Systemic Gene Therapy Holds Promise for Treating Certain Muscular Dystrophies

Columbus, OH — September 2017

The symptoms of dysferlinopathy first appear in the teens or early twenties and are characterized by slowly progressive muscle weakness. Regardless of where the muscle weakness begins, the disease progresses to the majority of muscles in the trunk, all limb muscles, the diaphragm, and, in some cases, the heart.

Dysferlinopathy is caused by mutations in the dysferlin gene. Since the exact genetic defect is known, it can be targeted by gene therapy.

Previous work from Louise Rodino-Klapac, PhD, principal investigator in the Section of Neurology and the Center for Gene Therapy at Nationwide Children’s Hospital, demonstrated that a gene therapy vector was effective in mouse models of dysferlinopathy when delivered to an individual muscle. However, for eventual use in human patients, systemic administration would be preferable, as it can target all the affected muscles.

In a new study, Dr. Rodino-Klapac and colleagues show that systemic delivery of a gene therapy vector is safe and effective in animal models of dysferlinopathy.

Dr. Rodino-Klapac and colleagues treated dysferlin-deficient mice systemically with their gene therapy vector and evaluated them for more than a year using measures of functional improvement and magnetic resonance imaging (MRI). Systemic treatment resulted in widespread DYSF gene expression in the muscles and functional recovery.

“In this long-term study, our MRIs showed that after 15 months, we could preserve the muscles, whereas untreated mice had hardly any muscle left,” says Dr. Rodino-Klapac, who is also an associate professor of Pediatrics at The Ohio State University College of Medicine.

The safety and efficacy results confirm previous findings and validate translation of systemic gene delivery for dysferlinopathy patients.

What’s more, the results suggest patients may be able to benefit from gene therapy regardless of the state of their disease. Although the most striking results were obtained with young mice treated prior to disease onset, the researchers also achieved positive results in aged animals. When six month-old mice that were already exhibiting muscle loss were treated, they still experienced muscle membrane repair. So while systemic treatment at a young age may prevent dysferlinopathy, starting treatment after symptoms arise may still help patients regain some muscle loss.

This study sets the stage for the next clinical trial, says Dr. Rodino-Klapac.

“We will initiate the study in the next one to two years and the goal will be to show that intravenous gene therapy is safe and clinically effective in dysferlinopathy patients,” she says. “The results of this current study have paved the way for gene therapy in humans by establishing efficacy, safety, and absence of toxicity in different animal models.”

There is no cure or treatment for dysferlinopathy. However, gene therapy is a promising avenue for one day stopping the progression of dysferlinopathy in its tracks.

Potter RA, Griffin DA, Sondergaard PC, Johnson RW, Pozsgai ER, Heller KN, Peterson EL, Lehtimäki KK, Windish HP, Mittal PJ, Albrecht DE, Mendell JR, Rodino-Klapac LR. Systemic delivery of dysferlin overlap vectors provides long-term gene expression and functional improvement for dysferlinopathy.Human Gene Therapy.2017 Jul 13. [Epub ahead of print].