Abstract
Strides in advancements of care of persons with hemophilia include development of
long-acting factor replacement therapies, novel substitution and hemostatic rebalancing
agents, and most recently approved gene therapy. Several decades of preclinical and
clinical trials have led to development of adeno-associated viral (AAV) vector-mediated
gene transfer for endogenous production of factor VIII (FVIII) in hemophilia A (HA).
Only one gene therapy product for HA (valoctocogene roxaparvovec) has been approved
by regulatory authorities. Results of valoctocogene roxaparvovec trial show significant
improvement in bleeding rates and use of factor replacement therapy; however, sustainability
and duration of response show variability with overall decline in FVIII expression
over time. Further challenges include untoward adverse effects involving liver toxicity
requiring immunosuppression and development of neutralizing antibodies to AAV vector
rendering future doses ineffective. Real-life applicability of gene therapy for HA
will require appropriate patient screening, infrastructure setup, long-term monitoring
including data collection of patient-reported outcomes and innovative payment schemes.
This review article highlights the success and development of HA gene therapy trials,
challenges including adverse outcomes and variability of response, and perspectives
on approach to gene therapy including shared decision-making and need for future strategies
to overcome the several unmet needs.
Keywords
hemophilia A - gene therapy - valoctocogene roxaparvovec
