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 Muscular Dystrophy Association (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.”
The mystery deepened further when T cell immunity to dystrophin was found to have been present in this patient even before treatment. Careful examination of the muscle revealed that the T cells present before gene therapy recognized dystrophin that is produced in a very small percentage of muscle cells that naturally self-correct the defective DMD gene. Delivery of the gene therapy vector to biceps muscle boosted and accelerated this pre-existing immune response.
“This study is significant because it documents immunity against a dystrophin protein designed to treat the disease. That may be broadly important to the entire field of gene therapy,” said Dr. Mendell. “But it is even more important because of what it might mean for our basic understanding of muscle disease in DMD. We’ve known for a long time that T cells naturally invade muscles of DMD patients. Drugs that suppress immunity can prolong the time until they are confined to a wheelchair, but we never knew how or why this worked. This gene therapy study has lead to the new basic discovery that even small amounts of dystrophin naturally produced from self-correcting DMD genes can trigger destructive T cells, and they may target muscle cells in a process that resembles autoimmunity.”
“The results from this small gene therapy trial underscore the importance of rigorous safety monitoring during all phases of clinical trials, but particularly at the early stages,” said neurologist Valerie Cwik, MDA executive vice president for research and medical director. “The wealth of information about the immune system’s reaction to gene therapy obtained from this study will aid in design of future clinical trials for DMD and, perhaps, other genetic neuromuscular diseases.”
“Many of the on and off switches that regulate T cell immunity in humans are being identified,” said Dr. Walker. “We are now attempting to manipulate these switches to enhance T cell immunity in patients with cancer and chronic viral infections. Once we understand the scope and significance of the T cell response against muscle in DMD, it may be possible to harness the same approaches to shut them off. This would move us closer to the goal of slowing muscle loss in DMD and ultimately to prevent immune responses against therapeutic dystrophin protein.”
This research was made possible by support from the Muscular Dystrophy Association and Jesse’s Journey, and the U.S. Department of Health and Human Services.