Coagulation factors (F) are proteins that maintain blood homeostasis. They comprise both proteins with coagulant properties that help to stop bleeding, forming a clot at the site of injury, and proteins with inhibitor properties that limit the growth of the clot. Inherited deficiencies in these blood coagulation factors or its inhibitors are caused by mutations in the corresponding genes and are clinically associated with either bleeding or increased risk of thrombosis due to low activity of these proteins in the blood. Deficiencies in almost all coagulation factors have been described, with FVIII and FIX deficiency (causing Hemophilia A and B, respectively) and FVII deficiency being the most common. FVII deficiency can cause bleeding with different degrees of severity, and the only available treatment is based on replacement therapy with coagulation factor concentrates either purified from plasma or produced by recombinant technology (rFVII). This treatment is expensive, requires frequent injections, needs careful monitoring, and importantly, does not address the underlying genetic cause of the disease. So new treatments that can prevent the bleeding and maintain stable levels of an active FVII in the blood are needed. Recent advances in gene therapy now allow for the correction of gene mutations in the patients’ cells resulting in the production of a normal protein. These cells can then be transplanted back into the patients with consequent amelioration of the disease. Although this technology is not yet used to correct all genetic disorders, it has been successfully used in some other inherited blood diseases. Coagulation factor deficiencies and particularly FVII deficiency are good candidates for this therapy since only one gene is affected and only a modest increase in functional protein levels in the blood is necessary to ameliorate the bleeding phenotype and thus have a major impact on the patients’ lives.
The maintenance of blood homeostasis depends on procoagulant and anticoagulant pathways, and protein deficiency in one of these systems may lead to either bleeding or thrombotic tendency. Inherited coagulation factor (F) VII deficiency is a monogenic disease caused by mutations in the gene encoding F7, leading to reduced circulating protein levels and activity in the blood, and bleeding. Current treatment is based on replacement therapy of the deficient factor, and although it significantly improves the quality of life for these patients, it has several limitations. Thus, there is an unmet need for new and improved ways of treating these patients. Gene editing is a powerful tool that can be used for genome modifications in research and in gene therapy, and it is now being tested in clinical trials with positive results. The present project will focus on the development of a cell-based therapy approach where we correct the F7 mutation in patient-derived cells, to restore FVII synthesis and function. Two different FVII mutations have been selected for this project, and all patients carrying these mutations present bleeding diathesis. Utilizing gene editing technology to correct the disease-causing mutation in the patients’ own cells and then using these cells as therapy for the disease constitute a big step in translational medicine for patients with severe FVII deficiency. In inherited bleeding disorders, it is paramount that a modest increase in the level of a functional factor could recover hemostasis and thus improve the health status of the patients. This project will combine highly specialized and state-of-the-art technologies to achieve breakthrough research. By demonstrating that gene edited patient-derived cells can be transplanted to restore FVII function, the project will significantly advance in the development of a cell-based therapeutic strategy that can improve the current clinical treatment of FVII and other coagulation factor deficiencies.