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 so-called “undruggable” diseases. His progress has been swift and exciting, so much so that researchers around the world have adopted the approach he invented.

Disney avoids the standard path of making medicines that modify proteins. He focuses instead on preventing disease-causing proteins from being built in the first place. That requires looking to RNA, which reads and transcribes genes from DNA, then assembles them into proteins. Making drugs that act on RNA makes sense from a mathematical standpoint: A small fraction of the human genome encodes proteins. Yet most of the human genome, about 70 to 80 percent, is transcribed into RNA molecules. Disney reasoned that because of the larger pool of potential targets available, targeting RNA involved in disease could be the key to addressing many diseases whose key proteins can’t readily be modified with medications.

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 exists briefly to do its job, and is then recycled into other things. His ideas were repeatedly turned down for grants at first, 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 starts by analyzing the molecular folds and shapes of RNA sequences implicated in disease, looking for tell-tale loops or other structures that make suitable docking sites for a medicine. They have painstakingly documented thousands of RNA structures that can be drugged in this way. Meanwhile, they assembled a database of compounds expected to bind to these types of structures. Then, they went a step further. They engineered their RNA-binding compounds to act like multi-tools. One of the add-on tools is called a RIBOTAC, short for ribonuclease-targeting chimera. It doesn’t just bind to the RNA target, it recruits the cell’s own recycling enzymes to chop up the RNA for recycling. In lab studies, this invention is producing impressive results, serving as a search-and-destroy system able to thwart the cause of multiple incurable diseases.

These studies have already provided multiple lead, prototype medicines for incurable genetic diseases, including forms of muscular dystrophy such as 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, metastatic 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.