Abstract: The present invention relates to a Factor VIII (FVIII) polypeptide, a polynucleotide comprising a Factor VIII nucleotide sequence, and a recombinant AAV construct. The invention further relates to an AAV viral particle comprising the recombinant AAV construct of the invention, and a composition comprising the Factor VIII polypeptide, polynucleotide, recombinant AAV construct or AAV viral particle of the invention. The invention also relates to methods of using, and uses of, the Factor VIII polypeptide, polynucleotide, recombinant AAV construct, AAV viral particle and/or composition of the invention. The invention also relates to uses of the recombinant AAV construct of the invention for the production of AAV viral particles, and methods for producing AAV viral particles using the recombinant AAV constructs of the invention.

Abstract: The present invention provides Factor VIII polypeptides which comprise one or more substitution mutations compared to a corresponding wild-type Factor VIII, wherein the one or more substitution mutations are located at an inter-domain interface between two domains of the Factor VIII polypeptide. Also provided are polynucleotides comprising a Factor VIII nucleotide sequence encoding a Factor VIII polypeptide of the invention, recombinant AAV constructs comprising such polynucleotides, AAV viral particles comprising such recombinant AAV constructs, compositions comprising the Factor VIII polypeptide, polynucleotide, recombinant AAV construct, or AAV viral particle of the invention, and the use of the Factor VIII polypeptides, polynucleotides, recombinant AAV constructs, AAV viral particles and compositions of the invention in therapy.