Tumour suppression by targeted intravenous non-viral CRISPRa using dendritic polymers

Jessica A. Kretzmann, Cameron W. Evans, Colette Moses, Anabel Sorolla, Amy L. Kretzmann, Edina Wang, Diwei Ho, Mark J. Hackett, Benjamin F. Dessauvagie, Nicole M. Smith, Andrew D. Redfern, Charlene Waryah, Marck Norret, K. Swaminathan Iyer, Pilar Blancafort

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Aberrant gene expression is a hallmark of cancer. Although transcription is traditionally considered 'undruggable', the development of CRISPR-associated protein 9 (Cas9) systems offers enormous potential to rectify cancer-associated transcriptional abnormalities in malignant cells. However delivery of this technology presents a critical challenge to overcome in order to realize clinical translation for cancer therapy. In this article we demonstrate for the first time, a fully synthetic strategy to enable CRISPR-mediated activation (CRISPRa) of tumour suppressor genes in vivo using a targeted intravenous approach. We show this via highly efficient transcriptional activation of two model tumour suppressor genes, Mammary Serine Protease Inhibitor (MASPIN, SERPINB5) and cysteine-rich 61/connective tissue growth factor/nephroblastoma-overexpressed 6 (CCN6, WISP3), in a mouse model of breast cancer. In particular, we demonstrate that targeted intravenous delivery of can be achieved using a novel nanoscale dendritic macromolecular delivery agent, with negligible toxicity and long lasting therapeutic effects, outlining a targeted effective formulation with potential to treat aggressive malignancies.

Original languageEnglish
Pages (from-to)7718-7727
Number of pages10
JournalChemical Science
Volume10
Issue number33
DOIs
Publication statusPublished - 7 Sep 2019

Cite this