Advancements in gene transfer-based therapy for hemophilia A

Abstract

Gene therapy has promised clinical benefit to those suffering with hemophilia A, but this benefit has not yet been realized. However, during the past two decades, basic and applied gene therapy research has progressed and the goal of gene therapy for hemophilia A is once again in our sights. The hemophilia A patient population suffers from a disease that requires invasive, lifelong management, is exorbitantly expensive to treat, has geographically limited treatment access and can become untreatable due to immune reactions to the treatment product. Subsequent to the cloning of the factor VIII gene and cDNA in the early 1980s, academic and commercial research laboratories began to pursue gene transfer-based therapies to supplement or supplant the available protein replacement therapy. However, to date, clinical trials for gene therapy of hemophilia A have been unsuccessful. Three trials have been conducted with each having tested a different gene-transfer strategy and each demonstrating that there is a considerable barrier to achieving sustained expression of therapeutic amounts of factor VIII. Recent progress has been made in gene-transfer technology and, relevant to hemophilia A, towards increasing the biosynthetic efficiency of factor VIII. These advances are now being combined to develop novel strategies to treat and possibly cure hemophilia A.

Keywords::

• adeno-associated virus
• adenovirus
• factor VIII
• gene therapy
• hematopoietic stem cell transplantation
• hemophilia A
• lentivirus
• oncoretrovirus
• transposon
• viral vector

Financial & competing interests disclosure

The authors are supported by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health to H Trent Spencer and Christopher B Doering (HL083531, HL092179 and HL084132) and Children’s Healthcare of Atlanta. HTS and CBD are cofounders of Expression Therapeutics, LLC, which is developing novel treatments for hemophilia A. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.