Robust Cardiac Gene Delivery and Evasion of Neutralizing Antibodies by Extracellular Vesicle-Associated AAV Vectors
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Adamiak, Marta | - |
dc.contributor.author | Liang, Yaxuan | - |
dc.contributor.author | Mathiyalagan, Prabhu | - |
dc.contributor.author | Agarwal, Neha | - |
dc.contributor.author | Jha, Divya | - |
dc.contributor.author | Kohlbrenner, Erik | - |
dc.contributor.author | Chepurko, Elena | - |
dc.contributor.author | Jeong, Dongtak | - |
dc.contributor.author | Ceholski, Delaine | - |
dc.contributor.author | Dubois, Nicole | - |
dc.contributor.author | Hajjar, Roger | - |
dc.contributor.author | Sahoo, Susmita | - |
dc.date.accessioned | 2021-06-22T11:21:48Z | - |
dc.date.available | 2021-06-22T11:21:48Z | - |
dc.date.issued | 2018-11 | - |
dc.identifier.issn | 0009-7322 | - |
dc.identifier.issn | 1524-4539 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/5134 | - |
dc.description.abstract | Introduction: Due to their excellent safety profile in clinical trials, adeno-associated virus (AAV) has become the vector of choice for gene delivery to the myocardium. However, pre-existing immunity to AAV from naturally present neutralizing antibodies (NAbs, present in >60% of the human population) significantly limits the potential candidates for the AAV-based gene therapy. NAbs bind to AAV and block its infection, greatly reducing transduction and clinical efficacy. Thus, development of novel AAV-based vectors that can circumvent the effect of NAbs is essential for clinical administration of AAVs. Objectives: We investigated the effectiveness of extracellular vesicle (EV)-associated AAV (EV-AAV) in resisting NAbs and enhancing vector transduction in the myocardium. Methods and Results: We isolated EV-AAV from the conditioned medium of infected 293 cells using a multi-step iodixanol density gradient ultracentrifugation. Electron microscopy, flow cytometry, bioluminescence imaging and echocardiography were used to quantify AAV-mediated gene delivery and transduction efficiency. EV-AAV6-mCherry and EV-AAV9-FLuc were more resistant to antibody-mediated neutralization than conventional AAV and induced significantly higher mCherry or firefly luciferase (FLuc) expression both in vitro and in vivo. To test the therapeutic efficacy, EV-AAV9-SERCA2a or AAV9-SERCA2a were injected intramyocardially in post-MI mice preinjected with human NAbs (IVIg). Remarkably, EV-AAV9-SERCA2a outperformed standard AAV, significantly improving cardiac function both in the presence and absence of NAbs (%EF 57.4 ± 4.7 vs. 29.2± 2.3, respectively; 6 weeks after surgery). Conclusion: EV-AAV highly outperforms conventional AAV in delivering beneficial genes, such as SERCA2a. The use of naturally enveloped AAV vectors represents a promising approach to evade NAbs, and to facilitate the clinical translation of AAV-based gene therapies to a larger human population. | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | Lippincott Williams & Wilkins Ltd. | - |
dc.title | Robust Cardiac Gene Delivery and Evasion of Neutralizing Antibodies by Extracellular Vesicle-Associated AAV Vectors | - |
dc.type | Article | - |
dc.publisher.location | 미국 | - |
dc.identifier.wosid | 000528619406249 | - |
dc.identifier.bibliographicCitation | Circulation, v.138, no.1(suppl.), pp A16378 - A16378 | - |
dc.citation.title | Circulation | - |
dc.citation.volume | 138 | - |
dc.citation.number | 1(suppl.) | - |
dc.citation.startPage | A16378 | - |
dc.citation.endPage | A16378 | - |
dc.type.docType | Meeting Abstract | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | sci | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Cardiovascular System & Cardiology | - |
dc.relation.journalWebOfScienceCategory | Cardiac & Cardiovascular Systems | - |
dc.relation.journalWebOfScienceCategory | Peripheral Vascular Disease | - |
dc.identifier.url | https://oce.ovid.com/article/00003017-201811061-03186?sequence=1&clickthrough=y | - |
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
55 Hanyangdeahak-ro, Sangnok-gu, Ansan, Gyeonggi-do, 15588, Korea+82-31-400-4269 sweetbrain@hanyang.ac.kr
COPYRIGHT © 2021 HANYANG UNIVERSITY. ALL RIGHTS RESERVED.
Certain data included herein are derived from the © Web of Science of Clarivate Analytics. All rights reserved.
You may not copy or re-distribute this material in whole or in part without the prior written consent of Clarivate Analytics.