Heparan sulfate proteoglycan affinity of adeno-associated virus vectors: Implications for retinal gene delivery

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-01-11 DOI:10.1016/j.ejps.2025.107012
Dimitri Romanovsky , Hanna Scherk , Bastian Föhr, Sabrina Babutzka, Jacqueline Bogedein, Yi Lu, Alice Reschigna, Stylianos Michalakis
{"title":"Heparan sulfate proteoglycan affinity of adeno-associated virus vectors: Implications for retinal gene delivery","authors":"Dimitri Romanovsky ,&nbsp;Hanna Scherk ,&nbsp;Bastian Föhr,&nbsp;Sabrina Babutzka,&nbsp;Jacqueline Bogedein,&nbsp;Yi Lu,&nbsp;Alice Reschigna,&nbsp;Stylianos Michalakis","doi":"10.1016/j.ejps.2025.107012","DOIUrl":null,"url":null,"abstract":"<div><div>Adeno-associated virus (AAV)-based vectors have emerged as an effective and widely used technology for somatic gene therapy approaches, including those targeting the retina. A major advantage of the AAV technology is the availability of a large number of serotypes that have either been isolated from nature or produced in the laboratory. These serotypes have different properties in terms of sensitivity to neutralizing antibodies, cellular transduction profile and efficiency. The infectivity of AAV vectors depends on the affinity to certain molecules on the cell surface, in particular to cellular glycosaminoglycans (GAGs) such as heparan sulfate proteoglycans (HSPGs). Here, we tested how altering HSPG affinity in AAV vectors affects cellular tropism and transduction efficiency. The previously developed AAV2.GL variant was used as a starting variant to alter or disrupt HSPG affinity. The HSPG-independent AAV9 serotype was used to introduce different HSPG-binding sites. As an indicator of HSPG affinity, we measured the binding strength of the vector variant on a heparin chromatography column. We show that modification of capsid-exposed residues has a strong impact on HSPG affinity, cellular tropism and transduction efficiency in HeLa cells and in vivo in mouse retina. Our study shows that key properties of AAV vectors can be tailored in different directions and used to improve tropism and efficiency.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107012"},"PeriodicalIF":4.3000,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Pharmaceutical Sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0928098725000119","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Adeno-associated virus (AAV)-based vectors have emerged as an effective and widely used technology for somatic gene therapy approaches, including those targeting the retina. A major advantage of the AAV technology is the availability of a large number of serotypes that have either been isolated from nature or produced in the laboratory. These serotypes have different properties in terms of sensitivity to neutralizing antibodies, cellular transduction profile and efficiency. The infectivity of AAV vectors depends on the affinity to certain molecules on the cell surface, in particular to cellular glycosaminoglycans (GAGs) such as heparan sulfate proteoglycans (HSPGs). Here, we tested how altering HSPG affinity in AAV vectors affects cellular tropism and transduction efficiency. The previously developed AAV2.GL variant was used as a starting variant to alter or disrupt HSPG affinity. The HSPG-independent AAV9 serotype was used to introduce different HSPG-binding sites. As an indicator of HSPG affinity, we measured the binding strength of the vector variant on a heparin chromatography column. We show that modification of capsid-exposed residues has a strong impact on HSPG affinity, cellular tropism and transduction efficiency in HeLa cells and in vivo in mouse retina. Our study shows that key properties of AAV vectors can be tailored in different directions and used to improve tropism and efficiency.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
腺相关病毒载体的硫酸肝素蛋白聚糖亲和力:对视网膜基因传递的影响。
基于腺相关病毒(AAV)的载体已成为体细胞基因治疗(包括针对视网膜的基因治疗)的一种有效且广泛应用的技术。AAV 技术的一大优势是可提供大量从自然界分离或在实验室生产的血清型。这些血清型在对中和抗体的敏感性、细胞转导特征和效率方面具有不同的特性。AAV 载体的感染性取决于与细胞表面某些分子的亲和力,特别是与细胞糖胺聚糖(GAGs),如硫酸肝素蛋白聚糖(HSPGs)的亲和力。在这里,我们测试了改变 AAV 载体的 HSPG 亲和力如何影响细胞趋向性和转导效率。以前开发的 AAV2.GL 变体被用作改变或破坏 HSPG 亲和力的起始变体。不依赖 HSPG 的 AAV9 血清型被用来引入不同的 HSPG 结合位点。作为 HSPG 亲和力的指标,我们测量了载体变体在肝素层析柱上的结合强度。我们的研究表明,在 HeLa 细胞和小鼠视网膜中,对囊膜暴露残基的修饰对 HSPG 亲和力、细胞滋养性和转导效率有很大影响。我们的研究表明,AAV载体的关键特性可以从不同方向进行定制,并用于提高其趋向性和效率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
期刊最新文献
Hierarchical clustering of therapeutic proteins based on agitation-induced aggregation propensity and its relation to physicochemical parameters Transport of statins by multidrug resistance-associated proteins 1 and 5. Direct comparison of single peak and gradient chromatographic methods for routine analysis of surfactants in biopharmaceuticals. DprE1 Inhibitors: An insight into the recent developments and synthetic approaches. Enhancing Martini 3 for protein self-interaction simulations
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1