Hemophilia A occurs in approximately 1 in 5000 births, with estimates of 20,000 patients in the US – of which approximately 3,000 reside in California – and over 400,000 patients worldwide. Of these, about half of the patients have an inversion at Intron 22 (I22) of the clotting factor VIII (FVIII) gene. Primary management consists of either blood transfusion or lifelong infusions of recombinant FVIII, resulting in staggering costs from both economical and quality of life standpoints. Successful correction of the FVIII inversion I22 on endothelial stem cells will cause the replacement of defective liver sinusoidal endothelia with FVIII-producing sinusoidal cells derived from the corrected stem cells, shifting the paradigm of hemophilia A treatment from chronic management to permanent cure. Here we are using genome editing tools to correct the genetic abnormality that causes hemophilia A. We expect that this project will lead to clinical therapy for this debilitating disease.