(From the December 2015 issue of Research Now)
Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disorder that affects 1/5,000 males born. DMD is caused by mutations in the DMD gene, which provides instructions for making a protein called dystrophin that is located primarily in the skeletal and cardiac muscles. This absence of dystrophin results in progressive or worsening muscle weakness, leading to a loss of walking ability in the early teens and premature death in the early 20s.
Because direct gene replacement using mini- or micro-dystrophins poses a number of challenges, in part due to the adverse immune response involved in gene transfer, a recent study published in the journal Human Gene Therapy investigated whether an alternative strategy could serve as a potential therapy for DMD.
“We had two motivations for this study,” explains Louise Rodino-Klapac, PhD, principal investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital and senior author of the study. “First, we wanted to develop a therapy for DMD that was universal, meaning that it does not depend on what type of mutation a DMD patient has. As a second benefit, we wanted to combine this therapy with another therapy that replaces the dystrophin gene, for an additive effect.”
Specifically, Dr. Rodino-Klapac and her team built upon the work of their lab led by Kristin Heller, PhD, and others, who have researched the potential of alpha7 as a therapy for DMD. Alpha7 integrin is a protein that is encoded by the ITGA7 gene and is highly expressed in cardiac and skeletal muscle. Altered expression levels of alpha7 integrin have been identified in various forms of muscular dystrophy, including DMD.
“As part of this study, we created a gene therapy virus that contains the alpha7 integrin gene and injected it intravenously to a severe mouse model of DMD,” says Dr. Rodino-Klapac, who is also an assistant professor in the Department of Pediatrics at The Ohio State University College of Medicine. “We then tested the mice for expression of the alpha7 integrin gene and measured its ability to restore strength to the mouse.”
According to Dr. Rodino-Klapac, the most important finding is that the alpha7 integrin gene therapy extended the lifespan of models with severe DMD, restoring strength and preventing kyphosis, or curvature of the spine. The functional improvements demonstrated by the study highlight the benefit of increased overexpression of ITGA7 as a potential therapy for DMD.
However, additional research needs to be conducted to evaluate the efficacy of this gene therapy to obtain a better understanding of what would be required in human clinical trials.
“We would like to test ITGA7 gene therapy in a larger animal model of DMD,” says Dr. Rodino-Klapac, “In addition, our team would also like to test its effectiveness in combination with other gene replacement strategies.”
The study team also consisted of Jerry R. Mendell, MD, director of the Center for Gene Therapy; Kristin Heller, PhD, postdoctoral scientist in the Rodino-Klapac Lab at the Center for Gene Therapy; K. Reed Clark, PhD, former principal investigator at the Center for Gene Therapy; Kimberly Shontz, research associate in the Mendell Lab; and Chrystal Montgomery, research chief associate in the Mendell Lab in The Research Institute at Nationwide Children’s.
Heller KN, Montgomery CL, Shontz KM, Clark KR, Mendell JR, Rodino-Klapac LR. Human Alpha7 Integrin Gene (ITGA7) Delivered by Adeno-Associated Virus Extends Survival of Severely Affected Dystrophin/Utrophin-Deficient Mice. Human Gene Therapy. 2015; 26(10):647-656.