RNA Modulators

RNA modulators target the genetic instructions to treat disease.

RNA splicing removes unnecessary sections (introns) of RNA, allowing the necessary sections (exons) to be stitched together. When this process occurs incorrectly, the resulting protein (in black) can be dysfunctional. RNA modulators can be designed to bind RNA and correct errors in RNA splicing to generate a functional protein (in pink). In partnership with Skyhawk Therapeutics, we are working to predict variations in RNA splicing to help us identify small molecule modulators that can address challenging targets in oncology and neurological disease.

Most diseases are driven by dysfunctional proteins, so it makes sense that the majority of treatment strategies target them. However, the key to treating a disease might not always be the protein itself, but rather the instructions to make it.

Targeting the faulty genetic instructions that lead to disease is slowly becoming possible, thanks to advances like gene therapy and CRISPR gene editing that allow researchers to modify a cell’s DNA. Small-molecule RNA modulators, however, offer a simpler and perhaps more elegant approach than these other emerging methods. Rather than modify a cell’s essential genetic information, these modulators can be designed to bind RNA molecules and change how they direct protein synthesis, for example, by either stopping protein production or modifying the type of protein that’s being made.

“Many of today’s medicines work to shut off function of a target protein. But by targeting RNA, you also have the possibility of restoring function or changing function depending on the particular biology involved,” says Chris Siebel, Principal Scientist, Discovery Oncology.

One area we’re interested in is how to alter or correct errors in RNA processing. Typically, after RNA is copied from DNA, but before it can direct protein production, it needs to be modified to remove unnecessary sections in a process known as RNA splicing. If mistakes occur during this splicing process, the resulting flawed proteins can cause disease. Alternatively, if we can deliberately introduce a splicing error into a harmful protein, then we could potentially slow, or even stop, its production.

That’s why in 2019, we began a collaboration with Skyhawk Therapeutics to discover and develop RNA splicing modulators. Together, through a combination of cell-based screening, bioinformatics and biochemistry, we’re working to better understand and predict RNA structure and variations in splicing that will help us identify new RNA modulators that can be directed to challenging targets in oncology and neurological disease.

Another area of interest is targeting the three-dimensional (3D) structure of RNA. After RNA is synthesized from DNA, it folds into a 3D structure creating pockets that medicines can bind to. This in turn can disrupt the function of harmful RNA or protein via several mechanisms, including inhibiting protein production. In 2020, we partnered with Ribometrix for their RNA-targeting platform that helps to elucidate RNA structure to discover and develop small molecules that can bind to pockets in disease-causing RNAs.

“Unlike prior RNA targeting technologies with several limitations, what makes these new approaches particularly appealing is that it uses traditional small molecules with favorable drug-like properties that offer advantages to patients, such as taking a pill rather than an injection. We therefore have a chance to go after challenging targets with a more familiar modality,” says Tapan Maniar*, Genentech Site Head of Business Development for Research Technologies, Pharma Partnering.

There’s another inherent advantage in the versatility of this approach. “The beauty of targeting RNA is that it renders the protein’s properties moot,” says John Moffat, Senior Scientist, Biochemical & Cellular Pharmacology. “For RNA, it doesn’t matter what the structure of the protein is. That opens up a lot of possibilities.”

*While Tapan was an employee at the time this article was published, he has since left Genentech.