Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy

作者：Haiyan Fu, Aaron S. Meadows, Ricardo Pineda, K.L. Kunkler, Kristen Truxal, Kim L. McBride, Kevin M. Flanigan, Douglas M. McCarty · 发表于：Human Gene Therapy Clinical Development · 年份：2017 · DOI：10.1089/humc.2017.109 · 被引用次数：43 · 研究领域：Virus-based gene therapy research、Viral Infectious Diseases and Gene Expression in Insects、Viral Infections and Immunology Research

Recombinant adeno-associated virus (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 mucopolysaccharidosis (MPS) III patients, the seroprevalence profiles of AAV1-9 and rh74 were investigated in MPS IIIA/IIIB patients and in healthy children. Using enzyme-linked immunosorbent assay for αAAV-IgG, significantly higher seroprevalence was observed for AAV1 and AAVrh74 in 2- to 7-year-old MPS III patients than in healthy controls. Seroprevalence for the majority of tested AAV serotypes appears to peak before 8 years of age in MPS III subjects, with the exception of increases in αAAV8 and αAAV9 Abs in 8- to 19-year-old MPS IIIA patients. In contrast, significant increases in seroprevalence were observed for virtually all tested AAV serotypes in 8- to 15-year-old healthy children compared to 2- to 7-year-olds. Co-prevalence and Ab level correlation results followed the previously established divergence-based clade positions of AAV1-9. Interestingly, the individuals positive for αAAVrh74-Abs showed the lowest co-prevalence with Abs for AAV1-9 (22-40%). However, all or nearly all (77-100%) of subjects who were seropositive for any of serotypes 1-9 were also positive for αAAVrh74-IgG. Notably, the majority (78%) of αAAV seropositive individuals were also Ab-positive for one to five of the tested AAV serotypes...