Meumann, Nadja, Cabanes-Creus, Marti, Ertelt, Moritz, Navarro, Renina Gale, Lucifora, Julie, Yuan, Qinggong, Nien-Huber, Karin, Abdelrahman, Ahmed, Vu, Xuan-Khang, Zhang, Liang, Franke, Ann-Christin, Schmithals, Christian, Piiper, Albrecht, Vogt, Annabelle, Gonzalez-Carmona, Maria, Frueh, Jochen T., Ullrich, Evelyn, Meuleman, Philip ORCID: 0000-0001-6821-234X, Talbot, Steven R., Odenthal, Margarete, Ott, Michael, Seifried, Erhard, Schoeder, Clara T., Schwable, Joachim, Lisowski, Leszek and Buning, Hildegard (2023). Adeno-associated virus serotype 2 capsid variants for improved liver-directed gene therapy. Hepatology, 77 (3). S. 802 - 816. HOBOKEN: WILEY. ISSN 1527-3350

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Abstract

Background and Aims Current liver-directed gene therapies look for adeno-associated virus (AAV) vectors with improved efficacy. With this background, capsid engineering is explored. Whereas shuffled capsid library screenings have resulted in potent liver targeting variants with one first vector in human clinical trials, modifying natural serotypes by peptide insertion has so far been less successful. Here, we now report on two capsid variants, MLIV.K and MLIV.A, both derived from a high-throughput in vivo AAV peptide display selection screen in mice. Approach and Results The variants transduce primary murine and human hepatocytes at comparable efficiencies, a valuable feature in clinical development, and show significantly improved liver transduction efficacy, thereby allowing a dose reduction, and outperform parental AAV2 and AAV8 in targeting human hepatocytes in humanized mice. The natural heparan sulfate proteoglycan binding ability is markedly reduced, a feature that correlates with improved hepatocyte transduction. A further property that might contribute to the improved transduction efficacy is the lower capsid melting temperature. Peptide insertion also caused a moderate change in sensitivity to human sera containing anti-AAV2 neutralizing antibodies, revealing the impact of epitopes located at the basis of the AAV capsid protrusions. Conclusions In conclusion, MLIV.K and MLIV.A are AAV peptide display variants selected in immunocompetent mice with improved hepatocyte tropism and transduction efficiency. Because these features are maintained across species, MLIV variants provide remarkable potential for translation of therapeutic approaches from mice to men.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Meumann, NadjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cabanes-Creus, MartiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ertelt, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Navarro, Renina GaleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lucifora, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yuan, QinggongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nien-Huber, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdelrahman, AhmedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vu, Xuan-KhangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, LiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franke, Ann-ChristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmithals, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piiper, AlbrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, AnnabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Carmona, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frueh, Jochen T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, EvelynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meuleman, PhilipUNSPECIFIEDorcid.org/0000-0001-6821-234XUNSPECIFIED
Talbot, Steven R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ott, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seifried, ErhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoeder, Clara T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwable, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lisowski, LeszekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buning, HildegardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-695369
DOI: 10.1002/hep.32733
Journal or Publication Title: Hepatology
Volume: 77
Number: 3
Page Range: S. 802 - 816
Date: 2023
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1527-3350
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEPARAN-SULFATE PROTEOGLYCAN; IN-VIVO; HEPATOCELLULAR-CARCINOMA; PRIMARY HEPATOCYTES; AAV CAPSIDS; TRANSDUCTION; TYPE-2; VECTORS; TROPISM; IDENTIFICATIONMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69536

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