An RNA editing technique called “exon skipping” has shown preliminary success in treating a rare and severe form of muscular dystrophy that currently has no treatment, based on a new study from Northwestern University and the University of Chicago. Children with the disease lose significant muscle strength early in life.
The discovery stems from the persistence of a father, Scott Frewing, whose two sons were diagnosed with Limb Girdle Muscular Dystrophy Type 2C, and his partnership with Prof. Elizabeth McNally, A Northwestern genetic scientist who studies muscular dystrophy.
The new therapy has been licensed to the Kurt+Peter Foundation, an organization founded by Frewing along with his family and friends to support muscular dystrophy research, and is being developed with the goal of clinical trials and eventual commercial treatments. In a partnership negotiated by UChicagoTech—UChicago’s Center for Technology Development & Ventures—the University of Chicago, Northwestern University and The Kurt+Peter Foundation will support the development of therapies.
McNally began her research on exon skipping as the director of the Institute of Cardiovascular Research at UChicago. She is now director of the Center for Genetic Medicine at Northwestern University’s Feinberg School of Medicine and a physician at Northwestern Medicine.
Originally developed to treat Duchenne Muscular Dystrophy, another form of muscle disease, exon skipping coaxes cells to “skip” over abnormal sections of the genetic code, so that the body can make a functional protein, which in this case governs muscle function and development.
In a paper published Oct. 12 in the Journal of Clinical Investigation, lead investigator McNally summarizes her research in fruit fly and mouse models. Her team, which included Quan Gao, a UChicago graduate student, and Eugene Wyatt, a postdoctoral fellow at Northwestern, demonstrated that protein made from exon skipping functioned to stabilize and slow progress of the disease. Working with human cells obtained from individuals with the disease, the team showed that exon skipping can be successfully induced with antisense compounds.
“We recognize that this is version 1.0,” McNally said. “But if this can stabilize individuals with this disease, even if it gave them 10 more years of walking, that’s huge. That would also mean 20 to 30 more years of breathing, and that is hugely beneficial for the patients and for their parents who are caring for them. And, of course, we’re interested in developing version 2.0 that will be even better.”
Limb Girdle Muscular Dystrophy is caused by mutations in any of at least 15 different genes and affects one in 14,500 to one in 123,000 annually. Individuals with Limb Girdle Muscular Dystrophy Type 2C have detrimental mutations in a key protein, gamma sarcoglycan, which is necessary for normal muscle development and function. The disease is an inherited disorder that is found in patients around the world and is prevalent in France, northern Africa and parts of South America.
Although children with the disease are able to live normally at young ages, over time their deteriorating muscles prevent them from engaging in a number of typical childhood activities. Many of the children with the disease are in a wheelchair by their mid-to-late teenage years. Frewing’s sons, Kurt and Peter, were diagnosed with the disease in 2009 and 2010 respectively.
A rare partnership
In 2010, Frewing, president of the Kurt+Peter Foundation, began proactively looking for scientists researching Limb Girdle Muscular Dystrophy Type 2C and similar forms of muscular dystrophy, with the hope of supporting research to find a treatment. When Frewing approached McNally in 2010, she was one of the only researchers worldwide working on the disease. Frewing had heard of exon skipping and wondered if it would work for his boys. McNally didn’t think that exon skipping would make the tiny relevant protein in the disease functional. But, after Frewing persisted, she did a predictive analysis, which showed that less than half of the protein would be left, but that three key parts of the protein remained. The Kurt+Peter Foundation has provided annual grants to fund further evaluation and development of this potential therapy.
“There are always new ways to treat a disease, and sometimes it is the patients and families who push us to think of these,” McNally said. “This partnership is a perfect example of how precision medicine can help address very rare diseases.”
The Kurt+Peter Foundation is licensing McNally’s research and hopes to turn her discoveries in the laboratory into treatments that could help to slow the decline in muscle function. The foundation will continue to partner with McNally to further test and develop the therapy.
Obstacles remain to commercialize the treatment, including the high cost of manufacturing the antisense oligonucleotides, the molecules that function to regulate gene expression that are necessary to make the treatment.
“We are thrilled to be able to continue development of this promising treatment technique,” Frewing said. “This is a terrible disease affecting children worldwide, and we hope to soon be able to provide families with treatment techniques that can lessen the disease’s severity.”
The agreement among the Kurt+Peter Foundation, UChicago and Northwestern is the first license UChicago has executed with a foundation.
“This arrangement is a great example of how research institutions and foundations can bring their respective strengths and resources to the table and work together to develop new therapeutics for small groups of patients,” said Thelma Tennant, assistant director at UChicagoTech. “In a purely market-driven world, these patients would have very few options.”