Precision medicine for severe muscular dystrophy heads for clinical trials.
Limb Girdle Muscular Dystrophy is caused by mutations in any of at least 15 different genes and affects 1 in 14,500 to 1 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 in their mid-to-late teenage years with no cure currently available.
Now, researchers at Northwestern Medicine and the University of Chicago have used an RNA editing technique called ‘exon skipping’, showing preliminary success in treating Limb Girdle Muscular Dystrophy. The team state that their findings take a massive step towards providing families with treatment techniques that can lessen the disease’s severity. The opensource study is published in the Journal of Clinical Investigation.
Previous studies show that exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. 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. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. The current study showed that multiple exon skipping could be induced in RNA that encodes the mutant human γ-sarcoglycan found in Limb Girdle Muscular Dystrophy, thus expanding on previous Duchenne muscular dystrophy studies.
The current study used fruit flies and mouse models to demonstrate that protein made from exon skipping was successful in stabilizing and slowing progress of the disease. Results showed that exon skipping can be successfully induced with antisense compounds in human cells obtained from individuals with the disease. The lab hypothesize if this can stabilize individuals with this disease, even if it gave them 10 more years of walking, that’s huge. They go on to add 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.
The team surmise that their study has demonstrates that exon skipping is plausible, since the mRNA product can be detected. They go on to add that further optimization is required to demonstrate that protein made from exon skipping is expressed in cell lines from human patients. For the future, the researchers are looking to clear the hurdles necessary to begin clinical trials and stress that 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.
Source: Northwestern University