Research Spotlight: Chemist targets RNA to attack incurable disease from a new direction

Professor Matthew D. Disney, Ph.D. is developing potential RNA-targeting medications for ALS, adult-onset muscular dystrophy (MD1), metastatic “triple-negative” breast cancer, Parkinson’s, dementia, COVID-19, and rare diseases including Alport syndrome. He has also shown it may be possible to treat diseases including cystic fibrosis, Alzheimer’s and heart failure by targeting RNA with small-molecule medicines.

Trailblazing professor targets ALS, myotonic dystrophy, Parkinson’s, metastatic breast cancer, viral diseases and more by attacking key RNA, silencing disease genes.

Many diseases, including ALS, some aggressive cancers, muscular dystrophy, Parkinson’s and many viral diseases, lack effective treatments, despite significant effort and investment.

Chemist Matthew D. Disney, Ph.D., had a different idea of how to attack these “undruggable” diseases. His progress has been swift and exciting, so much so that researchers around the world are now emulating his work and methods.

Most drugs work by binding with proteins. A small fraction of the human genome encodes proteins, however, and many of those have been deemed “undruggable” because of their shape or location. DNA cannot be built into proteins without its cousin, RNA. In fact, most of the human genome, about 70 to 80 percent, is transcribed into RNA. Disney reasoned that targeting RNA involved in disease could offer a totally different approach to finding cures, simply because of the larger pool of potential targets.

Disney pursued this idea at a time when the prevailing thought among scientists worldwide was that RNA was not druggable, because of its constantly changing shape, and because it’s there briefly to do its job, and then gone. It’s recycled into other things. His proposal was repeatedly turned down for grants, because reviewers said it would be impossible and a waste of money. But Disney kept trying.

After more than a decade, Disney’s group has changed minds.

His group uses RNA sequences involved in a disease as the template to engineer potential medicines. They have painstakingly documented thousands of RNA structures that can be drugged, and assembled a database of compounds that can bind the structures. Then, they have gone further. They have taken the compounds and designed an add-on to them that recruits the cell’s own recycling enzymes to chop up the disease-causing RNA. It’s a search-and-destroy system for multiple incurable diseases.

These studies have already provided multiple lead, prototype medicines for incurable genetic diseases, including forms of muscular dystrophy, including myotonic dystrophy type 1, known as adult-onset muscular dystrophy, plus the inherited form of ALS/frontotemporal dementia, and difficult-to-treat cancers such as triple-negative breast cancer. Other targets include Parkinson’s, Alzheimer’s and heart failure.

Because of Disney’s early work, almost every drug company and many smaller biotechnology companies are now pursuing RNA as a viable drug target.

“I have been blessed with an excellent research environment at The Wertheim UF Scripps Institute, where science is enabled by our staff,” Disney says. “I am especially grateful for the wonderful students and postdoctoral fellows in the lab who have signed on to this once controversial idea.”

Disney’s colleague, Chemistry Professor Ben Shen, Ph.D., predicts Disney’s work will soon benefit many people who now have untreatable conditions.

“Matt’s research has fundamentally changed how the scientific community approaches RNA as drug targets for diseases with no known cure or treatment options,” Shen says.

Further Reading: Scientists behind RNA-repairing strategy recognized with Nobel-signature award.