Progress, and prospects in the therapeutic armamentarium of persons with congenital hemophilia. Defining the place for liver-directed gene therapy

In persons with congenital severe hemophilia A (HA) living in high-income countries, twice weekly intravenous infusions of extended half-life (EHL) factor VIII (FVIII) products, or weekly/biweekly/monthly subcutaneous injections of emicizumab are the gold standard home treatments to grant days without hurdles and limitations. Once weekly/twice monthly infusions of EHL Factor IX (FIX) products achieve the same target in severe he-mophilia B (HB). Gene therapy, which is likely to be licensed for clinical use within 1-2 years, embodies a shift beyond these standards. At an individual patient level, a single functional gene transfer leads to a > 10-yr almost full correction of the hemostatic defect in HB and to a sustained (3-6-yrs) expression of FVIII sufficient to dis-continue exogenous clotting factor administrations. At the doses employed, the limited liver toxicity of sys-temically infused recombinant adeno-associated virus (rAAV) vectors is documented by long-term (12-15 yrs) follow-ups, and pre-existing high-titer neutralizing antibodies to the AAV5 vector are no longer an exclusion criterion for effective transgene expression with this vector. A safe durable treatment that converts a challenging illness to a phenotypically curable disease, allows persons to feel virtually free from the fears and the obligations of hemophilia for years/decades. Along with patient organizations and health care professionals, communicating to government authorities and reimbursement agencies the liberating potential of this substantial innovation, and disseminating across the Centers updated information on benefits and risks of this strategy, will align ex-pectations of different stakeholders and establish the notion of a potentially lifelong cure of hemophilia.

Automated summary

In individuals with severe hemophilia A, regular infusions of extended half-life factor VIII products or subcutaneous injections emicizumab are effective home treatments. Similarly, infusions of extended half-life factor IX products are recommended for individuals with severe hemophilia B. Gene therapy, currently being developed, offers a potential cure for hemophilia by correcting the hemostatic defect and providing sustained expression of clotting factors.