Scientists from Children’s National Hospital in Washington, D.C., have discovered a new treatment that can repair muscle fibres in patients with limb-girdle muscular dystrophy.
The study published in the Journal of Clinical Investigation found that one injection of a low dose gene therapy vector was able to restore the injured muscle fibres, enhance function, and prevent further degeneration.
Limb-girdle muscular dystrophy 2B (LGMD2B) affects movement in the arms, legs, fingers, toes, and face. LGMD2B is known to cause weakness and atrophy in the pelvic and shoulder muscles as well, according to the U.S. Department of Health and Human Services.
“Currently, patients with LGMD2B have no gene or drug-based therapies available to them, and we are amongst the few centres developing therapeutic approaches for this disease,” Jyoti K. Jaiswal, PhD, senior investigator of the Center for Genetic Medicine Research at Children’s National said in a statement. “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.”
The genetic defect works by essentially causing the body to fail at repairing muscles after they break down from use. The protein dysferlin blocks the muscles’ ability to heal themselves, and over a period of time can cause different types of muscular dystrophy. A more common gene therapy approach typically involves targeting the specific gene that is mutated, in this case it is the protein dysferlin, in the muscles to repair them and promote production of the missing proteins.
Jaiswal says due to the size of the gene mutated in LGMD2B, the entire body has difficulty getting the proteins it needs to build muscle and gene therapies are a significant challenge to develop. Researchers developed another way to slow the disease’s progression by expanding on a breakthrough they discovered earlier: that the acid sphingomyelinase (hASM) protein is necessary to rebuild injured muscle cells. That research was published in 2014 in the science journal Nature.
For the current study, a single dose of an Adeno-associated virus (AAV) that produces a version of the hASM acid in patients’ livers was administered. The acid was then transferred to the patients’ entire bodies thanks to their circulatory system, at a level that researchers say was determined to be effective for each individual patient in repairing LGMD2B in their muscles. Researchers were able to follow the acid around the body by using a monomeric red fluorescent protein that let them see where the acid had spread.
“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,” lead author of the study Daniel Bittel said.
A certain amount of hASM was required for all patients to see results however. Too little of the acid would not result in any noticeable difference in muscle degeneration or repair, a middle ground was found to halt the muscles from worsening, while more of it would eventually assist in repairing the muscle cells.
Researchers say that clinical trials are required next to examine the therapeutic uses of their new form of treating LGMD2B patients.
The numbers on limb-girdle muscular dystrophy are hard to quantify, with the U.S. National Library of Medicine citing prevalence estimates ranging between one in 14,500 to one in 123,000 people being affected.