Back in 1956, when scientists got their first good look at an RNA molecule, they already understood that RNA translates DNA into the protein machinery that carries out the work of a cell. They probably didn’t expect, however, that people would still be discovering new RNA functions 60 years later. We now know that RNA molecules are involved in all kinds of cellular functions, from regulating the expression of genes to slicing molecules into pieces and joining them together.
RNAs are also involved in many disease processes, from cancer to infectious disease to chronic diseases and more. So at the Genomics Institute of the Novartis Research Foundation (GNF), we have launched an effort to alter the functions of RNAs the same way we alter the functions of proteins, using small molecules to interfere with the machinery that is driving disease.
“There’s been a massive explosion in the discovery of functions of RNA. It is far more involved in cellular function than we initially thought,” says Jeff Rogers, Director of RNA Biology at GNF. “If we can tweak those functions the same way we can selectively tweak the functions of proteins, we’ll be off to the races in terms of RNA therapeutics.”
Novartis and many other companies have been successfully targeting proteins with small molecules for years, so it may sound as if a host of new RNA drugs might be just around the corner. But it’s not that simple. Even though the idea sounds appealing in theory, in practice there are several challenges. For instance, proteins have 20 building blocks, while RNAs have only 4. It thus is likely to be much easier to distinguish different proteins versus distinguishing different RNAs.
We’re at the forefront of RNA therapeutics, and there is enormous potential.
This difference is critical in targeted drug discovery. Compounds that interfere with the RNA in the crosshairs must not also interfere with other RNAs. Such off-target behavior could cause unwanted side effects. “You really want to make sure that your drug works only on the RNA you want it to work on,” says Rogers.
That is just the beginning of the challenges. Once we successfully target RNAs with small molecules — and we believe that if it is possible to do, we will do it — we still have to turn those promising compounds into safe, potent and effective drugs.
But high risk, high reward projects are what we do best here at GNF. “We’re trying to be as innovative as possible,” says Michael Bandell, an investigator in Rogers’ group. “We’re excited about trying new things.”
We take on high-risk projects at GNF because we have the capabilities to solve difficult problems. We start by building a basic understanding of an RNA’s involvement in disease. We have experts in a wide range of diseases working here. They are sitting right down the hall, ready to help the RNA therapeutics team identify which RNAs we should go after and how we might alter their functions to make a difference in almost any disease.
From there, we screen for compounds that interfere with the disease process. Our high-throughput screening capabilities allow us to screen millions of compounds very rapidly. If we do find a hit, we’ve got teams ready to turn those promising molecules into compounds that are safe and potent and have a shot at making it into the clinic.
We’re investing in RNA therapeutics because they open up the possibility of treating disease in new ways. Not only does RNA present a new range of targets, but also RNA therapeutics could be used in combination therapies with other drugs to dramatically alter a cellular process that is contributing to disease. “We’re at the forefront of RNA therapeutics, and there is enormous potential,” says Rogers. “But there’s a lot of work to be done to get us there.