Prevalence of Neutralizing Antibodies to AAV2 and AAV9 in Individuals with Niemann-Pick Disease, Type C1.

Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variations in NPC1. We and others have previously demonstrated the efficacy of systemic adeno-associated virus (AAV) gene therapy with AAV9 in murine models of NPC1. The presence of neutralizing antibodies (NAbs) caused by natural exposure to wildtype AAVs may impair AAV transduction efficacy and reduce or negate the benefit of gene therapy. In addition, there remains the question of whether individuals seroconvert with age and whether seroconversion limits the window of therapeutic efficacy. Thus, we assessed the prevalence of anti-AAV9 and anti-AAV2 NAbs in serum samples from 22 individuals with NPC1 at two different time points: one closer to diagnosis (0.9-17 years old) and another collected between 4 and 15 years later during follow-up (6-28 years old). At a titer of <1:5, we found that more than half of the cohort lacked NAbs against either AAV2 (68.2%) or AAV9 (59.1% at time 1, 63.6% at time 2). Notably, only 3 out of 22 individuals showed a transition from undetectable to detectable NAb titers, and most participants maintained stable titers over time, unaffected by age. These data support the feasibility of systemic or direct CNS AAV9 gene therapy in this patient population.