Gene therapy for hemophilia

PURPOSE OF REVIEW: Consistently measurable and persistent expression of circulating clotting factor activity, associated with decreased clinical bleeding, has been achieved for the first time in a hemophilia gene therapy trial. This review examines the successes and limitations of this clinical trial for hemophilia B and approaches to advance beyond this milestone. RECENT FINDINGS: Although a self-complementary serotype 8 adeno-associated virus (scAAV8) vector approach directed factor IX expression of up to 6% in a human trial, the apparent need to suppress vector dose-dependent immune-mediated liver inflammation in some patients at the highest dose highlighted the next steps to optimize the risk-benefit of hemophilia gene therapy. The approaches being pursued include manufacturing modifications to eliminate contaminating empty vector capsids, the utilization of factor IX and factor VIII modified transgenes to improve secretion or function of the transgene product, and adjunctive pharmacologic and molecular approaches to overcome limitations imposed by naturally occurring antibodies against vectors and by the large size of the factor VIII gene. SUMMARY: Preclinical data suggest strategies in development may build upon the first gene therapy success and achieve factor IX correction sufficient to prevent bleeding without toxicity and translate success to hemophilia A gene therapy.