title: Haemophilia gene therapy: Progress and challenges.
abstract: Current treatment for haemophilia entails life-long intravenous infusion of clotting factor concentrates. This is highly effective at controlling and preventing haemorrhage and its associated complications. Clotting factor replacement therapy is, however, demanding, exceedingly expensive and not curative. In contrast, gene therapy for haemophilia offers the potential of a cure as a result of continuous endogenous expression of biologically active factor VIII (FVIII) or factor IX (FIX) proteins following stable transfer of a normal copy of the respective gene. Our group has recently established the first clear proof-of-concept for a gene therapy approach to the treatment of severe haemophilia B. This entails a single intravenous administration of an adeno-associated virus vector encoding an optimised FIX gene, resulting in a long-term (>4 years) dose dependent increase in plasma FIX levels at therapeutic levels without persistent or late toxicity. Gene therapy therefore has the potential to change the treatment paradigm for haemophilia but several hurdles need to be overcome before this can happen. This review provides a summary of the progress made to date and discusses the remaining changes.
authors.affiliation: Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Foundation Trust, UK; Department of Haematology, UCL Cancer Institute, UK.
authors.forename: Elsa
authors.initials: E
authors.lastname: Lheriteau
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Foundation Trust, UK; Department of Haematology, UCL Cancer Institute, UK; National Health Services Blood and Transplant, UK. Electronic address: a.nathwani@ucl.ac.uk.
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
mesh_terms: D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000628:therapy*; D006801:Humans
keywords: Factor IX; Factor VIII; Gene therapy; Haemophilia; Vectors