Abstract
Several new therapies for hemophilia have emerged in recent years. These strategies range from extended half-life factor replacement products and non-factor options with improved pharmacokinetic profiles to gene therapy aiming for phenotypic cure. While these products have the potential to change hemophilia care dramatically, several challenges and questions remain regarding broader applicability, long-term safety, and which option to pursue for each patient. Here, we review these emerging therapies with a focus on controversies and unanswered questions in each category.
Highlights
Hemophilia is an X-linked bleeding disorder resulting from deficiency of factor VIII (FVIII) or factor IX (FIX) due to mutations in the F8 or F9 genes, respectively
The disorder affects approximately 1 in 10,000 male births worldwide; 80% of cases are of FVIII deficiency or hemophilia A (HA), and 20% are FIX deficiency or hemophilia B (HB)
The rate of immune responses to associated virus (AAV) was lower, as only two out of 10 subjects required immunosuppression. These results demonstrate that FIX-Padua is safe and allows therapeutic levels with a lower risk of vector capsid immune responses
Summary
Hemophilia is an X-linked bleeding disorder resulting from deficiency of factor VIII (FVIII) or factor IX (FIX) due to mutations in the F8 or F9 genes, respectively. The use of a transgene with enhanced biological activity allows an effective and safe strategy by minimizing vector-mediated cellular responses This is attractive since the AAV-5 trials showed that there is a dose-dependent elevation of the liver enzymes; lowering the therapeutic dose would likely benefit all future studies. If a very high vector dose is needed to achieve high therapeutic levels, the impact on the vector manufacturing to a large patient population may be hampered by production feasibility issues and raises safety concerns Another possibility is that of a strategy with minimal or no risk of vector-mediated immune responses yet with factor levels in the mild disease range. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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