TABLE 2.

Hemophilia is an optimal candidate for gene therapy

Rationale	Description
Monogenic inheritance	Correction in a single gene provides long‐term symptom relief and is potentially curative110
Gene addition is sufficient for clinical benefit	Mutations that cause hemophilia are not dominant‐negative, and thus gene addition is sufficient to correct the phenotype
Cargo capacity for efficient transduction	The coding region of the F9 gene fits into AAV vectors; the F8 gene can be modified to fit by deleting the B‐domain, which does not affect FVIII activity79
Target tissue is well defined and accessible with current gene delivery methods	Hepatocytes can produce active FVIII, are the natural production site of FIX, and are the natural targets for many AAV vectors; expression is driven by liver‐specific promotors
Even minimal increases in clotting factor activity can significantly improve symptoms/QOL	Prophylaxis from an early age that maintains factor levels ≥1% significantly decreases bleeds and joint disease111 Generally, those with moderate hemophilia (continuous natural factor levels of 1%‐5%) experience rare spontaneous joint bleeds and less arthropathy compared with individuals with severe disease (<1% factor level)112, 113 Factor levels >12% in people with mild disease potentially eliminate bleeding events114 Factor levels up to 20% may be required to prevent all joint hemorrhages115
Well‐studied clinical readout/benefit	The two key measures of efficacy in hemophilia therapy, factor activity levels and reduction in ABRs, are the same for gene therapy and exogenous factor replacement therapy, the current standard of care The FDA guidance on gene therapy for hemophilia provides instructions for accommodating differences between exogenous recombinant factors and gene therapy products when measuring/assessing activity levels116
Animal models of hemophilia A and B are available	>30 years of studies in mice and dogs with hemophilia have established the feasibility, potential, and challenges of developing durable gene therapy using viral vectors3, 6 Unfortunately, animal models have not been useful for investigating the delayed humoral immune responses to recombinant vectors that are seen in human studies41

Abbreviations: AAV, adeno‐associated virus; ABRs, annualized bleeding rates; FDA, US Food and Drug Administration; FIX, factor IX; FVIII, factor VIII; QOL, quality of life.