Innovative gene therapy research for muscular dystrophy

A major grant of approximately $10 million from the National Institutes of Health will help investigators at Columbus Children's Research Institute (CCRI) at Columbus Children's Hospital learn more about strategies to treat muscular dystrophy, potentially leading to two new gene therapy approaches.

Muscular dystrophy is a group of debilitating hereditary diseases characterized by progressive muscle weakness. Duchenne muscular dystrophy (DMD), the most common and severe form of the disease, is caused by a deficiency of the dystrophin gene in skeletal and heart muscle.

The grant, from the National Institute of Neurological Disorders and Stroke, will provide funding for two diverse projects based upon proven laboratory investigations from members of the Center for Gene Therapy at CCRI.

The primary research focus is to use the circulatory system for gene delivery of the dystrophin gene, as opposed to gene injections into single muscle groups. The vascular delivery strategy provides a more favorable opportunity for correction of lost function throughout the body reaching many muscles, as well as the heart.

The first project, led by Jerry Mendell, MD, director of the Center for Gene Therapy, and K. Reed Clark, PhD, a principal investigator in the Center, will investigate the use of an adeno-associated virus (AAV) to deliver the dystrophin gene. Laboratory models have shown that AAV is ideally suited to be the carrier for the gene. An important potential obstacle to success is the immune system, normally in place to rid the body of viruses. Mendell and his team, including Louis Chicoine, M.D. and Brian Coley, M.D., will use specially designed catheters placed into the blood vessels of experimental models to protect the virus carrying the gene from attack by the immune system.

In addition to protecting the virus from exposure by use of catheters, immunosuppressant drugs will be tested in this system. As the virus leaves the body, the drugs should no longer be needed. Studies performed by this team, with special supervision by Christopher Walker, PhD, director of the CCRI Center for Vaccines and Immunity, will also determine if it is possible to use these medications to re-administer, at a later time, the virus carrying the dystrophin gene. This research is expected to lead to an investigational new drug study in patients with DMD.

The second project will be led by Paul Martin, PhD, also a principal investigator in the Center for Gene Therapy. It involves the study of CT GalNAc transferase, an enzyme normally expressed in muscle tissues. However, previous studies have shown that expression of CT GalNAc transferase under certain conditions may actually replace the dystrophin function in muscle cells, thus serving as a substitute, or “surrogate gene,” showing promise as another treatment option for DMD. As with the first project, the goal of this research is to gain positive results leading to an investigational new drug application.

“This grant and the studies it funds offer a precedent-setting opportunity for Columbus Children's Hospital. We're bringing together major resources and numerous investigators to collaborate on a common goal,” said Dr. Mendell. “Current limitations for vector production and unproven immune responses to these virus delivery systems are some of the obstacles we have confidence will be overcome, leading to effective therapy against muscular dystrophy.”

“The innovative strategies and collaborative efforts of these investigators resulted in an outstanding NIH grant award, which adds to the tremendous growth in our body of work over the last few years,” said John Barnard, MD, president, CCRI. “This level of funding is positive proof that our research initiatives are on track and highly valued for the promise they offer in treating deadly childhood diseases.”