New Long-term Approach for Limb-girdle Muscular Dystrophy

Researchers developed the first non-muscle targeted gene therapy that enhances diseased muscle fiber repair and improves muscle function in limb-girdle muscular dystrophy.

A new gene therapy for a rare disorder, known as limb-girdle muscular dystrophy (LGMD) was developed by experts at Children’s National Hospital.

The treatment was safe, and muscle strength, according to the study published in the Journal of Clinical Investigation.

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‘A single injection of a low dose gene therapy vector in limb-girdle muscular dystrophy restored the ability of injured muscle fibers.’

With an incidence of less than 1 in 100,000, LGMD2B is a rare disorder caused by a genetic mutation in a large gene called dysferlin. This faulty gene leads to muscle weakness in the arms, legs, shoulder, and pelvic girdle.

Affected children and adults face trouble walking, climbing stairs, and getting out of chairs. Individuals typically lose the ability to walk within years after the onset of symptoms and often need assistance with everyday tasks such as showering, dressing, and transferring.

A new study described an approach that avoids the need for packaging a large gene, like dysferlin, or giving a large vector dose to target the muscles, which are bottlenecks faced in ongoing gene therapy efforts aimed at muscular dystrophies.

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“Currently, patients with LGMD2B have no gene or drug-based therapies available to them, and we are amongst the few centers developing therapeutic approaches for this disease,” said Jyoti K. Jaiswal, M.Sc. Ph.D., senior investigator of the Center for Genetic Medicine Research at Children's National.

The genetic defect in dysferlin that is associated with LGMD2B causes the encoded protein to be truncated or degraded. This hinders the muscle fiber’s ability to heal, which is required for healthy muscles.

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In recessive genetic disorders, like LGMD2B, common pre-clinical gene therapy approaches usually target the mutated gene in the muscle, making them capable of producing the missing proteins.

The large size of the gene mutated in this disease, and impediments in body-wide delivery of gene therapy vectors to reach all the muscles, pose significant challenges for developing gene therapies to treat this disease.

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To overcome these challenges, researchers found another way to slow down the disease’s progression. They built upon their previous discovery that acid sphingomyelinase (hASM) protein is required to repair injured muscle cells.

Based on this fact, researchers administered a single in vivo dose of an Adeno-associated virus (AAV) vector that produces a secreted version of hASM in the liver, which then was delivered to the muscles via blood circulation at a level determined to be efficacious in repairing LGMD2B patient’s injured muscle cells.

Increased muscle degeneration necessitates greater muscle regeneration, and we found that improved repair of dysferlin-deficient myofibers by hASM-AAV reduces the need for regeneration, causing a 2-fold decrease in the number of regenerated myofibers.

These findings are also of interest to patients with Niemann-Pick disease type A since the pre-clinical model for this disease also manifests poor sarcolemma repair.

Researchers are working to further enhance the efficacy of this approach and perform a longer-term safety and efficacy study to enable the clinical translation of this therapy.

Source-Medindia