Pre-existing Anti-AAV9 Antibodies in the Chinese Healthy and Rare Disease Populations: Implications for Gene Therapy.

Abstract

The adeno-associated virus 9 (AAV9) vector was particularly notable for its broad tissue tropism, making it a preferred vector for gene therapy. Goals: The study aimed to investigate the patterns of pre-existing immunity against AAV9 in the Chinese population. In this study, we conducted a serological research from November 2022 to June 2024. The study included 341 participants in total with age ranged from 0-90 years old: 270 healthy individuals, 30 pediatric patients and 41 adults with rare diseases. Total AAV9-binding antibodies (TAbs) and neutralizing antibodies (NAbs) were measured. The seroprevalence of anti-AAV9 NAbs showed no significant differences between healthy individuals and rare disease patients across both pediatric and adult groups. Newborns exhibited a high NAb-positive rate (64.3%), while children aged 6 months to 3 years had the lowest prevalence (7.7%). This rate progressively increased through childhood and adolescence. Overall, 58.7% of the Chinese population aged 0-90 years tested positive for anti-AAV9 NAbs, with adults showing a significantly higher prevalence than children (75.0% vs. 34.3%). Additionally, 58.1% of the population exhibited low levels of anti-AAV9 NAb titers (IC₅₀ ≤ 100). No significant sex-specific differences were observed, and antibody titers (NAbs or TAbs) showed no strong correlation with age. A strong correlation was identified between TAb and NAb positivity rates and titers. The optimal AAV9-based GT period was between 6 months and 3 years in that patients possessed lowest pre-existing immunity. Since TAbs had a strong association with NAbs, TAbs was considered as an alternative indicator to screen rare diseases.