Hemophilia A gene therapy: current and next-generation approaches

Abstract

Gene replacement therapies provide safe, durable, and stable transgene expression while avoiding the challenges of clotting factor replacement therapies in patients with hemophilia. Improving the specificity of the viral construct and decreasing the therapeutic dose are critical toward minimizing cellular stress, induction of the unfolded protein response, and the resulting loss of protein production in liver cells. Next-generation gene therapies incorporating chimeric DNA sequences in the transgene can increase clotting factor synthesis and secretion, and advance the efficacy, safety, and durability of gene replacement therapy for hemophilia A as well as other blood clotting disorders.