Last updated March 10, 2022, by Teresa Carvalho, MS

✅ Fact-checked by José Lopes, PhD

SRP-9003 is a gene therapy candidate for limb-girdle muscular dystrophy (LGMD) type 2E being developed by Sarepta Therapeutics.

The treatment, formerly known as MYO-101, was initially developed at Nationwide Children’s Hospital, in Columbus.

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 the sarcoglycan protein complex, which is vital for muscle tissue health. This 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 — particularly in the shoulders, hips, and limbs — weaken and waste away.

SRP-9003 aims to restore the levels of beta-sarcoglycan in muscle tissues by delivering a functional copy of the SGCB gene to skeletal muscle, heart, and diaphragm. The diaphragm is the dome-shaped muscle that plays a key role in breathing.

AAVrh74, a virus 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 — a DNA sequence that controls the activity of a gene — to specifically enhance SGCB activity in muscle cells. MHCK7 is particularly important due to its ability to strongly express in the heart, which may be severely affected in people with LGMD2E.

SRP-9003 in clinical trials

An ongoing Phase 1/2 clinical trial (NCT03652259) is evaluating the efficacy and safety of SRP-9003 in children and adolescents, ages 4 to 13, with LGMD2E. Six patients were recruited and divided into two groups. Three children in group 1 received low dose SRP-9003 by intravenous (into-the-vein) infusion, while the three patients in group 2 were given a higher dose.

The trial’s main goal is to determine treatment-emergent adverse events. Secondary assessments include beta-sarcoglycan expression (production), assessed by muscle biopsies before and after treatment, as well as functional tests such as the North Star Assessment for Dysferlinopathy (NSAD), used to assess motor abilities. Timed tests also have been conducted, including time-to-rise, four-stair climb (time to climb four stairs), and the 100- and 10-meter walk time tests.

Results from muscle biopsies taken two months after treatment in the low-dose group showed 51% of muscle fibers were positive for beta-sarcoglycan, which was sustained at 48% at two years. In biopsies taken at two months, the researchers found mean beta-sarcoglycan levels at 72% of normal in the high-dose group. Benefits were sustained after one year, data showed.

Improvement in NSAD score and timed tests have been observed in the low-dose group at six months, one and two years, and in the high-dose patients at six months and one year.

In addition, muscle damage was significantly reduced, as seen by a decrease in blood levels of the biomarker creatine kinase. The low-dose group showed a 77% decrease at two years, while a 74% reduction was seen in the high-dose group at one year.

Levels of liver enzymes, an indicator of liver damage, were elevated in two low-dose patients, but this was resolved with steroid treatment. All adverse events in the high-dose group were resolved with therapy.

Other information

The U.S. Food and Drug Administration (FDA) awarded SRP-9003 orphan drug designation in April 2018. This designation provides financial benefits, exemption from fees, and seven years of market exclusivity should the therapy be approved.

SRP-9003 also received rare pediatric disease designation from the FDA, which grants eligibility for a priority review voucher if SRP-9003 is approved.


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