Surrogate Gene Therapy Protects Heart Muscle in Model of DMD

Treatment also maintains function of skeletal muscle, providing a tandem of desired impacts

A gene therapy developed at Nationwide Children’s Hospital appears to protect against heart damage in mouse models of Duchenne muscular dystrophy (DMD).

The research comes on top of earlier work showing the therapy, rAAVrh74.MCK.GALGT2, protects against skeletal muscle damage, which, in the natural course of DMD, reduces and eliminates the ability to walk and causes breathing problems as the disease progresses.

“Cardiomyopathy is a significant clinical concern in DMD and accounts for a significant cause of death in this patient population,” says Paul Martin, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and a leader of the research. “This therapy could address a serious issue for longevity.”

The most recent study is published in Molecular Therapy. Martin’s team believes the therapy, which causes the overexpression of the GALGT2 gene, may benefit skeletal and heart muscles in DMD patients and patients with Becker muscular dystrophy.

Children with DMD have a mutated dystrophin gene that results in a lack of functional dystrophin, a protein in their skeletal and heart muscle cells that protects muscle tissue from damage and weakening. Becker patients also have mutations to the dystrophin gene but produce a partially functional protein that results in a milder disease that progresses slower.

rAAVrh74.MCK.GALGT2 uses the adeno-associated virus rh74 to deliver and express the GALGT2 gene therapeutic in muscle cells. Replacing the entire dystrophin gene, one of the largest genes in the human body, is currently not possible using AAV. Instead, this surrogate gene therapy uses the GALGT2 gene to provide muscle protection similar to that provided by a working dystrophin gene. The therapy package includes a promoter, MCK, which enables the overexpression of GALGT2 only in skeletal and heart muscle. The technology is licensed by Sarepta Therapeutics.

In testing, mouse model hearts treated one day after birth prevented early left ventricular remodeling and reduced expression of fibrotic markers . Models treated at two months, which is considered young adulthood in mice, showed significantly improved stroke volume and cardiac output compared to untreated models when both were at 17 months of age, when mice are essentially aged adults.

Analyses showed the treatments resulted in overexpression of GALGT2 in as many as 94 percent of heart muscle cells. Molecular analysis found the therapy increased expression of utrophin protein, which is similar to dystrophin. It also induced a process called glycosylation, which modifies proteins, in this case α-dystroglycan protein. Utrophin and glycosylation of α-dystroglycan can provide protection from wear and tear in skeletal muscle, and this study suggests that they may also do so in heart muscle treated with GALGT2.

Dr. Martin, in collaboration with Kevin Flanigan, MD, and other colleagues in the Center for Gene Therapy, are in the midst of a phase 1/2 trial testing whether GALGT2 overexpression in the legs of DMD patients corrects muscle dysfunction. If the trial proves successful, the researchers plan to use that data and the data from this mouse study to pursue a trial testing the therapy in the heart and all skeletal muscles of children with DMD or Becker disease.

Citation: Xu r, Jia Y, Zygmunt DA, Martin PT. rAAVrh74.MCK.GALGT2 protects against loss of hemodynamic function in the aging mdx mouse heart. Molecular Therapy. 2019 Mar 6;27(3):636-649.