Leborgne C, Latournerie V, Boutin S, et al. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients. Cellular immunology 2018
Research has shown that approximately 50% of DMD patients has antibodies against the AAV-virus. These viruses are used in gene therapy trials with microdystrophins. After injection of the AAV-microdystrophin, antibodies are made, which prevents new treatment, since they would breakdown the injected AAV-microdystrophin. This makes it challenging, since the effect has been shown to fade over the years. At the moment patients with pre-existing AAV-antibodies are excluded from these trials, but it would be a hurdle if gene therapy would indeed prove to be effective and come on the market.
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 (13-24years 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 6years showed no change in antibody titers, suggesting that in this patient population, seroconversion is a rare event in humans.