Universität zu Köln

Rode, Laura, Baer, Christian, Gross, Sonja, Rossi, Axel, Meumann, Nadja, Viereck, Janika, Abbas, Naisam, Xiao, Ke, Riedel, Isabelle, Gietz, Anika, Zimmer, Karina, Odenthal, Margarete, Buening, Hildegard and Thum, Thomas (2022). AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes. Mol. Ther., 30 (12). S. 3601 - 3619. CAMBRIDGE: CELL PRESS. ISSN 1525-0024

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Abstract

AAV vectors are promising delivery tools for human gene ther-apy. 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 hyper-trophy. 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 -tar-geting and decreased transduction efficiency of non-cardiac cells. Capsid modification influenced immunogenicity as sera of mice treated with AAV2-THGTPAD and AAV2-NLPGSGD demon-strated 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., cardio-myocyte 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rode, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Baer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Gross, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Rossi, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Meumann, Nadja UNSPECIFIED UNSPECIFIED UNSPECIFIED Viereck, Janika UNSPECIFIED UNSPECIFIED UNSPECIFIED Abbas, Naisam UNSPECIFIED UNSPECIFIED UNSPECIFIED Xiao, Ke UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedel, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Gietz, Anika UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmer, Karina UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED Thum, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-671838
DOI:	10.1016/j.ymthe.2022.07.003
Journal or Publication Title:	Mol. Ther.
Volume:	30
Number:	12
Page Range:	S. 3601 - 3619
Date:	2022
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1525-0024
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADENOASSOCIATED VIRUS VECTOR; SPINAL MUSCULAR-ATROPHY; CALCIUM UP-REGULATION; GENE-THERAPY; VIRAL-VECTORS; TRANSDUCTION; MICE; EXPRESSION; EVOLUTION; EFFICIENT Multiple languages Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67183