MDA and AFM co-sponsored a symposium on neuromuscular gene therapy at the 2012 meeting of the American Society for Gene & Cell Therapy
Overcoming barriers to gene therapy — the delivery of therapeutic genes — to treat neuromuscular diseases was the topic of a symposium jointly sponsored by MDA and the Association Française Contre les Myopathies (French Association Against Myopathies, or AFM) at the 15th annual meeting of the American Society of Gene & Cell Therapy (ASGCT).
Kathryn Wagner, a neurologist and neurogeneticist at the Kennedy Krieger Institute in Baltimore, chaired the gene therapy symposium. Wagner is a longtime and current MDA research grantee who studies muscle regeneration.
Getting around the immune response
An obstacle to successful gene therapy in neuromuscular disease has been unwanted responses by patients’ immune systems.
For example, in a Duchenne muscular dystrophy (DMD) gene therapy clinical trial, an immune response was seen to the newly synthesized protein made from the transferred genes. In a limb-girdle muscular dystrophy (LGMD) gene therapy clinical trial, an immune response was seen to the viral vehicles used to deliver the genes.
Development of strategies to get around an unwanted immune response is crucial to the development of safe and effective gene therapy directed to muscle and nerve tissue, as well as to the development of gene therapy for other applications.
"This symposium was extremely valuable, as it provided an opportunity for the best gene therapy researchers from around the world to meet and discuss the results from clinical trials to date," said Jane Larkindale, MDA's director of translational research. "Trials have resulted in baffling results that inhibit our ability to move forward with gene therapy approaches. These issues were discussed at length, and new ideas about how to overcome these hurdles were suggested."
Symposium presenters have deep expertise
The following people were among the presenters.
Christopher Walker, an immunologist at the Research Institute at Nationwide Children's Hospital in Columbus, Ohio, has conducted extensive research on the immunological aspects of gene therapy for DMD.
Walker explained that in the DMD trials to date, some of the patients showed signs of an immune response to dystrophin, the muscle protein that's missing in DMD and which gene therapy aims to restore. The corticosteroid drugs prednisone and deflazacort reduce the immune response to dystrophin, he noted. However, it is still unclear what this immune response means. Apparently, if investigators look hard enough, even healthy people may appear to have a tiny immune response to dystrophin.
Katherine High, a hematologist at Children's Hospital of Philadelphia, is a specialist in gene therapy for hemophilia, a disease in which an immune response to newly synthesized proteins has been observed.
High discussed the immune responses seen in a gene therapy trial to restore a blood-clotting protein to people with hemophilia. She said they've seen responses to the viral vehicle in which the therapeutic genes were delivered. However, she said, it isn't clear that this immune response actually interferes with the therapy in this disease.
James Wilson, a physician-scientist and former MDA research grantee, focuses on the development of delivery vehicles for gene therapy.
Wilson also discussed immune responses to the gene therapy vehicle in the context of a clinical trial for alpha-1 antitrypsin deficiency, a genetic disorder that can cause lung and liver abnormalities. He noted that there are ways to alter the vehicle to reduce the immune response. In this trial, one patient also developed an immune response to the alpha-1 antitrypsin protein made from the transferred genes, as was seen in the DMD dystrophin trial. This particular patient was subsequently shown to have a predisposition to respond to this protein.
More info on immune response in gene therapy
To learn more, be sure to check out these past Quest News articles:
MDA 2012 symposium series
In addition to the gene therapy symposium, MDA’s 2012 series includes three other meetings: