{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:52:59Z","timestamp":1788789179608,"version":"build-2803163510"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims:<\/jats:title>\n            <jats:p>Current liver\u2010directed gene therapies look for adeno\u2010associated 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\u2010throughput <jats:italic toggle=\"yes\">in vivo<\/jats:italic> AAV peptide display selection screen in mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>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\u2010AAV2 neutralizing antibodies, revealing the impact of epitopes located at the basis of the AAV capsid protrusions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32733","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T09:16:00Z","timestamp":1660727760000},"page":"802-815","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Adeno\u2010associated virus serotype 2 capsid variants for improved liver\u2010directed gene therapy"],"prefix":"10.1097","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4929-249X","authenticated-orcid":false,"given":"Nadja","family":"Meumann","sequence":"first","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, Cologne, 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