New treatment strategy for dominant forms of muscular dystrophy

Investigators at The Research Institute at Nationwide Children's Hospital are studying a potential new treatment strategy for dominant forms of muscular dystrophy, thanks to preliminary funding from The Ohio State University Center for Clinical and Translational Science.

Muscular dystrophy is a group of inherited, sometimes life-threatening disorders involving muscle weakness and muscle tissue loss that gets worse over time.

"We know that mutations in at least 29 genes give rise to dominant myopathy," said Scott Harper, PhD, principal investigator in the Center for Gene Therapy at The Research Institute. Muscular dystrophy gene therapy has primarily focused on recessive genetic disorders, because the technology to replace missing recessive genes in muscle has already been developed.

"Autosomal dominant forms of muscular dystrophy would not benefit from gene replacement strategies, but instead would be treatable by knocking down expression of toxic genes," said Dr. Harper. Because feasible technology to accomplish this gene knockdown did not exist, dominant muscular dystrophies were historically difficult to treat. "But this is an important group of disorders, since two of the three most common types of muscular dystrophy are autosomal dominant," said Dr. Harper.

Seeing the need to develop new treatment options for autosomal dominant forms of muscular dystrophy, Dr. Harper submitted his project "A translational approach toward RNAi therapy for facioscapulohumeral muscular dystrophy" to The Ohio State University Center for Clinical and Translational Science. In 2009, he received a KL2 award.

With the KL2 funds, Dr. Harper hired a post-doc to lead the project. Together they worked to determine whether RNA interference (RNAi) could be used as a potential therapy for muscle disease. "RNAi takes advantage of a system within living cells that helps control which genes are expressed and how active they are," said Dr. Harper. "RNAi has been used to suppress dominant genes in HIV and Huntington's disease. No one had tried to apply RNAi to muscle disorders."

Dr. Harper's group used the RNAi strategy to knock down the FRG1 gene in a model of facioscapulohumeral muscular dystrophy and the DUX4 gene, which they found has the potential to cause muscular dystrophy. "Using the KL2 funding, we were able to prove that RNAi could be a potential therapy for muscle disease," said Dr. Harper. "It has opened up an entirely new arm of research in our lab."

Thanks to the data gathered in the KL2-funded study, Dr. Harper was able to secure an Exploratory/Developmental Research Grant Award (R21) from the National Institutes of Health (NIH). "An R21 application in this translational program requires data showing that the approach you're suggesting to use actually does work," said Dr. Harper.

With the NIH funds, Dr. Harper and his post-doc will use the RNAi strategy to suppress expression of the myotillin gene, which is known to cause an autosomal dominant form of limb girdle muscular dystrophy, in a preclinical mouse model. They will then use data from the R21 study to apply for a U01 grant to support a clinical study.

"I think we have our foot in the door to really develop a translational study that can someday be used to treat human disease," said Dr. Harper.