Genetic therapy for hemophilia: What’s new?

M.-K. Holz1, K. Waack-Buchholz1, D. Reinhardt1, H. Hanenberg2 (1Essen, Germany, 2Düsseldorf, Germany)

Bleeding disorders, coagulation and fibrinolytic factors
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: The standard-of-care therapy for haemophilia comprises frequent prophylactic administrations of factor concentrates to maintain factor levels >5%. This prophylaxis is associated with impaired quality of life for patients and high costs for the health care system. Numerous gene therapeutic strategies aimed at introducing functional copies of the mutated FVIII or FIX genes into somatic cells that then in vivo produce the missing factor have been developed. Here we summarize the recent advances in research and outline the clinical trials.

Methods: Review of literature and the website

Results: In preclinical studies, numerous gene therapy system have been utilized successfully to stably introduce the FVIII or FIX cDNAs into different target cell populations. For in vivo gene transfer, the most important vector systems were AAV, lentiviral, retroviral and nonviral vectors including DNA and the piggyback transposons. So far, only AAV-based vectors have achieved any meaningful efficacy in animal models or in early gene therapy trials. Currently, all ten clinical trials listed at the website are using a single i.v. injection of high-dose AAV vectors with different serotypes to express the therapeutic transgene(s) in the liver. Predominantly due to the limitations in transgene size (<4.5 kb) that can be efficiently delivered by AAV vectors, nine phase I/II studies are focussing on FIX. Only one study (NCT02576795, Biomarin) uses B-domain deleted FVIII as transgene. Six studies are actively recruiting, three are active but nonrecruiting and one is terminated. One ambitious study (NCT02695160, Sangamo) proposes to use coinjection of three different AAV vectors for delivery of two Zinc finger proteins and a promotorless FIX cDNA that is directed for integration in the highly expressed albumin intron 1. So far, limited data from the ongoing trials has been published, but the intermediate results seem to be quite promising, despite very high numbers of vector genomes/kg body weight (up to 6x10^13 vg/kg) and strong immune reactions directed against the AAV capsids. An interesting approach for haemophilia B uses a FIX variant with a gain-of-function mutation (Padua), thereby addressing the problem of low factor activities.

Conclusion: Despite ongoing challenges, genetic therapy of haemophilia A/B has finally come of age.