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Gene therapy reverses muscular dystrophy in mice

Date: Monday, July 11, 2022

Gene therapy was able to repair severely damaged muscle and significantly improved the survival of mice with a particular type of muscular dystrophy, according to a recent study from University of Iowa researchers. 

“Showing that we can rescue muscles already damaged by the disease is an important proof of concept, because most patients with this type of muscular dystrophy are not diagnosed until after onset of muscle degeneration, so any successful therapy would have to be able to repair that damage,” says Kevin Campbell, PhD, professor and chair of molecular physiology and biophysics at the UI Carver College of Medicine, and senior author of the study, which was published in Science Advances. 

Understanding muscular dystrophy

Campbell, who also is a Howard Hughes Medical Institute investigator, has spent decades identifying the genetic and molecular causes of various forms of muscular dystrophy. The discoveries he and his colleagues have made have laid the groundwork for developing gene therapy that could potentially treat these devastating diseases.  

Much of Campbell’s research has focused on a type of muscular dystrophy known as dystroglycanopathies. These conditions are caused by genetic mutations that damage the function of a critical muscle protein called alpha-dystroglycan, which acts as a structural bridge between muscle cells and their surrounding tissue. Specifically, the mutations disrupt the formation of a long sugar molecule called matriglycan that is attached to alpha-dystroglycan and is responsible for stabilizing muscle’s structural integrity.  

Previous work by Campbell’s team found that a protein, known as LARGE, is critical for building the matriglycan chains. Mice that are missing the LARGE protein do not make matriglycan chains and are good models for dystroglycanopathies. As these mice age, their muscles deteriorate, they lose weight, and they have shorter lifespans than wild type mice. The researchers previously showed that overexpressing LARGE can rescue muscle function in mice with dystroglycanopathies. 

Gene therapy rescues muscle and improves survival

In the new study, Campbell and his colleagues used the same genetically engineered mice but allowed them to age and develop advanced muscle disease before treating some of them with gene therapy that delivered LARGE protein back into the muscle cells. The treated mice recovered muscle strength and function, which led to improved mobility and respiratory function, and normalized metabolism. All but one of the treated mice lived to at least 65 weeks of age compared to only 50% of the untreated mice surviving to 45 weeks of age. 

“Although gene therapy has offered promise for treating muscular dystrophies, it hasn’t been clear that it would be able to rescue muscle tissue that had already been damaged by these diseases,” says Campbell, who also is the director of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at the UI. “What these exciting findings show is that skeletal muscle is resilient and plastic enough to recover from the damage, and that advanced disease may indeed be treatable with this approach.”  

In addition to Campbell, the UI research team included first author Takahiro Yonekawa, MD, PhD, and co-senior author Eric Taylor, PhD, as well as Adam Rauckhorst, Sara El-Hattab, Marco, Cuellar, David Venzke, Mary Anderson, Hidehiko Okuma, and Alvin Pewa. 

The study was funded in part by grants from the National Institutes of Health and the American Diabetes Association.