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The Beauty (and Challenge) of Developing RNA-Targeting Medicines

March 2020  For decades, companies have developed small molecule and antibody drugs that specifically target proteins, adjusting their signals – up or down – to alleviate symptoms or, in some cases, cure disease.

While this approach has produced many effective medicines, it has limits. Some disease-associated proteins are simply not druggable – they’re difficult to get at or offer no pockets for small molecules to bind.
 

Illumina Ventures company Ribometrix is taking a different approach – targeting the RNA that helps make those proteins. Intervening at the RNA level, upstream from protein synthesis, could provide a vast new set of drug targets and potentially even mitigate drug resistance, a major problem for cancer and anti-infective therapies.

“Up until now, pharmaceutical companies and biotechs have been narrowly focused on protein pathways,” said Wouter Meuleman, Principal at Illumina Ventures. “But Ribometrix is looking at a different pathway altogether, the one that goes from DNA, through RNA to create these proteins. Targeting RNA to modulate disease could be a gamechanger.”

The Challenge

Ribometrix may be one of just a few companies developing RNA-targeted small molecule drugs, and there’s a reason for that – the technical challenges are tremendous.

“This has never been done before, so we have to create an entirely new way of conducting drug discovery,” said Ribometrix CEO Mike Solomon, PhD. “RNA and proteins have very different personalities. We couldn’t just create a team of people who had worked exclusively on proteins their entire careers. We had to combine the knowledge and talents of scientists with drug discovery expertise and RNA researchers.”

Ribometrix began when co-founders Kevin Weeks, PhD, and Katie Warner, PhD, developed a new technique to create three-dimensional RNA images. When Solomon saw those pictures, he immediately grasped the potential.

“I was struck by how much the three-dimensional structure of RNA looked like a protein,” said Solomon. “It had pockets, and it looked like you could put small molecules in them. That's when a bell went off in my head – this is how we want to drug RNA.”

Starting with the 3-D images, Ribometrix isolates parts of the molecule that could be druggable, creating what they call an RNA screening construct. Researchers then conduct high-throughput screening, using a technique called affinity selection mass spectrometry. 

Ribometrix has embraced a number of assay techniques that had previously been used with proteins, adapting them to RNA. The team also develops functional assays that determine whether the small molecules binding to the target RNA are actually inhibiting protein production.  

Applications

RNA-based drug discovery is indication-agnostic, giving Ribometrix the freedom to target virtually any condition. Right now, the company is focusing on oncology. In addition to offering a favorable regulatory environment, RNA therapeutics could profoundly benefit patients whose cancers have become resistant to more traditional therapies.

“Kinase enzymes are big targets in multiple cancers,” said Solomon. “Typically, you inhibit the enzyme in its coding region, which can mutate and become resistant. We would be targeting the RNA in its non-coding region, and that could prevent translation of the mutated, drug-resistant protein.”

In addition, the company is partnering its RNA drug discovery platform with  pharmas and biotechs. Ribometrix recently began a collaboration with Vertex Pharmaceuticals to develop RNA-targeting drugs. Solomon looks forward to expanding to other companies.

“We have our own program in oncology, which we will progress into the clinic, and we are partnering with other companies to tackle different indications,” he said. “We believe the way we are managing RNA drug discovery – taking this rigorous approach to identify three-dimensional structures in the RNA – is going to be absolutely critical to getting actionable data and moving these programs into animal models and ultimately patients.”