Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice

Authors

  • Andrea Annoni,

    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
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    • These authors contributed equally to this work.
  • Alessio Cantore,

    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Vita Salute San Raffaele University, Milan, Italy
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    • These authors contributed equally to this work.
  • Patrizia Della Valle,

    1. Coagulation Service and Thrombosis Research Unit, San Raffaele Scientific Institute, Milan, Italy
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  • Kevin Goudy,

    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
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  • Mahzad Akbarpour,

    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Vita Salute San Raffaele University, Milan, Italy
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  • Fabio Russo,

    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
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  • Sara Bartolaccini,

    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
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  • Armando D'Angelo,

    1. Coagulation Service and Thrombosis Research Unit, San Raffaele Scientific Institute, Milan, Italy
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  • Maria Grazia Roncarolo,

    Corresponding author
    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Vita Salute San Raffaele University, Milan, Italy
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    • These authors share senior authorship.
  • Luigi Naldini

    Corresponding author
    1. TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Vita Salute San Raffaele University, Milan, Italy
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    • These authors share senior authorship.

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.

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