rAAVrh74.MHCK7.micro-dystrophin is a gene therapy candidate for the treatment of Duchene muscular dystrophy (DMD).

Scientists from Nationwide Children’s Hospital developed rAAVrh74.MHCK7.micro-dystrophin. The potential treatment is licensed to Sarepta Therapeutics as part of a research agreement for its clinical stage development.

How it works

DMD is a genetic condition that leads to progressive loss of muscle strength. It is caused by a mutation in the DMD gene that carries the instruction to make dystrophin, the protein that provides structural support and protection to the muscles. Several DMD mutations have been reported, and the majority result in little to no production of functional dystrophin. This affects muscle integrity and leads to the progressive breakdown of the muscles.

The DMD gene is the biggest gene in humans. The researchers from Nationwide Children’s Hospital designed a smaller version of it that carries specific functional regions. These particular regions have been modified for enhanced functioning of the resulting microdystrophin protein, which works similarly to normal dystrophin, albeit at a smaller size.

rAAVrh74.MHCK7.micro-dystrophin is a gene therapy candidate that is designed to deliver the microdystrophin-encoding gene directly to the muscle tissue for the targeted production of the microdystrophin protein. It uses a harmless modified virus (AAVrh74) that has a high affinity for muscle tissue, allowing for targeted delivery. Moreover, it has a muscle-specific promoter — a DNA element that controls the activity of a gene — called MHCK7. MHCK7 is designed to enhance the activity of the gene in heart and skeletal muscles — the main group of muscle tissue affected in DMD.

Clinical trials

Preclinical studies using a mouse model of DMD showed a minimum 70% increase in dystrophin production in the muscle fibers, four weeks after treatment with rAAVrh74.MHCK7.micro-dystrophin gene therapy. The treatment also produced a marked improvement in muscle function. According to Sarepta, preclinical studies also showed that rAAVrh74.MHCK7.micro-dystrophin treatment resulted in widespread high-level expression of dystrophin across multiple muscle types, including the heart muscles.

An ongoing Phase 1/2 study (NCT03375164) is evaluating the safety, efficacy, and tolerability of a single dose of rAAVrh74.MHCK7.micro-dystrophin, administered into the bloodstream of patients with DMD. The three-year study also will test the biological activity of the gene therapy candidate by measuring muscle function in the participants. Muscle biopsies before the treatment, and 90 days post-therapy, will be used to assess the expression of micro-dystrophin in the muscles. Patients will be monitored for any side effects throughout the course of the study. The trial aims to include a total 12 patients. Six patients, ages 3 months to 3 years, will be included in one group, while the second group will consist of six participants, ages 4 to 7.

According to the preliminary results presented at the 23rd International Congress of the World Muscle Society, rAAVrh74.MHCK7.micro-dystrophin treatment enhanced the expression of micro-dystrophin in the muscle fibers of four boys with DMD. Muscle biopsy showed high levels of micro-dystrophin protein in 81.2% of the muscle fibers in these patients after 90 days of treatment. Muscle inflammation was reduced by more than 78%, as indicated by reduced levels of creatine kinase, a marker of muscle inflammation. Motor function was measured using four different tests, which include time to stand up, time to climb four stairs, time to walk 100 meters, and North Star ambulatory assessment (NSAA), a measure of motor function based on 17 different activities. All four boys fared better in the tests 90 days after rAAVrh74.MHCK7.micro-dystrophin treatment, compared with baseline. Specifically, in NSAA, the boys showed an average improvement of 6.5 points from baseline in the first 90 days after treatment. Overall, the functional tests suggested an improvement in motor function following rAAVrh74.MHCK7.micro-dystrophin treatment. No serious adverse events were reported.

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