Gene therapy—trail blazer to game changer

Great strides have been made over the previous three decades in the field of gene therapy, with several gene therapy products being approved by regulatory authorities for other genetic diseases and complex disorders. It is encouraging that sustained therapeutic factor VIII and IX expression levels are being achieved through gene therapy in people with severe hemophilia A or B. In front of a packed auditorium, Thierry VandenDriessche, MD, PhD, Director of the Department of Gene Therapy and Regenerative Medicine at the Free University of Brussels said, “Gene therapy for hemophilia holds great potential but issues remain.”

The challenges that need to be overcome to maximize the benefit of gene therapy for people with hemophilia include interpatient variation in factor expression, response durability, safety considerations and risk of inhibitor development. Whether the procedure is applicable to children, people with inhibitors, and/or those with a preexisting immunity to the adenovirus-associated viral vector (AAV), including people who already received gene therapy for hemophilia, still needs to be addressed.

Mechanisms to enhance factor IX expression are being explored for hemophilia B. Methods include adding a promoter, modifying the vector to remain undetected by the immune system, and incorporating the highly active Padua variant of factor IX.

“Gene therapy is more challenging for hemophilia A due to bottlenecks of factor VIII production at the transcriptional, translational and post-translational level,” said VandenDriessche. However, a pivotal clinical trial using codon-optimized AAV serotype 5 recently published promising results in men with severe hemophilia A.

VandenDriessche ended the session on lentiviral vectors, a promising technology with several improvements over AAV. Current lentiviral vectors have the potential to sustain factor expression long-term since these are liver-directed therapies and pre-existing immunity is not an issue.

Mitch Semienchuk, Editor, Hemophilia World Online, wishes to thank Georghia Michael. PhD, for her contributions to this article.