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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

 

Muscular dystrophies (MDs) are genetic disorders that are characterized by progressive striated muscle degeneration. Deletions within the dystrophin gene account for the majority of cases, and loss-of-function mutations in SGCG, which encodes the γ- sarcoglycan transmembrane subunit account for a variety of limb girdle MDs (LGMDs). Antisense oligonucleotide (AON) therapies to promote exon skipping and the generation of truncated, partially functional proteins have been proposed for the treatment of MDs. Quan Gao and colleagues at the University of Chicago developed an exon skipping strategy that uses AONs designed to generate a truncated γ-sarcoglycan protein (termed Mini-Gamma) that retains integral functionality. Similar to full-length γ- sarcoglycan, Mini-Gamma co-localized with β- and δ-sarcoglycan subunits at the plasma membrane when expressed in cultured cells. In both an established Drosophila model of muscular dystrophy and γ-sarcoglycan-deficient mice, Mini-Gamma also localized to the plasma membrane. In the fly model, Mini-Gamma improved motility and restored heart morphology. Expression of Mini-Gamma in Sgcg null mice ameliorated skeletal muscle defects, reduced thickening of the diaphragm muscle, reduced fibrosis, and improved heart function. Importantly, treatment of human LGMD cells with Mini-Gamma produced the properly truncated SGCG transcript. Together, the results of this study demonstrate that AON-mediated exon skipping can rescue MD-associated phenotypes and suggest Mini-Gamma as a promising therapy for individuals with SGCG mutations. The accompanying image shows the expression of Mini-Gamma (green) in the heart tube of a γ-sarcoglycan-deficient fly. Note plasma membrane-associated staining within the heart tube structure. Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. McNally et al 2015.
Muscular dystrophies (MDs) are genetic disorders that are characterized by progressive striated muscle degeneration. Deletions within the dystrophin gene account for the majority of cases, and loss-of-function mutations in SGCG, which encodes the γ- sarcoglycan transmembrane subunit account for a variety of limb girdle MDs (LGMDs). Antisense oligonucleotide (AON) therapies to promote exon skipping and the generation of truncated, partially functional proteins have been proposed for the treatment of MDs. Quan Gao and colleagues at the University of Chicago developed an exon skipping strategy that uses AONs designed to generate a truncated γ-sarcoglycan protein (termed Mini-Gamma) that retains integral functionality. Similar to full-length γ- sarcoglycan, Mini-Gamma co-localized with β- and δ-sarcoglycan subunits at the plasma membrane when expressed in cultured cells. In both an established Drosophila model of muscular dystrophy and γ-sarcoglycan-deficient mice, Mini-Gamma also localized to the plasma membrane. In the fly model, Mini-Gamma improved motility and restored heart morphology. Expression of Mini-Gamma in Sgcg null mice ameliorated skeletal muscle defects, reduced thickening of the diaphragm muscle, reduced fibrosis, and improved heart function. Importantly, treatment of human LGMD cells with Mini-Gamma produced the properly truncated SGCG transcript. Together, the results of this study demonstrate that AON-mediated exon skipping can rescue MD-associated phenotypes and suggest Mini-Gamma as a promising therapy for individuals with SGCG mutations. The accompanying image shows the expression of Mini-Gamma (green) in the heart tube of a γ-sarcoglycan-deficient fly. Note plasma membrane-associated staining within the heart tube structure. Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. McNally et al 2015.

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