Novel gene therapy approaches for Hemophilia A

Hemophilia A (HemA, OMIM#306700) is an X-linked recessive bleeding disorder caused by a deficiency in the activity of coagulation factor VIII (F8). The incidence of HemA is estimated at about 1 in 6,000 male live births. The severity of the clinical manifestations depends on the extent of the factor VIII deficiency; if the biological activity of factor VIII is below 1%, the hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, requiring prophylactic infusions of F8. Gene therapy for hemophilia involves using a modified virus (which does not cause disease) to introduce a copy of the gene that encodes for the clotting factor that’s missing in patients. Following treatment with the virus, patients should begin producing their own clotting factor normally. Liver gene therapy with adeno-associated viral (AAV) vectors is recently emerging as a promising strategy for haemophilia. However, HemA poses a great challenge to AAV gene therapy which is the size of the coding sequence that needs to be transferred (6.96 kb) that exceeds the canonical AAV cargo capacity (~5 kb). Professor Alberto Auricchio is currently investigating the potential use of novel AAV gene therapy strategies, as the use of intein-mediated F8 trans-splicing in the liver and CRISPR/Cas9-mediated homology-independent targeted integration (HITI). His project has obtained promising results in cultured cells in vitro and is now moving to in vivo animal studies. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.