rAAVrh74.MCK.GALGT2, or short GALGT2 gene therapy, is an experimental treatment for Duchenne muscular dystrophy (DMD) being developed by Sarepta Therapeutics and tested in collaboration with the Nationwide Children’s Hospital in the U.S.
How it works
GALGT2 gene therapy uses adenovirus-based vectors (AAVs) to deliver the GALGT2 gene to the body. Adenoviral vectors are commonly used for gene therapy. They are not harmful because any disease-causing genes have been removed. The rAAVrh74-vector is designed in a way that makes the GALGT2 gene active in skeletal and heart muscle cells — the kind of cells that are affected in DMD.
The GALGT2 gene provides instructions to build a protein that upregulates, or increases, the production of other proteins essential for muscle function. Because it does not replace the defective gene itself (the DMD gene), the therapy is called surrogate gene therapy. Surrogate therapy has not only the potential to correct muscle pathologies, or abnormalities, that are caused by mutations in the DMD gene, but also other muscular dystrophies, such as limb girdle muscular dystrophy 2A (LGMD2A) and congenital muscular dystrophy type 1a (MDC1A).
rAAVrh74.MCK.GALGT2 in clinical trials
A preclinical study in a mouse model of DMD assessed the effect of GALGT2 gene therapy on heart function. The mice carried a mutation in the DMD gene that leads to an almost complete absence of the dystrophin protein. One group of mice received GALGT2 gene therapy one day after birth. At three months of age, the therapy had significantly improved heart function and cardiac output — the amount of blood pumped from the heart — compared with control mice. A second group of mice was treated at two months of age and was analyzed 15 months later. GALGT2-treated mice again had better heart function than control mice. GALGT2 gene therapy was well-tolerated, suggesting that the treatment is not toxic at the tested doses.
An open-label Phase 1/2 clinical trial (NCT03333590) assessing the safety and efficacy of GALGT2 gene therapy is ongoing. Patients with DMD receive either a low dose or a high dose of GALGT2 gene therapy, which is injected into the leg. They are evaluated regularly for up to 24 months after treatment. Efficacy is evaluated by a functional six-minute walk test, and by direct muscle testing for strength.
People who have been infected with adenovirus in the past may have developed antibodies against AAV, which may interfere with the success of treatment. For this reason, patients undergoing gene therapy need to be screened for AAV antibodies.
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