Professor Matthew Disney of The Scripps Research Institute led the new study. (Credit: The Scripps Research Institute)

Interested in novel science and its applications, but sick to death of hearing about CRISPR? Then this story is for you.

Rather than tinker with genes, chemist Matthew Disney, of The Scripps Research Institute in Florida, has developed a small-molecule-based tool that acts on RNA to selectively delete certain gene products.

Eliminating the ethical and technical difficulties associated with CRISPR, and directly editing the genome, Disney’s method could work as simply as swallowing a pill to correct genetic diseases. The approach would free up the body’s defence mechanisms to cure itself.

“These studies, like much science, were about a decade in the making. We are very excited to see how this initial application evolves,” Disney says. “This research further shows that RNA is indeed a viable target to make medicines.”

With a significant proportion of our genomes being classed as ‘junk DNA’, RNA offers a vast array of potential targets in comparison to protein coding genes. The main barrier to pursuing RNA as targets has been their small size and relative lack of stability.

So how has Disney made it work? Chimeras – you take a molecule that binds to a specific RNA, and tether it to a common RNA-degrading enzyme. This complex, then attaches on to RNA, that is then broken down by its other half. The new acronym to be welcomed into the modern lexicon of hot science is RIBOTAC, short for ‘ribonuclease-targeting chimeras’.

Disney demonstrated the success of the method by tethering RNase L to Targaprimir-96, a molecule engineered by his lab in 2016 to bind with a microRNA oncogene known to boost cancer cell proliferation (especially in difficult-to-treat triple-negative breast cancer). This resulted in a reawakening of the cancer cell’s innate self-destruct program.

“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,” said Matthew Costales, first author of the paper and a graduate student in the Disney lab.

“I believe this is just the tip of the iceberg of how this approach will ultimately be applied,” said Disney.

Disney’s lab has spent many years developing a computational method called InfornaTM to match RNAs with adequate stability and structure to small, drug-like molecules capable of binding to them. His technique led to the development of Targaprimir-96 and multiple other disease-modifying compounds, some of which are now moving toward clinical development.

“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 defences toward destroying disease-causing RNAs is likely broadly applicable. 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 says. “I am excited to see where we and others ultimately take this.”