Towards Improving the Treatment of Hemophilia A with Directed Evolution of the Factor VIII Transgene
Factor VIII likely has evolved in nature to be transiently expressed as needed in response to bleeds. However, the protein suffers from low yield, poor stability, and fast clearance from the blood, causing challenges for the treatment of HemA using protein replacement and gene therapy.
Using directed evolution, we discovered variants of FVIII-BDD, containing up to 31 amino acid modifications, that overcome the fundamental biophysical limitations of the native rhFVIII-BDD sequence and have:
- Improved expression & secretion
- Improved stability in HemA patient plasma at physiological conditions
- Improved cofactor potency (i.e., greater enhancement of Factor IXa activity)