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FRIPRO-Fri prosjektstøtte

Cell-based therapy for inherited bleeding disorders

Alternative title: Cellebasert terapi for arvelige blødningssykdommer

Awarded: NOK 12.0 mill.

Hereditary factor VII deficiency is a rare bleeding disorder that occurs more frequently in Norway than in most other countries. The condition is caused by mutations in the F7 gene, leading to lower FVII activity in the blood and acute bleeding episodes of varying severity. The only available treatment is to administer FVII to the patient, either purified from plasma or produced through recombinant technology (rFVII). However, this treatment is very costly, requires frequent injections and careful monitoring, and does not address the underlying genetic cause of the disease. In this project, we are developing a new treatment for these patients using gene editing tools to correct the mutation in the F7 gene to restore the production of active FVII in the patients' own cells. So far, we have harvested cells from two patients with severe FVII deficiency and reprogrammed these cells into pluripotent stem cells, corrected the defect in the F7 gene using CRISPR, and produced liver-like organoids from the stem cells, as FVII is made in the liver. In this way, we have been able to restore normal FVII production. We are now working on transplanting the organoids into mice to see if they produce human FVII and to test whether they can restore coagulation activity in a special mouse model lacking FVII, which we have developed. Throughout the project, we have presented our work at national and international conferences and received positive responses. The project has also signed an agreement with the OUS Center for Advanced Cell Therapy and been accepted into the University of Oslo's innovation program SPARK Norway, where we receive guidance and support on how to transfer this type of treatment to the clinic. The PhD candidate successfully completed a mid-term evaluation last year and has finished all mandatory courses. We have also established a productive international collaboration with renowned researchers at the University of Murcia, Spain.

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.

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FRIPRO-Fri prosjektstøtte

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