2024-03-28T14:20:13Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1116342021-11-22T12:55:09Zcom_10261_22com_10261_1col_10261_275
Tropism-modified AAV vectors overcome barriers to successful cutaneous therapy
Larcher, Fernando
Büning, Hildegard
German Research Foundation
Instituto de Salud Carlos III
Comunidad de Madrid
National Institutes of Health (US)
European Commission
et al.
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-/lentiviral 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 αvβ8 integrin as a target receptor thus solving a major challenge of directed evolution approaches and describing a promising candidate receptor for cutaneous gene therapy.
2015-03-02T13:39:50Z
2015-03-02T13:39:50Z
2014
artículo
Molecular Therapy 22(5): 929-939 (2014)
1525-0016
http://hdl.handle.net/10261/111634
10.1038/mt.2014.14
1525-0024
http://dx.doi.org/10.13039/501100001659
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/100000002
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/100012818
24468915
eng
http://dx.doi.org/10.1038/mt.2014.14
No
S2010/BMD-2359/SKINMODEL
closedAccess
Nature Publishing Group
American Society of Gene and Cell Therapy