Add Expansion Therapeutics to the growing list of biotech companies developing small molecules that target RNA—the intermediary messenger molecule between DNA and proteins. The start-up launched today with $55.3 million in series A funding from 5AM Ventures, Kleiner Perkins, Novartis Venture Fund, Sanofi Ventures, and others.
Nearly all small-molecule drugs bind to proteins, which are generally more structurally stable than RNA. Chemists have shunned RNA as a drug target for years, due to its floppy structure and the difficulty of designing drugs that selectively target one RNA sequence.
But Matthew Disney, a chemist at Scripps Research Institute in Florida, has been pushing for more than a decade to develop drugs that bind to RNA. RNA actually folds and loops back on itself, creating regions of three-dimensional structure that small molecules can potentially bind to. “That’s something that’s still not appreciated,” Disney says.
For years, he encountered criticism of his unorthodox idea from both academic and industry scientists. Eventually, he decided to launch Expansion Therapeutics along with Kevin M. Forrest, who will serve as the firm’s CEO.
The start-up’s first focus will be treatments for expansion repeat disorders, a group of about 30 genetic diseases marked by abnormally repetitive strings of genetic code. One such disease, myotonic dystrophy type 1 (DM1), is caused by repeating CUG bases in an RNA. This faulty elongated structure gives the mutant RNA an unusual ability to sequester a family of proteins essential for proper muscle, heart, and nerve cell functions.
Disney’s lab developed compounds that are able to selectively target the long CUG repeats that cause DM1, while leaving CUG bases found in other RNA strands alone. One version of the potential drug binds CUG repeats and blocks the mutant RNA’s ability to sequester essential proteins. Another version binds and cleaves the RNA into pieces.
The company also has earlier-stage programs for targeting RNAs related to other diseases. One tool to discover compounds that bind RNA is with a “library versus library” screen, in which RNA segments are paired with different small molecules to identify chemical structures that have affinity for a specific RNA structure. “In theory, this platform can go after any RNA that has a fold,” Forrest says.
Blocking RNA could potentially prevent the production of any protein or be used to stop the action of noncoding RNAs, which regulate the expression of other genes. This idea has been in development for years with therapies based on RNAi. “Our approach could be the small-molecule equivalent of RNAi compounds,” Forrest says.