Preclinical Evaluation of Ancestral Coagulation Factor VIII

ABSTRACT The development of transformative therapeutics including the possibility of a cure though gene therapy is the sole mission of Expression Therapeutics and continues to be a major research and development activity in the overall $ B USD hemophilia market space However progress in the field has been limited by significant hurdles including the size complexity instability immunogenicity and biosynthetic inefficiency of coagulation factor VIII FVIII Through the study of existing vertebrate species and even more recently predicted ancestral FVIII variants we have identified differentials in molecular cellular immunological and biochemical properties that are predicted to be pharmacologically beneficial Based on these data as well as existing knowledge of FVIII biosynthesis and mechanism of action we have bioengineered a novel FVIII candidate An for both protein infusion and gene based therapies In the current proposal we seek to compare the performance of An to existing FVIII candidates including the hybrid human porcine FVIII ET and B domain deleted human FVIII in lentiviral vector and adeno associated viral vector gene therapy platforms Additionally we will perform critical immunogenicity assessments that together with the gene transfer performance data will facilitate lead candidate selection by Expression Therapeutics NARRATIVE The milestones of this project are the identification of a lead candidate coagulation factor VIII transgene Expression Therapeutics scientific team has identified a bioengineered ancestral factor VIII molecule that displays superior pharmacological properties to existing factor VIII products The milestones of the current project are to complete performance validation studies and a rigorous immunogenicity assessment of this novel product candidate prior to initiation of IND enabling studies for both hematopoietic stem cell directed lentiviral gene therapy as well as liver directed adeno associated viral gene therapy programs