-Sarcoglycan-Deficient LGMD.)
LGMD2D, one of many forms of LGMD, is characterized by weakness and muscle atrophy, particularly of the muscles of the upper arms and upper legs. The underlying cause is a mutation in the gene for the alpha-sarcoglycan protein, which normally helps stabilize the membrane that surrounds each muscle fiber.
Raising alpha-sarcoglycan protein levels via gene therapy would target the fundamental problem in LGMD2D and has the potential to change the course of the disease.
Hints that this strategy could be effective came in April 2009, when Mendell and colleagues announced in Annals of Neurology that injection of alpha-sarcoglycan genes into a foot muscle in three young people with LGMD2D was safe and increased production of the alpha-sarcoglycan protein four to five times over baseline.
About the new grant
The new MDA grant, and funding from Nationwide Children's Hospital, will allow Mendell and colleagues to conduct the testing the U.S. Food and Drug Administration (FDA) requires to obtain permission to conduct a clinical trial of vascular gene delivery in people with LGMD2D.
The proposed human trial, which can be approved only after the testing results have satisfied the FDA, involves injecting alpha-sarcoglycan genes encased in adeno-associated viruses (AAVs), via the bloodstream, to the quadriceps muscles of the leg.
Mendell, a specialist in neuromuscular disease, is director of the Center for Gene Therapy at the Research Institute at Nationwide, where he also co-directs an MDA neuromuscular disease clinic; a professor of pediatrics, neurology and pathology at Ohio State University in Columbus; and a longtime MDA research grantee.
Meaning for people with LGMD2D
Vascular gene delivery to the leg muscles, the ultimate goal of this project, would, if successful, be a major step toward helping people with LGMD2D to walk.
In addition, success in LGMD2D could have implications for other forms of LGMD and perhaps other forms of muscular dystrophy and would suggest that gene therapy is moving ahead. This is good news after some hurdles and setbacks in the field that caused its development to stall in the early part of this decade.
Look for information about the anticipated vascular gene therapy trial as it becomes available online on MDA's Web site and in MDA's Quest magazine.