Development of novel AAV serotype 6 based vectors with selective tropism for human cancer cells

R. Sayroo, D. Nolasco, Z. Yin, Y. Colon-Cortes, M. Pandya, C. Ling, G. Aslanidi

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Viral vectors-based gene therapy is an attractive alternative to common anti-cancer treatments. In the present studies, AAV serotype 6 vectors were identified to be particularly effective in the transduction of human prostate (PC3), breast (T47D) and liver (Huh7) cancer cells. Next, we developed chimeric AAV vectors with Arg-Gly-Asp (RGD) peptide incorporated into the viral capsid to enable specific targeting of integrin-overexpressing malignant cells. These AAV6-RGD vectors improved transduction efficiency approximately 3-fold compared with wild-type AAV6 vectors by enhancing the viral entry into the cells. We also observed that transduction efficiency significantly improved, up to approximately 5-fold, by the mutagenesis of surface-exposed tyrosine and threonine residues involved in the intracellular trafficking of AAV vectors. Therefore, in our study, the AAV6-Y705-731F+T492V vector was identified as the most efficient. The combination of RGD peptide, tyrosine and threonine mutations on the same AAV6 capsid further increased the transduction efficiency, approximately 8-fold in vitro. In addition, we mutated lysine (K531E) to impair the affinity of AAV6 vectors to heparan sulfate proteoglycan. Finally, we showed a significant increase in both specificity and efficiency of AAV6-RGD-Y705-731F+T492V+K531E vectors in a xenograft animal model in vivo. In summary, the approach described here can lead to the development of AAV vectors with selective tropism to human cancer cells.

Original languageEnglish (US)
Pages (from-to)18-25
Number of pages8
JournalGene therapy
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr Arun Srivastava for critical reading of this manuscript. This research was supported in part by Children’s Miracle Network (to GA and CL).

Publisher Copyright:
© 2016 Macmillan Publishers Limited.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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