Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy |
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Authors: | Waddington Simon N Nivsarkar Megha S Mistry Ajay R Buckley Suzanne M K Kemball-Cook Geoffrey Mosley Karen L Mitrophanous Kyriacos Radcliffe Pippa Holder Maxine V Brittan Mairi Georgiadis Anastasios Al-Allaf Faisal Bigger Brian W Gregory Lisa G Cook H Terence Ali Robin R Thrasher Adrian Tuddenham Edward G D Themis Mike Coutelle Charles |
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Institution: | Imperial College London, Gene Therapy Research Group, Section of Cell and Molecular Biology, Sir Alexander Fleming Bldg, Imperial College Road, London, SW7 2AZ, United Kingdom. s.waddington@imperial.ac.uk |
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Abstract: | Hemophilia B, also known as Christmas disease, arises from mutations in the factor IX (F9) gene. Its treatment in humans, by recombinant protein substitution, is expensive, thus limiting its application to intermittent treatment in bleeding episodes and prophylaxis during surgery; development of inhibitory antibodies is an associated hazard. This study demonstrates permanent therapeutic correction of his disease without development of immune reactions by introduction of an HIV-based lentiviral vector encoding the human factor IX protein into the fetal circulation of immunocompetent hemophiliac and normal outbred mice. Plasma factor IX antigen remained at around 9%, 13%, and 16% of normal in the 3 hemophilia B mice, respectively, until the last measurement at 14 months. Substantial improvement in blood coagulability as measured by coagulation assay was seen in all 3 mice and they rapidly stopped bleeding after venipuncture. No humoral or cellular immunity against the protein, elevation of serum liver enzymes, or vector spread to the germline or maternal circulation were detected. |
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