CRISPR and gene editing technologies for bleeding disorders.

The first gene therapy products for hemophilia A and B have recently been approved by the regulatory authorities. Although this is an important milestone for people with hemophilia, there is still a need to further improve on the efficacy, safety, and stability of expression and to ultimately include pediatric patients before the onset of arthropathy and other complications caused by uncontrolled bleeding. To overcome some of the limitations of conventional gene therapy strategies, gene editing is currently being explored in preclinical studies. Gene editing allows for targeted modifications of the human genome with unprecedented specificity based on zinc finger nuclease, meganuclease, transcription activator-like endonuclease, or clustered regularly interspaced short palindromic repeats (CRISPR) technologies that induce double-strand DNA breaks (DSB). Next-generation gene editing strategies, such as those dependent on CRISPR-derived base or prime editors, allow targeted genetic modification independent of the induction of DSBs, offering a potential safer alternative. Sustained efficacy and production of factor VIII or factor IX can be achieved after gene editing in patient-derived cells or in adult or newborn hemophilia A or B mouse models. These preclinical studies pave the way toward phase I/II clinical trials in patients with severe hemophilia. The potential risk of undesired off-target modifications of the human genome and adverse immune reactions, and the need for efficient delivery of the gene editing components, need to be rigorously addressed before the promise of gene editing for hemophilia can ultimately be fulfilled.