Experts introduce new gene therapy approach for muscle weakness

Experts at Children’s National Hospital have created a new pre-clinical gene therapy for the rare condition limb-girdle muscular dystrophy (LGMD) 2B, which addresses the disease’s fundamental cellular weakness. Researchers used a single injection of a low-dose gene therapy vector to restore the ability of injured muscle fibers to heal in a way that reduced muscle degeneration and improved sick muscular function.

Research technician isolates DNA for muscular dystrophy research. Image Credit: Preston Keres/Children’s National Hospital.

According to the study published in the Journal of Clinical Investigation, the treatment was safe, reduced fibro-fatty muscle degeneration, and restored myofiber size and muscle strength.

LGMD2B is a rare condition that occurs due to a genetic mutation in a huge gene called dysferlin, with an incidence of less than 1 in 100,000. Muscle weakness in the arms, legs, shoulder, and pelvic girdle is caused by this defective gene.

Children and adults who are affected have difficulty walking, climbing stairs, and getting out of chairs. Within years of the onset of symptoms, most people lose their ability to walk and require assistance with daily functions such as showering, dressing, and moving.

This paper reported a new strategy that removes the need to package a big gene, such as dysferlin, or give a large vector dose to target the muscles, both of which are bottlenecks in current gene therapy efforts for muscular dystrophies.

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. We 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.”

Jyoti K. Jaiswal MSc, PhD, Senior Investigator, Center for Genetic Medicine Research, Children’s National Hospital

The encoded protein is shortened or degraded as a result of the genetic abnormality in dysferlin that is linked to LGMD2B. The capacity of the muscle fiber to mend, which is necessary for healthy muscles, is hampered as a result of all this. Common pre-clinical gene therapy techniques for recessive genetic disorders, such as LGMD2B, typically target the defective gene in the muscle, allowing it to generate 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.”

Jyoti K. Jaiswal MSc, PhD, Senior Investigator, Center for Genetic Medicine Research, Children’s National Hospital

To address these obstacles, the researchers devised a new method of slowing the disease's growth. The researchers built on their prior discovery that the protein acid sphingomyelinase (hASM) is necessary for muscle cell repair.

The researchers used a single in vivo dose of an adeno-associated virus (AAV) vector to produce a secreted version of hASM in the liver, which was subsequently carried to the muscles via blood circulation at a level that was found to be effective in mending LGMD2B patients’ 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.”

Daniel Bittel DPT, PhD, Study Lead Author and Research Postdoctoral Fellow, Center for Genetic Medicine Research, Children’s National Hospital

Sreetama Sen Chandra PhD, who was a research postdoctoral fellow at Children’s National at the time of this study and served as co-lead author, also added that “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 from the Center for Genetic Medicine Research and the Rare Disease Institute (RDI) at Children’s National are always looking for high-impact opportunities in pediatric genomics and precision medicine. Industry, universities, federal agencies, start-up enterprises, and academic medical institutes are among the public and private partners at both centers. They also act as an international referral center for patients with uncommon diseases.