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Small-Molecule RNA-Targeting Technology Kills Cancer Cells

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As scientists gain insights into which genes drive diseases, they are pursuing the next logical question: Can gene editing technologies be developed to treat or even cure those diseases? Much of that effort has focused on developing technologies such as CRISPR-Cas9, a protein-based system.

Scientists at The Scripps Research Institute have developed a small molecule-based RNA-editing tool that can selectively delete RNA targets associated with diseases such as cancer. Offering a potential alternative to CRISPR-Cas9 – based tools that edit DNA, the new technology, developed by Matthew D. Disney, Ph.D., attaches an RNA-targeting, drug-like molecule to an RNA-degrading enzyme. Because the technology uses small molecules rather than proteins, it could also feasibly be packaged into a convenient oral pill.

Initial tests demonstrated that a ribonuclease-targeting chimera (RIBOTAC) designed against a breast cancer microRNA (miRNA) oncogene caused the death of malignant cells, without harming normal cells. “I believe this is just the tip of the iceberg of how this approach will ultimately be applied,” says Dr. Disney. “Since it is now known that RNA is a key driver in nearly every disease, optimization of this approach that turns a cell’s natural defenses toward destroying disease-causing RNAs is likely broadly applicable.”


The Florida campus Scripps team reports its findings in the Journal of the American Chemical Society, in a paper entitled “Small Molecule Targeted Recruitment of a Nuclease to RNA.”

While only about 2% of the genome encodes proteins, 70% to 80% of the genome is transcribed into RNA, and this offers up potentially far greater numbers of targets. However, RNAs have traditionally been considered largely undruggable because of their small size and lack of stability. The Disney laboratory has developed a computational method, InfornaTM, that can match small, drug-like molecules with small, stable RNA-binding partners. This technology led to the development in 2016 of Targaprimir-96, which selectively binds with miRNA-96, a miRNA oncogene that promotes cancer cell proliferation in cancer, including hard-to-treat triple-negative breast cancer.

For their initial tests with the new small-molecule RNA-targeting technology, Dr. Disney’s laboratory combined Targaprimir-96 with RNase L as the RNA-degrading enzyme. RNase L is produced in small amounts by all cells as part of the human antiviral immune response and is upregulated to target viral RNAs during an infection. “A small molecule that selectively binds the oncogenic microRNA(miR)-96 hairpin precursor was appended with a short 2′-5′ poly(A) oligonucleotide,” the team explains.

When applied to cancer cells, the RNA-targeting complex effectively destroyed the target oncogenic miRNA-96 molecule. “The conjugate locally activated endogenous, latent ribonuclease (RNase L), which selectively cleaved the miR-96 precursor in cancer cells in a catalytic and sub-stoichiometric fashion,” they wrote.

Destroying the miRNA-96 effectively unblocked repression of the transcription factor FOXO1, which triggered the triple-negative breast cancer cells to self destruct. “Silencing miR-96 derepressed pro-apoptotic FOXO1 transcription factor, triggering apoptosis in breast cancer, but not healthy breast cells,” the authors write.

“Anchoring our previous work with Targaprimir-96 to the targeted recruitment of RNase L, we were able to program the RIBOTACs approach to only degrade cells that highly express the miRNA-96 oncogene, thus allowing FOXO1 to signal the selective destruction of triple-negative breast cancer cells,” comments Matthew G. Costales, a graduate student in the Disney lab, and first author of the team’s published paper. “These results demonstrate that small molecules can be programmed to selectively cleave RNA via nuclease recruitment and has broad implications,” the authors conclude.

“We will be laser-focused on diseases for which there are no known cure and have a poor prognosis, such as hard-to-treat cancers and incurable human genetic disease,” Disney comments. “I am excited to see where we and others ultimately take this.”

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