Obstacles and future of gene therapy for hemophilia

Abstract

Introduction: The recent success of early-phase clinical trials for adeno-associated viral (AAV) liver-directed gene therapy for hemophilia B (HB) demonstrates the potential for gene therapy, in the future, to succeed protein-based prophylaxis therapy for HB. Significant obstacles, however, need to be overcome prior to widespread adoption. The largest obstacles include immune responses to the AAV capsid including preexisting neutralizing antibodies (NAbs) and a delayed cellular immune response. Emerging evidence suggests that the latter is vector-dose dependent. Furthermore, the development and eradication of inhibitors remains a significant safety concern. Similarly, biological differences between Factor VIII and Factor IX (FIX) impose challenges to direct adoption of the successes for HB to hemophilia A (HA).

Areas covered: The advantages and limitations of the current strategies addressing these obstacles for gene therapy for HB and HA are discussed, as well as vector manufacturing issues relevant to widespread adoption. Alternative strategies including both ex-vivo and in-vivo lentiviral-based methods are discussed, though we focus on AAV-based approaches because of their recent clinical success and potential.

Expert opinion: Our opinion is that these obstacles can be overcome with current approaches, and AAV-based gene therapy for HB will likely translate into future clinical care. Innovative approaches are, however, likely needed to solve the current problems obstructing HA gene therapy.

Keywords:

• adeno-associated viral
• gene therapy
• genetic disease
• hemophilia
• recombinant vectors

Declaration of interest

This work was supported by NIH/NIHLBI grant P01 HL64190: Gene Therapy for Hemophilia (Poncz, PI: Arruda, Leader Project 1). BSJ is the recipient of an HTRS/Novo Nordisk 2015 Mentored Research Award in Hemophilia or Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society, Inc., which was supported by Novo Nordisk Inc. He also received a Bayer Fellowship Project Award 2015. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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