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

Area of Science:

• Oncology
• Molecular Biology
• Gene Therapy

Background:

• Aberrant gene expression is a key feature of cancer.
• CRISPR-associated protein 9 (Cas9) systems offer potential for correcting cancer-associated transcriptional abnormalities.
• Efficient delivery of CRISPR technology for cancer therapy remains a significant challenge.

Purpose of the Study:

• To demonstrate a fully synthetic strategy for CRISPR-mediated activation (CRISPRa) of tumor suppressor genes in vivo.
• To achieve targeted intravenous delivery of CRISPRa for cancer therapy.
• To evaluate the therapeutic potential of activating MASPIN and CCN6 in a breast cancer mouse model.

Main Methods:

• Development of a synthetic strategy for CRISPRa.
• Utilizing a novel nanoscale dendritic macromolecular delivery agent for targeted intravenous delivery.
• Assessing the transcriptional activation of Mammary Serine Protease Inhibitor (MASPIN) and CCN6 in a mouse model of breast cancer.

Main Results:

• Successful in vivo CRISPRa of two model tumor suppressor genes, MASPIN and CCN6.
• Demonstrated targeted intravenous delivery using a novel nanoscale dendritic macromolecular agent.
• Observed negligible toxicity and long-lasting therapeutic effects in a mouse model of breast cancer.

Conclusions:

• A fully synthetic strategy for targeted intravenous CRISPRa of tumor suppressor genes has been established.
• The developed delivery system shows promise for treating aggressive malignancies.
• This approach offers a potential new avenue for cancer therapy by rectifying transcriptional abnormalities.