AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes.
AAV library screening
AAV vectors
AAV2
adeno-associated virus
cardiac hypertrophy
gene therapy
heart
lncRNA H19
non-coding RNA
vector engineering
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
07 12 2022
07 12 2022
Historique:
received:
24
11
2021
revised:
06
07
2022
accepted:
06
07
2022
pubmed:
11
7
2022
medline:
15
12
2022
entrez:
10
7
2022
Statut:
ppublish
Résumé
AAV vectors are promising delivery tools for human gene therapy. However, broad tissue tropism and pre-existing immunity against natural serotypes limit their clinical use. We identified two AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, by in vivo AAV2 peptide display library screening in a murine model of pressure overload-induced cardiac hypertrophy. Both variants showed significantly improved efficacy in in vivo cardiomyocyte transduction compared with the parental serotype AAV2 as indicated by a higher number of AAV vector episomes in the nucleus and significant improved transduction efficiency. Both variants also outcompeted the reference serotype AAV9 regarding cardiomyocyte tropism, reaching comparable cardiac transduction efficiencies accompanied with liver de-targeting and decreased transduction efficiency of non-cardiac cells. Capsid modification influenced immunogenicity as sera of mice treated with AAV2-THGTPAD and AAV2-NLPGSGD demonstrated a poor neutralization capacity for the parental serotype and the novel variants. In a therapeutic setting, using the long non-coding RNA H19 in low vector dose conditions, novel AAV variants mediated superior anti-hypertrophic effects and revealed a further improved target-to-noise ratio, i.e., cardiomyocyte tropism. In conclusion, AAV2-THGTPAD and AAV2-NLPGSGD are promising novel tools for cardiac-directed gene therapy outperforming AAV9 regarding the specificity and therapeutic efficiency of in vivo cardiomyocyte transduction.
Identifiants
pubmed: 35810332
pii: S1525-0016(22)00424-5
doi: 10.1016/j.ymthe.2022.07.003
pmc: PMC9734024
pii:
doi:
Substances chimiques
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3601-3618Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests L.R., C.B., T.T., and H.B. have filed and/or been granted patents in the field of AAV evolution for clinical applications. T.T. and J.V. have filed and been licensed a patent on the use of H19 in cardiovascular disease. T.T. is a founder of and holds shares in Cardior Pharmaceuticals GmbH.
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