Global seroprevalence of neutralizing antibodies against adeno-associated virus serotypes used for human gene therapies

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-05-29 DOI:10.1016/j.omtm.2024.101273

Amit Chhabra, George Bashirians, Christos J. Petropoulos, Terri Wrin, Yuvika Paliwal, Peter V. Henstock, Suryanarayan Somanathan, Candida da Fonseca Pereira, Ian Winburn, John E.J. Rasko

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引用次数: 0

Abstract

Adeno-associated virus (AAV) vectors are promising gene therapy candidates, but pre-existing anti-AAV neutralizing antibodies (NAbs) pose a significant challenge to successful gene delivery. Knowledge of NAb seroprevalence remains limited and inconsistent. We measured activity of NAbs against six clinically relevant AAV serotypes across 10 countries in adults ( = 502) and children ( = 50) using a highly sensitive transduction inhibition assay. NAb prevalence was generally highest for AAV1 and lowest for AAV5. There was considerable variability across countries and geographical regions. NAb prevalence increased with age and was higher in females, participants of Asian ethnicity, and participants in cancer trials. Co-prevalence was most frequently observed between AAV1 and AAV6 and less frequently between AAV5 and other AAVs. Machine learning analyses revealed a unique clustering of AAVs that differed from previous phylogenetic classifications. These results offer insights into the biological relationships between the immunogenicity of AAVs in humans beyond that observed previously using standard clades, which are based on linear capsid sequences. Our findings may inform improved vector design and facilitate the development of AAV vector-mediated clinical gene therapies.

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用于人类基因疗法的腺相关病毒血清型中和抗体的全球流行率

腺相关病毒（AAV）载体是很有前景的基因治疗候选药物，但预先存在的抗 AAV 中和抗体（NAbs）对成功传递基因构成了巨大挑战。人们对NAb血清流行率的了解仍然有限且不一致。我们在 10 个国家的成人（= 502 例）和儿童（= 50 例）中使用高灵敏度的转导抑制测定法测量了 NAb 对六种临床相关 AAV 血清型的活性。一般来说，AAV1 的 NAb 感染率最高，而 AAV5 的 NAb 感染率最低。不同国家和地理区域之间的差异很大。NAb流行率随年龄增长而增加，女性、亚裔参与者和癌症试验参与者的NAb流行率较高。AAV1和AAV6之间的共患病率最高，而AAV5和其他AAV之间的共患病率较低。机器学习分析揭示了一种独特的 AAV 聚类，不同于以往的系统发育分类。这些结果提供了人类 AAV 免疫原性之间生物学关系的见解，超越了之前使用基于线性囊壳序列的标准支系所观察到的结果。我们的发现可为改进载体设计提供依据，并促进 AAV 载体介导的临床基因疗法的开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.