Originally developed by researchers at the Nationwide Children’s Hospital Center for Gene Therapy in Columbus, Ohio, SRP-9003 is currently being tested in clinical trials supported by Sarepta Therapeutics.
How SRP-9003 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.
SRP-9003 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.
SRP-9003 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.
SRP-9003 in clinical trials
In an LGMD2E mouse model, treatment with SRP-9003 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). SRP-9003 also significantly alleviated the bend in the spines of the LGMD2E mice and improved their mobility. No adverse effects of SRP-9003 were noted.
An ongoing Phase 1/2 clinical trial (NCT03652259) is evaluating the efficacy and safety of SRP-9003 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, a single, intravenous (IV) injection. Based on their response, the SRP-9003 dose may be increased for the next group of patients. In this second group, six patients will be randomly assigned to receive SRP-9003 or a placebo. The placebo-treated patients will receive SRP-9003 after the study is completed.
A preliminary report showed promising results from the first three patients treated with SRP-9003. 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 results of those first 3 patients were announced by Sarepta in October of 2019. All 3 patients showed functional and biomarker improvements 270 days after treatment. Creatine kinase, which is associated with muscle damage, was lower than baseline in all 3 patients and there was improvement in the North Star Assessment for Dysferlinopathy (NSAD) score, time-to-rise, four-stair climb (time to climb four stairs), 100-meter walk time test, and 10-meter walk time test.
The trial is still enrolling participants for the second cohort of the study at Nationwide Children’s Hospital and is expected to be completed in December 2020.
SRP-9003 received orphan drug designation from the U.S. Food and Drug Administration (FDA) in April 2018. The SRP-9003 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: Oct. 15, 2019
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