Hemophilia A/B.

Adeno-associated virus (AAV)-mediated gene transfer has successfully raised, and in some cases transiently normalized, FVIII or FIX activity levels in adults with severe hemophilia. Raising FVIII/IX levels, particularly greater than ∼15 IU/dL (mild deficiency), corresponds to a marked decrease in spontaneous and provoked bleeding, dramatic reduction in factor concentrate use, and improved quality of life (QoL). Limited understanding of innate and adaptive immune system responses and hepatocyte transgene expression and stress responses to AAV-mediated gene transfer contribute to the variability in initial and long-term factor protein expression. Lentiviral (LV) and CRISPR/Cas-9 gene therapy approaches may further bolster the range of eligible participants and improve transgene expression and durability.