Molecular therapeutics of hemophilia A and B.

INTRODUCTION

Hemophilia A (HA) or B (HB) is an X-linked recessive disorder caused by a defect in the factor VIII (FVIII) or factor IX (FIX) gene which leads to the dysfunction of blood coagulation. Protein replacement therapy (PRT) uses recombinant proteins and plasma-derived products, which incurs high cost and inconvenience requiring routine intravenous infusions and life-time treatment. Understanding of detailed molecular mechanisms on FVIII gene function could provide innovative solutions to amend this disorder. In recent decades, gene therapeutics have advanced rapidly and a one-time cure solution has been proposed.

AREAS COVERED: This review summarizes current understanding of molecular pathways involved in blood coagulation, with emphasis on FVIII's functional role. The existing knowledge and challenges on FVIII gene expression, from transcription, translation, post-translational modification including glycosylation to protein processing and secretion, and co-factor interactions are deciphered and potential molecular interventions discussed.

EXPERT OPINION: This article reviews the potential treatment targets for HA and HB, including antibodies, small molecules and gene therapeutics, based on molecular mechanisms of FVIII biosynthesis, and further, assessing the pros and cons of these various treatment strategies. Understanding detailed FVIII protein synthesis and secretory pathways could provide exciting opportunities in identifying novel therapeutics to ameliorate hemophilia state.