A March 2012 podcast from Nationwide Children's Hospital in Columbus, Ohio, presents the results of a phase 1 trial of gene therapy for gamma-sarcoglycan-deficientlimb-girdle muscular dystrophy (LGMD), also known as LGMD2C.
A deficiency of gamma-sarcoglycan protein, caused by the presence of a mutation in each of the two gamma-sarcoglycan genes located in each cell, underlies this disorder.
The 17-minute podcast features Thomas Voit, medical and scientific director of the Institut de Myologie in Paris. He's interviewed by Kevin Flanigan, a principal investigator at the Center for Gene Therapy at Nationwide Children's Hospital, as part of the hospital’s series called This Month in Muscular Dystrophy.
Voit was an investigator on the LGMD2C gene therapy trial, results of which were reported in the February 2012 issue of the journal Brain.
The phase 1 trial, conducted in Paris, showed that (at the dosages used) the gamma-sarcoglycan gene inside the shell of a type 1 adeno-associated virus (AAV1) can be injected into an arm muscle in people with LGMD2C without serious adverse effects.
It also showed that the three trial participants who received the highest gene dosage produced significant amounts of gamma-sarcoglycan protein from the transferred genes.
The trial was not expected to show benefit with respect to strength or muscle function and did not do so. That type of benefit, Voit noted, will have to wait for later trials.
Each of the nine participants in this early study received a low, intermediate or high dose of gamma-sarcoglycan genes encased in AAV1 delivery vehicles (vectors) into a forearm muscle, which was biopsied a month later.
The muscle biopsies from the participants who received the highest gene dosage showed production of gamma-sarcoglycan protein from the new genes in 4.7 to 10.5 percent of the sampled muscle fibers.
Voit said the gene transfer "appeared safe" in that there was no inflammation associated with the procedure. "That's very important," he noted, "because muscular dystrophy in itself [involves] an inflamed tissue." He said the chronic inflammatory state of MD-affected muscle results in a higher-than-normal number of immune system cells, which are "exquisitely sensitive to local alterations," such as the insertion of a new gene inside a viral shell.
"If there is one tissue that will easily react with inflammation toward an external stimulus, it is the skeletal muscle of a patient with muscular dystrophy," Voit said. "The fact that we did not see inflammation related to the administration of the product is really a very positive point."
The investigators did not see any immune responses to the newly made gamma-sarcoglycan protein, but they did see some immune responses against the AAV1 viral shell, which they had expected.
Voit said these immune responses can probably be avoided by treating only patients who have not been previously exposed to AAV1 viruses or viral vectors. Some, but not all, of the participants in this trial were screened for previous exposure to AAV1.
Similar results were found in a recent, MDA-supported trial to test the safety of transferring the alpha-sarcoglycan gene to a foot muscle in people with LGMD2D, a type of LGMD that results from a deficiency of the alpha-sarcoglycan protein due to mutations in both alpha-sarcoglycan genes.
In that six-person, two-part trial, five out of six participants produced alpha-sarcoglycan protein in the injected foot muscle. However, one person mounted a significant immune response against the AAV1 delivery vehicle.
Attempts to transfer dystrophin genes to treat Duchenne muscular dystrophy (DMD) have, by contrast, been impeded by immune responses to the newly synthesized dystrophin protein.
Next steps will require increasing production of the gene therapy product for regional delivery to a muscle group.
"Upscaling, from the industrial production side, requires … much higher production rates," Voit said. "This next step of industrial production has been taken by Généthon, which is the not-for-profit company that produces the vectors. They are now in a position to produce large batches."