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.
At The Scripps Research Institute campus in Florida, chemist Matthew D. Disney, PhD, has taken a different approach, developing a small-molecule-based tool that acts on RNA to selectively delete certain gene products.
Disney’s deletion tool opens the possibility of creating drugs that can be taken conveniently as pills to correct genetic diseases—by destroying toxic gene products, and by chemically controlling the body’s defense mechanisms. The paper, “Small molecule targeted recruitment of a nuclease to RNA,” was published online by the Journal of the American Chemical Society.
“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.”
RNAs represent a diverse group of molecules within cells that act like the cells’ laborers, reading, regulating and expressing DNA’s genetic instructions. Within our cells, RNAs are constantly in motion. They assemble, they carry out their duties, and then they are broken up for recycling by RNA-degrading enzymes, which are chemical scissors that cut apart other molecules.
While about 2 percent of our genome encodes proteins, 70 to 80 percent of the genome is transcribed into RNA, potentially offering significantly more druggable targets, Disney says. Until recently, however, most researchers considered RNAs undruggable, because of their small size and relative lack of stability.
Disney’s innovation tethers a drug-like molecule—one engineered to bind precisely and selectively to a specific RNA—to a common RNA-degrading enzyme. The small-molecule/enzyme complex is designed to latch onto the undesirable gene product and destroy it. Disney named the technology RIBOTAC, short for “ribonuclease-targeting chimeras.”
To test the RIBOTAC technology, Disney chose for his RNA-degrading enzyme RNase L, which is a critical part of the human antiviral immune response. Present in small amounts in every cell, production of RNase L typically surges on viral infection to destroy the viral RNA and overcome the illness.
For the other piece of the RIBOTAC complex, its drug-like molecule, Disney chose 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, miRNA-96.
Destroying the oncogene led to a reawakening of the cancer cell’s innate self-destruct program, via an increase in the FOXO1 gene, which ultimately spurred the death of the malignant cells, says Matthew G. Costales, first author of the paper and a graduate student in the Disney lab.
“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,” says Costales.
Awakening the body’s ability to kill its own cancer by exploiting cells’ RNA degradation system offers a novel approach to attacking cancer, Disney says. The RIBOTAC technology has potentially broad applications for cancer and other gene-driven diseases as well, he says.
“I believe this is just the tip of the iceberg of how this approach will ultimately be applied,” says 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 defenses 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.”
Receive an email update when we add a new RNA article.
The Latest on: RNA-modifying tool
via Google News
The Latest on: RNA-modifying tool
- Epigenetics Market is Predicted to reach USD 1310.46 Million by 2023 on November 29, 2018 at 4:00 pm
Based on Enzymes, market is further segmented into DNA-Modifying Enzymes, Protein-Modifying Enzymes, RNA-Modifying Enzymes. Further based on Instruments & Consumables, market is segmented into Mass Sp... […]
- RNA metabolism-focused Gotham Therapeutics launches with $54M Series A round on October 10, 2018 at 8:58 am
A company developing a class of RNA-modifying proteins to potentially treat cancers, autoimmune disorders and neurodegenerative diseases has launched with a pool of cash from several investors. New Yo... […]
- Global Epigenetics Market to 2026: Market is Expected to Reach US$ 16.50 Billion, from $4.63 Million in 2017 on June 15, 2018 at 8:15 am
protein-modifying enzymes and RNA-modifying enzymes), instruments and bioinformatics tools. Currently, the demand for kits is highest in the market and anticipated to exhibits fastest market growth ov... […]
- Novel RNA-modifying tool corrects genetic diseases, including driver of triple-negative breast cancer on May 29, 2018 at 12:58 pm
Professor Matthew Disney of The Scripps Research Institute led the new study. Credit: The Scripps Research Institute As scientists gain insights into which genes drive diseases, they are pursuing the ... […]
- Accent Therapeutics launches with $40 million Series A round on May 23, 2018 at 12:44 pm
18, 2017. The company plans to establish a drug-discovery platform focused on product candidates targeting RNA-modifying proteins, or RMPs, based on epitranscriptomics – the role of RNA structure, sta... […]
- Accent Therapeutics Debuts With $40M To Target RNA Modification on May 18, 2018 at 2:04 am
Now it’s up to the Accent team to find the RNA-modifying enzymes that are most relevant in cancer. To do this, Copeland says his group is using, among other tools, a CRISPR-based system that allows th... […]
- Stress-induced changes of genetic information : new details discovered about mysterious protein on February 14, 2018 at 5:23 pm
"Deciphering the molecular function of these RNA-modifying enzymes is an important step towards ... extending personalized therapeutic approaches with ‘epitranscriptomic’ tools. The international stud... […]
- Stress-induced changes of genetic information—new details discovered about the function of a mysterious protein on February 13, 2018 at 4:00 pm
"Deciphering the molecular function of these RNA-modifying enzymes is an important step towards ... extending personalized therapeutic approaches with 'epitranscriptomic' tools. […]
- Middle East and Africa Epigenetics Market is poised to cross USD 87.68 million in 2021 on January 17, 2018 at 10:57 am
Some of these traits are passed down to future generations as heritable traits. Browse market data tables and in-depth TOC of the Middle East and Africa Epigenetics Market to 2021 @ https://www.market... […]
via Bing News