title: Gene therapy for haemophilia: prospects and challenges to prevent or reverse inhibitor formation.
abstract: Monogenic hereditary diseases, such as haemophilia A and B, are ideal targets for gene therapeutic approaches. While these diseases can be treated with protein therapeutics, such as factor VIII (FVIII) or IX (FIX), the notion that permanent transfer of the genes encoding these factors can cure haemophilia is very attractive. An underlying problem with a gene therapy approach, however, is the patient's immune response to the therapeutic protein (as well as to the transmission vector), leading to the formation of inhibitory antibodies. Even more daunting is reversing an existing immune response in patients with pre-existing inhibitors. In this review, we will describe the laboratory and clinical progress, and the challenges met thus far, in achieving the goal of gene therapy efficacy, with a focus on the goal of tolerance induction.
authors: Uniformed Services University for the Health Sciences, Bethesda, MD 20814, USA. david.scott@usuhs.mil
authors: David W
authors: DW
authors: Scott
authors: Jay N
authors: JN
authors: Lozier
mesh_terms: D017690:Cell Transplantation; D017321:Clinical Trials, Phase I as Topic; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D005164:Factor IX / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D005544:Forecasting; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005813:Genes, Synthetic; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D006467:Hemophilia A / Q000235:genetics / Q000628:therapy*; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007518:Isoantibodies / Q000096:biosynthesis; D008297:Male; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D012190:Retroviridae / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D007518:Isoantibodies; D011993:Recombinant Fusion Proteins; D005169:Factor VIII; D005164:Factor IX