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 Blood, 1 November 2004, Vol. 104, No. 9, pp. 2714-2721.
Prepublished online as a Blood First Edition Paper on July 1, 2004; DOI 10.1182/blood-2004-02-0627.

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GENE THERAPY

Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy

Simon N. Waddington, Megha S. Nivsarkar, Ajay R. Mistry, Suzanne M. K. Buckley, Geoffrey Kemball-Cook, Karen L. Mosley, Kyriacos Mitrophanous, Pippa Radcliffe, Maxine V. Holder, Mairi Brittan, Anastasios Georgiadis, Faisal Al-Allaf, Brian W. Bigger, Lisa G. Gregory, H. Terence Cook, Robin R. Ali, Adrian Thrasher, Edward G. D. Tuddenham, Mike Themis, and Charles Coutelle

From the Gene Therapy Research Group, Section of Cell and Molecular Biology, Imperial College London, United Kingdom; Molecular Immunology Unit, Institute of Child Health, University College London, United Kingdom; Haemostasis and Thrombosis, MRC Clinical Sciences Centre, Imperial College London, United Kingdom; Renal Medicine Section, Faculty of Medicine, Imperial College London, United Kingdom; Oxford BioMedica, Oxford, United Kingdom; Histopathology Unit, Cancer Research United Kingdom, London, United Kingdom; and Department of Molecular Genetics, Institute of Ophthalmology, University College London, United Kingdom.

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. (Blood. 2004;104: 2714-2721)


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Testing novel hemophilia therapies: of mice and men
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