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

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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.

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

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Publication details

The article was received on 28 Mar 2019, accepted on 26 Jun 2019 and first published on 27 Jun 2019


Article type: Edge Article
DOI: 10.1039/C9SC01432B
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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

    J. A. Kretzmann, C. W. Evans, C. Moses, A. Sorolla, A. L. Kretzmann, E. Wang, D. Ho, M. J. Hackett, B. F. Dessauvagie, N. M. Smith, A. D. Redfern, C. Waryah, M. Norret, K. S. Iyer and P. Blancafort, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC01432B

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