Haemophilias: Gene Therapy

Abstract

Haemophilia A and B are the two most common severe congenital bleeding disorders and each is corrected with infusion of a single plasma protein. Preliminary data from animal models and from clinical trials in humans suggest that gene therapy may be effective in the haemophilias. Advances in vector technology combined with improved trangenes and knowledge of factors VIII and IX secretion in target tissues over the past several years have improved the prospects of gene therapy for the haemophilias.

Key Concepts

  • Understand the roles of factors VIII and IX in the intrinsic coagulation cascade.

  • Understand that both haemophilia A and B are caused by single gene mutations inherited in an X‐linked recessive pattern.

  • Understand the clinical features of haemophilia A and B.

  • Understand that haemophilia A and B are excellent models for gene therapy because of the wide range of protein levels that can be both therapeutic and not toxic.

  • Understand issues that determine target tissue suitability for gene therapy.

  • Understand the importance of efficient transgene transfection and secretion and the role of bioengineered transgenes.

  • Understand the potential for accumulation of unfolded or misfolded protein accumulation with overexpression of a transgene in a target tissue and the possibility of toxicity through induction of the unfolded protein response.

  • Understand the advantages and disadvantages of available vector technologies including: nonviral delivery systems, retroviral vectors, adenoviral vectors and adeno‐associated viral vectors.

  • Become familiar with results from gene therapy clinical trials in the haemophilias.

  • Become aware of the ethical and regulatory considerations in haemophilia gene therapy.

Keywords: factor VIII; factor IX; immune response; coagulation factors

Figure 1.

The clotting cascade: Exposure of tissue factor (TF) to blood upon vascular or endothelial cell injury initiates the extrinsic pathway of blood coagulation. TF acts with factor VIIa and phospholipid (PL) to convert factor IX to IXa and factor X to Xa. The intrinsic pathway includes ‘contact’ activation by factor XI with XIIa in the presence of high molecular weight kininogen. Factor XIa converts factor IX to IXa, and factor IXa in turn converts factor X to Xa, in concert with factor VIIIa and PL. Factor Xa catalyses the conversion of prothrombin to thrombin in the presence of factor Va and PL. Thrombin cleaves fibrinogen to generate insoluble fibrin. Protein C (PC) is activated by thrombomodulin on intact endothelium to generate activated protein C (APC) that cleaves and inactivates factors VIIIa and FVa. Dashed lines represent feedback pathways.

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Web Links

F8 (coagulation factor VIII, procoagulant component (hemophilia A)); Locus ID: 2157. LocusLink:http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2157.

F9 (coagulation factor IX (plasma thromboplastic component, Christmas disease, hemophilia B)); Locus ID: 2158. LocusLink:http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2158.

F8 (coagulation factor VIII, procoagulant component (hemophilia A)); MIM number: 306700. OMIM:http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?306700.

F9 (coagulation factor IX (plasma thromboplastic component, Christmas disease, hemophilia B)); MIM number: 306900. OMIM:http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?306900.

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How to Cite close
Callaghan, Michael, and Kaufman, Randal J(Sep 2009) Haemophilias: Gene Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005750.pub2]