RNA Interference May Provide the First Therapy for Facioscapulohumeral Muscular Dystrophy

July 23, 2012

Scientists may one day be able to treat the third most common muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), by taking advantage of a system within living cells that helps control gene activation. A recent Nationwide Children’s Hospital study provides the first evidence that RNA interference can reduce expression of the gene suspected to cause muscle deterioration in FSHD patients.   

Patients are typically diagnosed with FSHD during young adulthood. Over years, their facial and shoulder girdle muscles progressive waste away and they eventually become wheelchair-dependent.  There is currently no treatment for FSHD and very few FSHD-targeted translational studies have been published.

“FSHD is a complex disease and it has taken nearly two decades for scientists to decipher the mechanisms underlying its development,” said Scott Harper, PhD, principal investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital. “Unlike other muscular dystrophies, FSHD is not caused by mutations in the coding region of a single gene.  It requires complex genetic changes that allow one or more genes to be overexpressed.”

Several candidate genes have been identified, but the current consensus is that the overexpression of the DUX4 gene is FSHD’s primary contributor. “We have been able to overexpress DUX4 in muscle of zebra fish and mice,” said Dr. Harper, the study’s lead author. “What we see are abnormalities associated with muscular dystrophy.”   

In the study appearing in Molecular Therapy, Dr. Harper and colleagues at Nationwide Children’s used RNA interference to reduce DUX4 expression. RNA interference (RNAi) involves delivering RNA molecules to specific regions within the body in an attempt to reconfigure which proteins are being produced. RNAi has been used to try and suppress dominant genes in HIV and Huntington’s disease, but applying it to muscle diseases is a new direction for this therapeutic strategy.

Dr. Harper’s team used a viral vector to deliver an engineered microRNA to the muscle of mice overexpressing DUX4. Results showed that the approach was able to silence DUX4 gene expression, with no evidence of toxic side effects.  

“Our data demonstrate proof-of-principle for DUX4 gene silencing as a promising therapeutic approach for FSHD,” said Dr. Harper. Dr. Harper emphasizes that there is much work still to be done, but says we are entering an exciting period of FSHD research. “New basic discoveries have opened the door to begin developing, for the first time, FSHD-specific therapeutic strategies,” he said. “Such approaches will likely include DUX4 inhibition, as we described here using RNAi.  RNAI therapy is still a new and clinically unproven approach. Still, our findings set the stage for applying the approach to muscle diseases like FSHD.”  

Wallace LM, Liu J, Domire JS, Garwick-Coppens SE, Guckes SM, Mendell JR, Flanigan KM, Harper SQ. RNA Interference Inhibits DUX4-induced Muscle Toxicity In Vivo: Implications for a Targeted FSHD Therapy. Mol Ther. 2012 Apr 17. doi: 10.1038/mt.2012.68. [Epub ahead of print]

About Nationwide Children's Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2019-20 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit freestanding pediatric health care systems providing wellness, preventive, diagnostic, treatment and rehabilitative care for infants, children and adolescents, as well as adult patients with congenital disease. Nationwide Children’s has a staff of more than 13,000 providing state-of-the-art pediatric care during more than 1.5 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Abigail Wexner Research Institute at Nationwide Children’s Hospital is one of the Top 10 National Institutes of Health-funded freestanding pediatric research facilities. More information is available at NationwideChildrens.org.