Identification of a novel neutralization epitope in rhesus AAVs.

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-10-04 eCollection Date: 2024-12-12 DOI:10.1016/j.omtm.2024.101350

Gabriel Dagotto, Jana L Fisher, David Li, Zhenyu Li, Simon Jenni, Zongli Li, Lawrence J Tartaglia, Peter Abbink, Dan H Barouch

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Abstract

Adeno-associated viruses (AAVs) are popular gene therapy delivery vectors, but their application can be limited by anti-vector immunity. Both preexisting neutralizing antibodies (NAbs) and post-administration NAbs can limit transgene expression and reduce the clinical utility of AAVs. The development of novel AAVs will advance our understanding of AAV immunity and may also have practical applications. In this study, we identified five novel AAV capsids from rhesus macaques. RhAAV4282 exhibited 91.4% capsid sequence similarity with AAV7 and showed similar tissue tropism with slightly diminished overall signal. Despite this sequence homology, RhAAV4282 and AAV7 showed limited cross-neutralization. We determined a cryo-EM structure of the RhAAV4282 capsid at 2.57 Å resolution and identified a small segment within the hypervariable region IV, involving seven amino acids that formed a shortened external loop in RhAAV4282 compared with AAV7. We generated RhAAV4282 and AAV7 mutants that involved swaps of this region and showed that this region partially determined neutralization phenotype. We termed this region the hypervariable region IV neutralizing epitope (HRNE). Our data suggests that modification of the HRNE can lead to AAVs with altered neutralization profiles.

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恒河猴 AAV 中新型中和表位的鉴定。

腺相关病毒（AAV）是常用的基因治疗传递载体，但其应用可能受到抗载体免疫的限制。预先存在的中和抗体（NAbs）和给药后的NAbs都会限制转基因的表达，降低AAV的临床实用性。新型 AAV 的开发将促进我们对 AAV 免疫的了解，并可能具有实际应用价值。在这项研究中，我们从猕猴身上鉴定出了五种新型 AAV 病毒外壳。RhAAV4282 与 AAV7 的噬菌体序列相似度高达 91.4%，并表现出相似的组织滋养性，但总体信号略微减弱。尽管存在序列同源性，RhAAV4282 和 AAV7 仍表现出有限的交叉中和作用。我们以 2.57 Å 的分辨率确定了 RhAAV4282 包囊的低温电子显微镜结构，并确定了超变异区 IV 中的一小段，涉及 7 个氨基酸，与 AAV7 相比，RhAAV4282 形成了一个缩短的外环。我们生成了涉及该区域互换的 RhAAV4282 和 AAV7 突变体，结果表明该区域部分决定了中和表型。我们将这一区域称为超变异区 IV 中和表位（HRNE）。我们的数据表明，修改 HRNE 可导致 AAV 的中和特征发生改变。

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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.