The current data directly support the benefit of incorporating the high expression fVIII sequence elements encoded within ET3 into AAV gene transfer systems for treatment of hemophilia A. The rAAV-HCR-ET3 vector provided a long-term source circulating fVIII activity and correction of bleeding diathesis at vector doses lower than those of other bioengineered fVIII variants despite its larger size, making ET3 an ideal candidate transgene for incorporation into smaller AAV vector systems. Here, EDN3 is linked to hemophilia A.