Gene Therapy Reveals Unexpected Immunity to Dystrophin in Patients with Duchenne Muscular Dystrophy

An immune reaction to dystrophin, the muscle protein that is defective in patients with Duchenne muscular dystrophy, may pose a new challenge to strengthening muscles of patients with this disease, suggests a new study appearing in the October 7, 2010, issue of The New England Journal of Medicine.

Duchenne muscular dystrophy (DMD) is a hereditary and lethal neuromuscular disease characterized by progressive loss of muscle strength and integrity. Genetic information important for production of a functional dystrophin protein is deleted from the DMD gene of many patients. Studies by investigators at Nationwide Children’s Hospital have examined the possibility of improving muscle strength by using modified viruses to deliver a corrected copy of the DMD gene to patients’ muscles.

“DMD genes packaged into viral vectors strengthen muscles in mouse models of muscular dystrophy,” said Jerry R. Mendell, MD, director, Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital and one of the study authors.

“In this study we attempted to translate basic research from the animal model to patients with DMD.” Six boys with DMD gene deletions were treated by injecting a viral vector containing a corrected DMD gene into the biceps muscle of one arm. However, when the patients were evaluated three months later, long-term production of dystrophin protein from the corrected DMD gene was not detected.

"With one safety trial involving six patients, Drs. Mendell and Walker have provided a tremendous service to scientists advancing gene therapy research - particularly for muscular dystrophy," said Louis M. Kunkel, Ph.D., chairman of the MDA Scientific Advisory Committee. "By uncovering a somewhat surprising T cell immune response to dystrophin, they're helping investigators refine several distinct and promising approaches to treating Duchenne muscular dystrophy (DMD) by correcting or adding the dystrophin protein that is defective in the disease."

To understand why this therapy failed, the researchers measured immune responses against dystrophin. “We were concerned about immunity caused by a certain type of white blood cell called the T lymphocyte. The natural role of T cells is to protect us from infection and cancer by destroying cells that are recognized as different or foreign,” said Christopher M. Walker, PhD, director, Center for Vaccines and Immunity at The Research Institute and one of the study authors. “Parts of the corrected dystrophin protein are clearly foreign because of the patient’s DMD gene deletion, and so unwanted T cell immunity targeting the repaired muscle cells was a possibility.”

The researchers did detect T cell immunity was against foreign segments of the corrected dystrophin protein in one patient with a large DMD gene deletion. However, stronger and faster T cell immunity was detected in a second patient with a much smaller DMD gene deletion.

“Strong, rapid immunity in the second patient with a very small DMD gene deletion was a surprise,” said Dr. Walker. “The amount of corrected dystrophin protein that is foreign should also be small, and possibly ignored altogether by the T cells.”