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

Andrea Annoni, Alessio Cantore, Patrizia Della Valle, Kevin Goudy, Mahzad Akbarpour, Fabio Russo, Sara Bartolaccini, Armando D'Angelo, Maria Grazia Roncarolo, Luigi Naldini

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1684-1697
Number of pages14
JournalEMBO Molecular Medicine
Issue number11
Publication statusPublished - Nov 2013


  • Gene therapy
  • Haemophilia
  • Immune tolerance

ASJC Scopus subject areas

  • Molecular Medicine


Dive into the research topics of 'Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice'. Together they form a unique fingerprint.

Cite this