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Developments in the treatment of hemophilia B: focus on emerging gene therapy

Authors Cancio MI, Reiss UM, Nathwani AC, Davidoff AM, Gray JT

Received 24 July 2013

Accepted for publication 28 August 2013

Published 18 October 2013 Volume 2013:6 Pages 91—101

DOI https://doi.org/10.2147/TACG.S31928

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4


Maria I Cancio,1 Ulrike M Reiss,2 Amit C Nathwani,3 Andrew M Davidoff,4 John T Gray2

1Department of Hematology-Oncology, 2Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, USA; 3Department of Haematology, University College London Cancer Institute, London, UK; 4Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN, USA

Abstract: Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX) and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should lead to vector designs that result in higher FIX activity at lower vector doses and with reduced host immune responses to the vector and the transgene product.

Keywords: hemophilia B, factor IX deficiency, adeno-associated virus, adenovirus gene therapy

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