The Scripps Research Institute
Chemistry Professor Matt Disney isn’t just inventing medicines—he’s opening a whole new front in the war on disease. The drugs he’s developing on the Florida campus of The Scripps Research Institute are of the ordinary kind that can be taken as pills. But in a twist, they work by targeting RNAs instead of proteins.
Virtually all existing drugs work against proteins. Proteins are prime targets for drugs because they are crucial for cellular operations. They also tend to be relatively big molecules with complex, stable structures to which drug compounds can fasten tightly and selectively.
RNAs represent a very different sort of target. They are the molecules that cells make when copying out the genetic information contained in DNA. Some RNAs carry genetic instructions for making proteins. Many fulfill other important functions in cells. In principle, targeting RNAs would allow one to influence virtually any process in cells, and thereby treat any disease. The problem has been that RNAs tend not to form the complex, stable structures that proteins form. That makes them harder to hit selectively with ordinary drug molecules.
However, Disney and his lab in recent years have developed a way to decode a subset of RNAs that do possess enough structure to be targeted with normal drugs.
“Our targets are targets that the big pharma companies would never consider because they see them as too risky,” Disney says. “But we’ve been able to de-risk them. Because of these efforts, every big pharma company is starting to pursue RNA as a small-molecule drug target.”
Targeting RNA may sometimes be the best option in fighting an illness. That is particularly so when RNA molecules themselves are the immediate causes of illness, as in the so-called repeat-expansion diseases. In this class of genetic ailments, mutations elongate genes, resulting in the production of abnormal, extra-long strands of RNA. These extra-long RNAs can form abnormal loops and other complex structures that often are toxic to the cells they inhabit.
Repeat-expansion diseases, which affect millions of people worldwide, tend to be progressive and fatal. “Not one of them has a cure,” Disney says. That may soon change. The abnormal structural complexities of repeat-expansion RNAs in principle make them more targetable with drugs, and Disney is pursuing that opportunity. His years of basic, grant-funded science in this field led to the recent spinoff of a startup biotech company, Expansion Therapeutics, which is now well along in developing candidate anti-RNA compounds to treat this class of ailments.
Their most advanced project involves a candidate drug against myotonic dystrophy type 1 (MD1), an inherited disease that kills motor neurons and causes muscle weakness, wasting, and abnormal tensing, in addition to cataracts and heart problems.
“We’ve shown that we can hit the RNA target in MD1, and we’re now optimizing some promising compounds to maximize their effectiveness and minimize side-effects—everything is looking good so far,” Disney says.
He and his team are, moreover, investigating potential drug compounds to help people who have ALS or frontotemporal dementia—many cases of which involve toxic repeat-expansion RNAs. Candidate anti-RNA treatments for Huntington’s disease, autism, myotonic dystrophy type 2, and even some infectious diseases and advanced cancers are also in the works.
“The technological platform we’ve established for finding candidate anti-RNA drugs is applicable to nearly every human disease,” Disney says.