Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients

Christian Leborgne (1, 2) , Virginie Latournerie (1, 2) , Sylvie Boutin (1, 2) , Diana Desgue (1, 2) , Aliénor Quéré (1, 2) , Elodie Pignot (1, 2) , Fanny Collaud (1, 2) , Severine Charles (1, 2) , Marcelo Simon Sola (1, 2) , Elisa Masat (3) , Fabienne Jouen (4) , Olivier Boyer (4) , Carole Masurier (1, 2) , Federico Mingozzi (1, 2) , Philippe Veron (1, 2)

1 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
2 Généthon
3 Centre de recherche en Myologie – U974 SU-INSERM
4 PANTHER - Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices

Adeno-associated virus (AAV) vectors are promising candidates for gene therapy and have been explored as gene delivery vehicles in the treatment of Duchenne Muscular Dystrophy (DMD). Recent studies showed compelling evidence of therapeutic efficacy in large animal models following the intravenous delivery of AAV vectors expressing truncated forms of dystrophin. However, to translate these results to humans, careful assessment of the prevalence of anti-AAV neutralizing antibodies (NAbs) is needed, as presence of preexisting NABs to AAV in serum have been associated with a drastic diminution of vector transduction. Here we measured binding and neutralizing antibodies against AAV serotype 1, 2, and 8 in serum from children and young adults with DMD (n = 130). Results were compared with to age-matched healthy donors (HD, n = 113). Overall, approximately 54% of all subjects included in the study presented IgG to AAV2, 49% to AAV1, and 41% to AAV8. A mean of around 80% of IgG positive sera showed neutralizing activity with no statistical difference between DMD and HD. NAb titers for AAV2 were higher than AAV1, and AAV8 in both populations studied. Older DMD patients (13-24 years old) presented significantly lower anti-AAV8 IgG4 subclass. Anti-AAV antibodies were found to be decreased in DMD patients subjected to a 6-month course of corticosteroids and in subjects receiving a variety of immunosuppressive drugs including B cell targeting drugs. Longitudinal follow up of humoral responses to AAV over up to 6 years showed no change in antibody titers, suggesting that in this patient population, seroconversion is a rare event in humans.

Keywords: AAV humoral immunity; Duchenne Muscular Dystrophy; Gene therapy

Domains: Adaptive immunology; Immunology

Christian Leborgne, Virginie Latournerie, Sylvie Boutin, Diana Desgue, Aliénor Quéré, et al.. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients. Cellular Immunology, 2018, pp.103780. ⟨10.1016/j.cellimm.2018.03.004⟩. ⟨hal-02179236⟩