Originally developed by researchers at the Nationwide Children’s Hospital Center for Gene Therapy in Columbus, Ohio, MYO-101 is currently being tested in clinical trials supported by Sarepta Therapeutics.
How MYO-101 works
LGMD type 2E (LGMD2E) is a type of muscular dystrophy caused by a mutation in the SGCB gene that provides the instructions to make a protein called beta-sarcoglycan. Beta-sarcoglycan is part of a larger protein called the sarcoglycan protein complex, which is vital for muscle tissue health. The sarcoglycan protein complex maintains muscle structure by binding to and stabilizing dystrophin proteins, which strengthen and protect muscle fibers.
In LGMD2E, a mutation in SGCB results in insufficient levels of beta-sarcoglycan being produced. Decreased levels of beta-sarcoglycan hinder the proper formation of the sarcoglycan protein complex, which interferes with the functioning of dystrophin. As a result, muscles weaken, causing the symptoms associated with LGMD. The defect is more pronounced in skeletal, heart, and diaphragm muscles.
MYO-101 aims to restore the levels of beta-sarcoglycan in muscle tissues by delivering a functional copy of the human SGCB gene to skeletal, heart, and diaphragm muscles. AAVrh74, a virus which is modified to be harmless and have increased affinity to these muscles, is used for the targeted delivery of the healthy gene.
MYO-101 also uses MHCK7, a muscle-specific promoter or DNA sequence that controls the activity of a gene, to specifically enhance SGCB activity in muscle cells.
MYO-101 in clinical trials
In an LGMD2E mouse model, treatment with MYO-101 improved the force produced by the diaphragm by 94.4%, thereby improving breathing (the diaphragm is the skeletal muscle that supports breathing and sits below the lungs). MYO-101 also significantly alleviated the bend in the spines of the LGMD2E mice and improved their mobility. No adverse effects of MYO-101 were noted.
An ongoing Phase 1/2 clinical trial (NCT03652259) is evaluating the efficacy and safety of MYO-101 in children, 4 to 15 years old, with LGMD2E. The study aims to enroll a minimum of nine participants. Initially, three patients will receive the treatment. Based on their response, the MYO-101 dose may be increased for the next group of patients. In this second group, six patients will be randomly assigned to receive MYO-101 or a placebo. The placebo-treated patients will receive MYO-101 after the study is completed.
A preliminary report showed promising results from the first three patients treated with MYO-101. Two months after treatment, muscle biopsies revealed the presence of beta-sarcoglycan in 51% of the patients’ muscle fibers. Researchers also found a significant reduction in muscle damage as seen by a more than 90% decrease in blood levels of creatine kinase, a biomarker for muscle damage. Levels of liver enzymes (an indicator of liver damage) were elevated in the patients’ blood, which was resolved with steroid treatment. No other serious adverse events were reported.
The trial is still enrolling participants at Nationwide Children’s Hospital and is expected to be completed in December 2020.
MYO-101 received orphan drug designation from the U.S. Food and Drug Administration (FDA) in April 2018. The MYO-101 development program was also granted a rare pediatric disease designation by the FDA, which makes the therapy eligible for priority review, potentially accelerating its approval.
Last updated 07/18/2019
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