Differential prevalence of antibodies against adeno-associated virus in healthy children and patients with mucopolysaccharidosis III: perspective for AAV-mediated gene therapy

Recombinant AAV vectors are promising gene therapy tools. However, pre-existing antibodies (Abs) to many useful AAV serotypes pose a critical challenge for the translation of gene therapies. As part of AAV gene therapy program for treating MPS III patients, we investigated the seroprevalence profiles of AAV1-9 and rh74 in MPS IIIA/IIIB patients and in healthy children. Using ELISA for αAAV-IgG, we observed significantly higher sero-prevalence for AAV1 and AAVrh74 in 2-7y-old MPS III patients than in healthy controls. Seroprevalence for the majority of tested AAV serotypes appear to peak before age 8y in MPS III subjects, with the exception of increases in αAAV8 and αAAV9 Abs in 8-19y-old MPS IIIA patients. In contrast, we observed significant increases in seroprevalence for virtually all tested AAV serotypes in 8-15y-old healthy children compared to 2-7y-olds. Co-prevalence and Ab level correlation results followed the previously established divergence-based clade positions of AAV1-9. Interestingly, the i...