SRP-9004 (MYO-102) is an experimental gene therapy being developed by Sarepta Therapeutics to possibly treat limb-girdle muscular dystrophy type 2D (LGMD2D), a subtype of LGMD that often is diagnosed early in childhood.
How SRP-9004 works
LGMD2D is a rare genetic disease characterized by progressive muscle wasting and weakness. The first muscles affected are those of the shoulders and hips, which can make walking difficult.
LGMD2D is caused by mutations in the SGCA gene, which provides instructions to make a protein called alpha-sarcoglycan, one subunit of a complex protein called sarcoglycan. The sarcoglycan protein complex is normally located in the cellular membrane surrounding muscle cells. It helps maintain the structure of the muscle tissue by binding and stabilizing another protein complex — the dystrophin complex. The dystrophin complex strengthens muscle fibers and protects them from injury as muscles tense and relax by forming an anchor point.
Mutations in SGCA lead to the alpha-sarcoglycan protein not being made correctly, so it does not work as it should. Without alpha-sarcoglycan, the sarcoglycan complex cannot bind and localize properly. Without this complex, muscle cells cannot interact as intended with the dystrophin complex, and muscles are more fragile and easily damaged.
SRP-9004 is a type of gene therapy. It consists of a modified and safe virus that carries a healthy, working copy of the SGCA gene. Once inserted into the cell, the gene should be able to produce the alpha-sarcoglycan protein. This may allow the sarcoglycan complex to assemble normally and interact with the dystrophin complex as it is supposed to, correcting the problems caused by mutations in the patient’s SGCA gene.
SRP-9004 in clinical trials
A Phase 1 clinical trial (NCT00494195) recruited six LGMD2D patients for a dose-ascending, open-label study of safety and efficacy testing SRP-9004. The treatment’s safety was first assessed by injecting it in a single limb of an adult who could no longer walk. The treatment was injected into the patient’s femoral artery (the large blood vessel in the upper leg). After safety was established, five children still able to walk were enrolled and the treatment was injected in both their legs. A limb delivery, rather than systemic delivery, was used because this limits the therapy’s circulation to the treated limb. The six-minute walk test (6MWT) was the trial’s primary outcome measure. Secondary outcomes included a measure of muscle strength and levels of SGCA protein in muscle biopsies.
Study results were published in the journal Human Gene Therapy. All four patients biopsied had confirmed SGCA gene delivery and protein expression. Muscle strength in knee muscles showed improvement in two patients. Walk times in the 6MWT either improved (decreased) or remained the same over an equal distance. Researchers concluded that vascular delivery of SRP-9004 was effective in producing the SGCA protein and could lead to functional improvements in targeted muscles.
A Phase 1/2 clinical trial (NCT01976091) assessed the safety and efficacy of SRP-9004 in people with LGMD2D, assigned to one of three patient groups. The first group (1A) consisted of two wheelchair-dependent adults given a single dose of SRP-9004 in one leg. Three ambulatory (able to walk) patients made up groups 1B and 2. Group 1B received the same dose of SRP-9004 given to 1A but in both legs. Group 2 was a high dose group, given a three-fold larger dose of SRP-9004 in both legs.
Safety was monitored as the primary outcome. The treatment’s efficacy was assessed by the 6MWT as well as direct muscle testing for strength, where patients were asked to move a weight with their leg. Quantitative measures were taken at the study’s start (before treatment); again at days 30, 60, 90, 180; and at the end of the first and second years. A muscle biopsy was taken at the study’s end from treated and untreated legs to compare the size of muscle fibers and look for evidence of toxicity. The study completed in July of 2019 but no results have been announced yet.
SRP-9004 was designated an orphan drug as a possible treatment of LGMD type 2D by the U.S. Food and Drug Administration (FDA) in January 2019. The designation, which applies to therapies for rare diseases, offers incentives to support and speed its development.
Last updated: Oct. 23, 2019
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