|R. Jude Samulski|
A clinical trial designed to replace the genetic defect causing the most common form of muscular dystrophy has uncovered an unexpected aspect of the disease. The trial, based on therapy designed by scientists at the University of North Carolina at Chapel Hill School of Medicine, showed that some patients mount an immune response to the dystrophin protein even before they have received the gene therapy.
According to a press release, the puzzling results, which came from trials at Columbus Children’s Hospital in Ohio, suggest that the immune systems of a number of patients — once thought to be completely devoid of the dystrophin protein — are actually primed by the prior existence of tiny amounts of this important component of muscle.
Published in the New England Journal of Medicine, the study demonstrates how such careful and critical observation in early clinical trials of new therapies can yield new insights into the causes of even the “simplest” single gene disorders.
“These findings are going to be studied intensely going forward, and should help us to understand how to better tailor our treatment approaches to suit the patients’ needs,” study author R. Jude Samulski, professor of pharmacology and director of the Gene Therapy Center at UNC, stated in a press release.
Duchenne muscular dystrophy is a genetic disease that begins in early childhood, causes progressive muscle weakness, and usually leads to death by the age of 20 years from respiratory or cardiac muscle failure. The illness, which primarily affects boys, occurs when a gene on the X chromosome fails to make the essential muscle protein dystrophin. Currently, the best medical therapy can only slow its progression.
The use of gene therapy to correct such single gene disorders has been explored for more than two decades and has been met with a number of challenges. In the case of muscular dystrophy, the dystrophin gene is far too large to fit into the typical virus used to carry it into the patient’s cells. So collaborator Xiao Xiao, PhD, from UNC Eshelman School of Pharmacy, engineered a smaller yet functional version of the gene — called a minigene — to place within the viral carrier. His virus of choice was adeno-associated virus or AAV, a small virus that most humans are exposed to at some point in life.
In the first trial of this form of gene therapy, which began in 2006, six boys with muscular dystrophy received the virus containing the dystrophin minigene. A phase I trial, the goals of the study were to assess the efficacy and safety of the new approach. The replacement genes were injected into the bicep in one arm and a placebo was injected into the other arm of each of the patients.
The researchers found that the immune response to the gene varied from patient to patient, perhaps in part because the patients harbored different amounts of “revertant” dystrophin fibers, fibers that have escaped the fate of their mutation. This finding suggests that some patients may benefit from immunosuppression prior to receiving gene therapy.