Sallach, Jessica, Di Pasquale, Giovanni, Larcher, Fernando ORCID: 0000-0002-6771-3561, Niehoff, Nadine, Ruebsam, Matthias, Huber, Anke, Chiorini, Jay, Almarza, David, Eming, Sabine A., Ulus, Hikmet, Nishimura, Stephen, Hacker, Ulrich T., Hallek, Michael, Niessen, Carien M. and Buening, Hildegard (2014). Tropism-modified AAV Vectors Overcome Barriers to Successful Cutaneous Therapy. Mol. Ther., 22 (5). S. 929 - 940. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1525-0024

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Abstract

Autologous human keratinocytes (HK) forming sheet grafts are approved as skin substitutes. Genetic engineering of HK represents a promising technique to improve engraftment and survival of transplants. Although efficacious in keratinocyte-directed gene transfer, retro-/lenti-viral vectors may raise safety concerns when applied in regenerative medicine. We therefore optimized adeno-associated viral (AAV) vectors of the serotype 2, characterized by an excellent safety profile, but lacking natural tropism for HK, through capsid engineering. Peptides, selected by AAV peptide display, engaged novel receptors that increased cell entry efficiency by up to 2,500-fold. The novel targeting vectors transduced HK with high efficiency and a remarkable specificity even in mixed cultures of HK and feeder cells. Moreover, differentiated keratinocytes in organotypic airlifted three-dimensional cultures were transduced following topical vector application. By exploiting comparative gene analysis we further succeeded in identifying alpha v beta 8 integrin as a target receptor thus solving a major challenge of directed evolution approaches and describing a promising candidate receptor for cutaneous gene therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sallach, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Pasquale, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larcher, FernandoUNSPECIFIEDorcid.org/0000-0002-6771-3561UNSPECIFIED
Niehoff, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruebsam, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiorini, JayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Almarza, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eming, Sabine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ulus, HikmetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nishimura, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hacker, Ulrich T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niessen, Carien M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buening, HildegardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-439391
DOI: 10.1038/mt.2014.14
Journal or Publication Title: Mol. Ther.
Volume: 22
Number: 5
Page Range: S. 929 - 940
Date: 2014
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1525-0024
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ADENOASSOCIATED VIRUS TYPE-2; HEPARAN-SULFATE PROTEOGLYCAN; GROWTH-FACTOR RECEPTOR; MOUTH-DISEASE VIRUS; GENE-THERAPY; INTEGRIN ALPHA-V-BETA-8; HUMAN KERATINOCYTES; VIRAL-VECTORS; EPIDERMAL MORPHOGENESIS; TRANSDUCTION EFFICIENCYMultiple languages
Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43939

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