by Mary Ann Liebert, Inc

Prevalence of Nabs. NAb seroprevalence within the NPC1 cohort (n = 22) with titer distribution of antibodies against AAV2 (A) and AAV9 (B) at time 1 and time 2. Seroprevalence ranges from <1:5 (lower limit of detection) up to 1:640. Number of individuals with antibodies against AAV2 (C) and AAV9 (D) at each titer level, at both time points (n = 22). Age distribution of only seronegative individuals for AAV2 (E) and AAV9 (F). (G) Seropositivity rate in an NPC1 cohort compared with published pediatric controls in AAV2 with titer ≥1:20. Comparison of AAV2 seropositivity at time 1 with control (p > 0.99), comparison of AAV2 seropositivity at time 2 with control (p = 0.61). Credit: Human Gene Therapy (2025). DOI: 10.1089/hum.2024.233

A new study in the journal Human Gene Therapy showed that more than half of individuals with Niemann-Pick disease, type C1 (NPC1) who were tested lacked neutralizing antibodies against either adeno-associated virus (AAV) 2 or AAV9.

NPC1 is a rare, fatal neurodegenerative disorder, for which systemic AAV9-based gene therapy in mouse models has shown some success. The presence of neutralizing antibodies against AAV can reduce or negate the benefit of gene therapy.

Forbes Porter, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and co-authors assessed the prevalence of anti-AAV9 and anti-AAV2 neutralizing antibodies (NAbs) in serum samples from individuals with NPC1 at two different time points: around the time of diagnosis (0.9–17 years old) and between 4–15 years later (6–28 years old).

The investigators found that more than half of patients were seropositive at both time points, with 68.2% of individuals lacking antibodies against AAV2 at both timepoints and 59.1% and 63.6% lacking antibodies to AAV9 at the first and second time points, respectively.

"These data support the feasibility of systemic or direct central nervous system AAV9 therapy in this patient population, " concluded the investigators.

"Studies like these are very important to plan delivery strategies for gene therapy treatments in general and for NPC1 patients specifically, such as determining enrollment criteria for trials, whether the treatment protocol needs to mitigate pre-existing NAbs, and the possibility that the development of NAbs during the course of life could impact the durability of treatment, " says Managing Editor of Human Gene Therapy Thomas Gallagher, Ph.D., from the University of Massachusetts Chan Medical School.

More information: Avani V. Mylvara et al, Prevalence of Neutralizing Antibodies to AAV2 and AAV9 in Individuals with Niemann-Pick Disease, Type C1, Human Gene Therapy (2025). DOI: 10.1089/hum.2024.233  Journal information: Human Gene Therapy