Gene Therapy Reaches Human Trials in Peripheral Nerve, Muscle

When investigators transferred AAV with mini-dystrophin to the biceps of six patients with Duchenne muscular dystrophy, it provoked a new and unexpected immune response when it incorporated itself into the domain of the deleted endogenous gene and was expressed. Muscle fibers that expressed the mini-dystrophin gene also developed new epitopes that were immunogenic, making it difficult for the transferred gene to escape T-cell immunity, said Dr. Mendell, director of the Center for Gene Therapy at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus.

In future trials, “patients should be checked for preexisting immunity to dystrophin prior to gene transfer” and the transgene should not be expressed in an area of gene deletion, he suggested.

In a separate randomized, double-blind study, Dr. Mendell and his associates successfully transferred the large limb-girdle muscular dystrophy type 2D gene via the AAV by using a muscle-specific promoter to avoid off-target gene expression (Ann. Neurol. 2009;66:290-7).

New data on 6-month follow-up in six patients who received the gene therapy injections in the extensor digitorum brevis muscle showed persistent gene expression and muscle effects in five patients, but one patient showed no increased gene expression and developed a significant immune response, he reported.

“Preexisting immunity to AAV is a potential barrier to success,” Dr. Mendell said.

Disclosures: Diamyd Medical funded Dr. Fink’s trial and provided the human-grade vectors for it. Dr. Fink has no financial relationship with Diamyd, but he is the inventor on patents that have been licensed by Diamyd from Dr. Fink’s institution and two others. Dr. Ropper and Dr. Mendell said they have no pertinent conflicts of interest.