Stem Cell Therapies for Hemophilia A
AuthorSanada, Chad Douglas
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Hemophlia A (hemA), caused by a deficiency in coagulation factor VIII (FVIII), is the second most common hereditary bleeding disease and affects 1 in 5000 males at birth worldwide. Currently, treating hemophiliac patients requires constant prophylactic injections of FVIII which can be very expensive. As such, alternative ways to treat hemA have been studied including gene therapy and stem cell based therapy which could provide long term treatment for patients and dramatically reduce costs and other complications associated with giving constant FVIII injections. Though current animal models of hemA have similar mutations in their FVIII gene as humans, successful treatment of them has not translated to humans. This created a need for an animal model that recapitulates the human disease more closely. Subsequently, we developed a sheep model of hemA that seems to mimic the human disease more closely than other animal models and also discovered a mutation in the FVIII gene of HemA sheep that is not present in other animal models, but is similar to some human mutations. A stem cell-based therapy for hemA was then tested involving intraperitoneal (IP) transplant of FVIII-transduced mesenchymal stem cells (MSCs) into hemA sheep. The transplants resulted in a phenotypic improvement of those animals, but also caused an unexplained rise in inhibitory antibodies against FVIII. In order to facilitate the development of hematopoietic stem cell-based therapies for hemA in sheep, new antibodies against sheep CD34 were created and validated. Finally, a novel source of circulating FVIII in the human body was potentially identified, MSCs. The studies show that MSCs produce endogenous FVIII in vitro and may do the same in vivo. In conclusion, the sheep model of hemA may represent an improved preclinical model to test hemA therapies and human MSCs may be a novel cell type capable of producing FVIII in vivo. Future studies exploring the physiological role of MSCs producing FVIII are warranted as well as investigation into the etiology of inhibitor formation in hemA sheep upon transplant of FVIII transduced MSCs.