GENEFIX: Development of muscle-targeted gene therapy for hemophilia B using longer-acting clotting factor IX

Hemophilia B is a genetic disease due to a defect in the gene coding for clotting factor IX (IX). Current treatment of patients suffering from hemophilia B requires injection of purified FIX protein. Though this has significantly improved their quality of life it is not a cure and patients can still have serious bleeding episodes. Moreover, the immune system in some of the patients recognize the FIX protein as “foreign”. This results in the induction of antibodies, called “inhibitors”, that inactivate FIX. Patients with inhibitors have an increased risk of potential life-threatening bleeds. Hence, there is a need to develop new therapies for hemophilia that allow for sustained FIX production and minimize the risk of developing inhibitors to FIX. This could be achieved by introducing a functional copy of the factor IX gene into the patient’s cells using gene therapy. The objective of the present project proposal is to develop a more efficient and safer gene therapy approach using 'second-generation' adeno-associated viral vectors specifically designed to obtained robust circulating levels of FIX after muscle-directed gene therapy by (i) incorporating robust muscle-specific regulatory elements into the vector that boost muscle-specific expression >100-fold and (ii) by using longer-acting FIX factors.This approach may ultimately lead to a bona fide cure for hemophilia B.