Gene Therapy for Hemophilia

The X-linked bleeding disorder hemophilia causes frequent and exaggerated bleeding that can be life-threatening if untreated. Conventional therapy requires frequent intravenous infusions of the missing coagulation protein (factor VIII [FVIII] for hemophilia A and factor IX [FIX] for hemophilia B). H...

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Bibliographic Details
Published in:Molecular therapy 2017-05, Vol.25 (5), p.1163-1167
Main Authors: Nienhuis, Arthur W., Nathwani, Amit C., Davidoff, Andrew M.
Format: Article
Language:English
Subjects:
Animal models
Bleeding
Blood Transfusion
clinical trial
Clinical trials
Coagulation factors
Dependovirus - genetics
Dependovirus - immunology
Expression vectors
Factor IX - genetics
Factor IX - metabolism
Factor IX deficiency
Factor VIII - genetics
Factor VIII - metabolism
Gene Expression
Gene therapy
Genetic Therapy - methods
Genetic Therapy - trends
Genetic Vectors - chemistry
Genetic Vectors - immunology
Genomes
Hemophilia
Hemophilia A - genetics
Hemophilia A - metabolism
Hemophilia A - pathology
Hemophilia A - therapy
Hemophilia B - genetics
Hemophilia B - metabolism
Hemophilia B - pathology
Hemophilia B - therapy
Humans
Immune response
Immune response (cell-mediated)
Immunoglobulins
Infections
Intravenous administration
Lentivirus - genetics
Lentivirus - immunology
Liver
Mutation
Pediatrics
Proteins
Review
Vectors (Biology)
Veins & arteries
Viruses
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Description
Summary:The X-linked bleeding disorder hemophilia causes frequent and exaggerated bleeding that can be life-threatening if untreated. Conventional therapy requires frequent intravenous infusions of the missing coagulation protein (factor VIII [FVIII] for hemophilia A and factor IX [FIX] for hemophilia B). However, a lasting cure through gene therapy has long been sought. After a series of successes in small and large animal models, this goal has finally been achieved in humans by in vivo gene transfer to the liver using adeno-associated viral (AAV) vectors. In fact, multiple recent clinical trials have shown therapeutic, and in some cases curative, expression. At the same time, cellular immune responses against the virus have emerged as an obstacle in humans, potentially resulting in loss of expression. Transient immune suppression protocols have been developed to blunt these responses. Here, we provide an overview of the clinical development of AAV gene transfer for hemophilia, as well as an outlook on future directions. Several successful studies of AAV-mediated, liver-targeted transfer of genes encoding clotting factors FIX and FVIII are ongoing for patients with severe hemophilia B and A, respectively. The early results of these studies and the critical questions that remain to be answered are discussed in this review.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2017.03.033