Tools for editing the genome and epigenome have revolutionised the field of molecular biology and represent a new frontier in targeted therapeutic intervention. Cancers are a pathological disease which characteristically demonstrate genome-wide altered gene expression, in which tumours may be driven by the activation of oncogenes and inactivation of tumour suppressor genes. CRISPR-based technology enables precise and robust genetic and epigenetic modulation for virtually any potential target gene. Recent developments highlight the potential for epigenetic reprogramming using CRISPR platforms, which could potentially be used in the treatment of cancers. However, clinical implementation of these technologies is problematic as safe and effective delivery of all CRISPR components to the target tissue remains a challenge. Here we describe the design and synthesis of a novel dendronised polymer for the efficient delivery of a CRISPR/dCas9 platform aimed at the targeted upregulation of tumour suppressor genes. We show significant activation of tumour suppressor genes in vitro, leading to a loss of proliferative and tumorigenic properties in the MCF-7 breast adenocarcinoma cell line. Following that, we modify the polymer for non-toxic, targeted in vivo delivery. We show efficient intravenous delivery of the CRISPR-based platform resulting in targeted upregulation of tumour suppressor genes in an MCF-7 xenograft model, causing long-term tumour suppression and regression.

Development of a polymeric agent for the in vivo delivery of CRISPR system to activate tumour suppressor genes

254th National Meeting (2017)

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