1. Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice.
- Author
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Annoni A, Cantore A, Della Valle P, Goudy K, Akbarpour M, Russo F, Bartolaccini S, D'Angelo A, Roncarolo MG, and Naldini L
- Subjects
- Animals, Antibodies immunology, B-Lymphocytes immunology, Cell Line, Factor IX immunology, Genetic Vectors genetics, Genetic Vectors physiology, Hemophilia B immunology, Humans, Lentivirus genetics, Liver immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Factor IX genetics, Genetic Therapy, Hemophilia B genetics, Hemophilia B therapy, Lentivirus physiology, Liver virology
- Abstract
A major complication of factor replacement therapy for haemophilia is the development of anti-factor neutralizing antibodies (inhibitors). Here we show that liver gene therapy by lentiviral vectors (LVs) expressing factor IX (FIX) strongly reduces pre-existing anti-FIX antibodies and eradicates FIX inhibitors in haemophilia B mice. Concomitantly, plasma FIX levels and clotting activity rose to 50-100% of normal. The treatment was effective in 75% of treated mice. FIX-specific plasma cells (PCs) and memory B cells were reduced, likely because of memory B-cell depletion in response to constant exposure to high doses of FIX. Regulatory T cells displaying FIX-specific suppressive capacity were induced in gene therapy treated mice and controlled FIX-specific T helper cells. Gene therapy proved safer than a regimen mimicking immune tolerance induction (ITI) by repeated high-dose FIX protein administration, which induced severe anaphylactoid reactions in inhibitors-positive haemophilia B mice. Liver gene therapy can thus reverse pre-existing immunity, induce active tolerance to FIX and establish sustained FIX activity at therapeutic levels. These data position gene therapy as an attractive treatment option for inhibitors-positive haemophilic patients., (© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)
- Published
- 2013
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