Factor VII deficiency
Congenital FVII deficiency is caused by mutations in the F7 gene coding for FVII resulting in low or undetectable FVII levels. Homozygotes develop a hemorrhagic syndrome, were heterozygotes are asymptomatic. Symptoms may differ greatly; some have almost no symptoms while at least 20% of patients may experience life-threatening bleedings. Typically, there is a tendency to easy bruising, nose bleeding, menorrhagia, dental and surgical associated bleeding. Also, bleedings can occur in the gut, in muscles or joints, or the brain. Infants with severe factor VII deficiency may develop fatal intracranial hemorrhage within hours or days of birth. Congenital FVII deficiency provides an excellent model for gene transfer as a therapeutic approach because its clinical manifestations occur solely due to the lack of FVII, a protein that circulates in small amounts in the plasma. Unlike other congenital liver disorders, the therapeutic goal for congenital FVII deficiency is an increase of FVII to > 5% of normal which will be sufficient to ameliorate the bleeding tendency. Notably, FVII is structurally and functionally related to human FIX, a molecule for which successful gene therapy has been developed and has been filed for approval at the FDA and EMA.
Factor X deficiency
Factor X deficiency is a severe rare inherited bleeding disorder (RBDs) and affects 1 in 500,000 people. FX is a glycoprotein in the coagulation cascade and is the first enzyme in the common pathway of thrombin formation. FX is synthesized in the liver and encoded by the FX gene (F10). The bleeding symptoms start at any age, although the more severely affected (<1% activity) present early in life with umbilical stump, central nervous system, or gastrointestinal bleeding and commonly experience hemarthroses and hematomas. The proportion of FX-deficient patients requiring treatment is higher than in other rare bleeding disorders. There is currently no cure for FX deficiency and the main therapy is the administration of plasma-derived purified FX protein or plasma derived prothrombin complex concentrate (PCC) by intravenous infusion. Both of these therapies are suboptimal treatments, as they must be infused on a regular basis (twice per week) for the entire life of the patient. This results in a high treatment burden for the patient and a very high cost for the healthcare system, as the biologic therapies are expensive and must be continually used. An ideal treatment would be a one-time cure, which is durable and provides superior efficacy than current options. Our gene therapy program attempts to make this ideal cure a reality.