Therapies Improve Life for Youth with Muscular Dystrophy

Research led by experts at Cincinnati Children’s Heart Institute is providing hope for muscular dystrophy patients. Gene therapy treatments and new ways to provide better heart care for children and young adults living with muscular dystrophy can improve quality of life.

As more muscular dystrophy therapies advance through clinical testing, cardiologists are paying attention to what those treatments mean for the heart over the long term, says Chet Villa, MD, a pediatric cardiologist who specializes in heart failure.

Duchenne, the most common type of muscular dystrophy, is X chromosome-linked and only impacts boys. With better treatment of the skeletal muscle component of the disease, greater than 50 percent of boys with Duchenne muscular dystrophy (DMD) are now dying from cardiac manifestations of the disease.

“Our goal is to show how or if gene therapy and other new skeletal muscle therapies impact the heart,” Villa says. “These medications appear to keep boys stronger for longer, but their impact on the heart is really unknown.”

Modified Viruses Show Benefits in Mouse Models

Work directed by Doug Millay, PhD, a scientist with the Division of Molecular Cardiovascular Biology was funded by the National Institutes of Health through a Research Innovations for Scientific Knowledge (RISK) award. Millay’s lab showed the feasibility of a completely novel approach where viruses are modified to therapeutically deliver the missing gene responsible for DMD.

This new therapy uses enveloped viruses coated with myogenic cell fusogens–known as myomaker and myomerger–to target skeletal muscles for gene delivery. The research was published in the journal Cell in April 2023.

In Millay’s lab, Sajedah Hindi, PhD, reengineered those fusogens onto the virus surface to deliver therapeutic material (the expression of the missing gene) to the muscle cells. This creates a first-of-its-kind specialized class of delivery vehicles.

Specifically, the reengineered virus system successfully delivered a version of the dystrophin gene that is missing in DMD. Millay’s lab showed that skeletal muscle in a mouse model of DMD received the modified dystrophin gene into the diaphragm muscle where it resulted in improved function and less disease.

Researchers hope using this approach to deliver modified viruses or even lipid nanoparticles will allow for repeated treatments without an immune rejection response. Much testing must occur to ensure the muscle fusogen vehicles are safe and nontoxic. Plans for testing in large animal models of DMD are underway, Millay says.

Optimizing Cardiac Clinical Care of DMD Patients

Cincinnati Children’s also is working on ways to adopt these same therapies to address heart pathology and lethality due to DMD, which has traditionally lagged behind treatments for skeletal muscle. For example, in the past, many DMD patients were not offered ventricular assist devices (VADs) as their hearts began to fail. And current gene therapy strategies in DMD do not effectively target the heart.

To address these limitations and move heart research forward in DMD patients, Villa and his colleagues–with funding from the Parent Project Muscular Dystrophy (PPMD)–are innovating new ways to treat heart failure in these patients.

Their research will investigate how early treatment of the heart and skeletal muscle impact heart function over time. Then, later in the disease course, the focus will be to identify which patients may benefit most from advanced therapy, including the use of VADs.

“While DMD is the most common childhood muscular dystrophy, it is still somewhat rare, so tracking long-term cardiac outcomes has been a challenge,” Villa says. “By working together, we can understand what new therapies are making a difference faster.”

New questionnaires and methods for assessing patients with muscular dystrophy are also being created to better determine how therapies impact symptoms and quality of life.

Read about another muscular dystrophy research breakthrough also ongoing within the Heart Institute.