Despite all the excitement gene-editing systems like CRISPR have generated, there have been challenges when it comes to delivering the technology. Viral vectors are commonly used but can lead to off-target editing and side effects such as cancer. Researchers from The Scripps Research Institute have been working on an alternative: a small molecule that can selectively target RNA and could pave the way to a pill that can treat genetic diseases.
DNA-targeting CRISPR has dominated the gene editing landscape, but RNA-focused systems are on the rise. These systems target RNA to bring about reversible changes to DNA, but are delivered in much the same way—via injection.
Matthew Disney, a professor at Scripp's Florida campus, has been working on small molecules that target RNAs, which have historically been considered undruggable due to their small size and relative lack of stability. What's more, it is difficult to selectively target RNAs because they are made of just four ingredients: the nucleotide bases A, T, G and C. Proteins, on the other hand, are composed of many different amino acids.
Disney's approach combines an RNA-degrading enzyme with a druglike molecule that binds selectively to a specific RNA. The complex, dubbed RIBOTAC (ribonuclease-targeting chimeras) is designed to latch onto and destroy an "undesirable gene product," such as a disease-causing RNA, according to a statement from Scripps.
The team tested their technology against miRNA-96, a microRNA oncogene that fosters cancer cell proliferation. They tethered the RNA-degrading enzyme RNase L to Targaprimir-96, a molecule they created in 2016 to bind with miRNA-96. The treatment selectively cleaved the miRNA-96 precursor in cancer cells, silencing the oncogene. It "derepressed" the transcription factor FOXO1, unleashing cell death in triple-negative breast cancer cells, but not in healthy breast cells. The findings appear in the Journal of the American Chemical Society.
Others have tried to target RNA with an antisense approach, using strands of DNA or RNA to knock down specific molecules of RNA and treat disease. Ionis Pharma has licensed out antisense treatments to Roche, AstraZeneca and Janssen in deals targeting Huntington disease, kidney disease and gastrointestinal disease, for example.
On the flip side, Accent Therapeutics launched this year to drug RNA-modifying proteins (RMPs), which have been linked to certain cancers. The biotech is working to understand which proteins are involved in which cancer indications and to identify the patients who would be most likely to respond to treatment.
Accent has selected 20 RMPs it believes have "strong implications" in specific cancer indications and prioritized them according to unmet medical need and what it knows about the biology of those targets, including whether they are likely to be a druggable. Of these, it has picked four targets and is working to identify chemical matter for each one, Chief Scientific Officer Robert Copeland told FierceBiotech.
Awakening the body’s ability to kill its own cancer by exploiting cells’ RNA degradation system offers a novel approach to attacking cancer, says Disney of Scripps.
Scripps intends to apply its technology to hard-to-treat cancers, genetic disorders and other diseases for which there are no known cures. "The applications range from cancer to incurable disease—basically any disease where RNA is a key driver," Disney told FierceBiotechResearch in an email.