Clone of Finding New Osteoarthritis Medicines Via AI and Genetics

Key points:

• Researchers combined family genetic studies with AI molecular biology to find a new candidate drug to treat osteoarthritis.

• In cells in a dish, the new compound prevents OA-associated changes and promotes cell health.

• The drug has not yet been tested in people or animals.

IMPACT: The new drug is a starting point for therapies that treat OA at its source.

What is Osetoarthritis (OA)?

Osteoarthritis is a chronic, painful joint disease and a leading cause of disability. Despite its prevalence, therapies for osteoarthritis are limited and focus on symptom management.

Now, researchers are combining genetic studies of Utah families with AI-based molecular biology tools to find new medications that may ultimately help treat OA at its source.

One such new drug appears to promote joint health and reduce inflammation-related genes in a model of osteoarthritis based on cells in a dish. While it has yet to be tested for safety and efficacy in a living organism, the new compound provides a starting point for innovative OA therapies.

“Our goal really comes down to treating patients,” says Michael Jurynec, PhD, associate professor of orthopedic surgery at University of Utah Health and the senior author on a paper describing the new results. “Right now, the only thing we can do for OA is joint replacement or pain medication. So, if we can find something that slows down the disease process, giving people an extra 10 or 20 years of pain-free living, that’s a huge advancement.”

The results are published in ACS Omega.

Finding new medicines for Osetoarthritis

Using AI tools, the researchers were able to narrow a pool of half a million drug candidates down to six in a matter of weeks.

Previous human genetics research with Utah families had found that, for several forms of highly hereditary OA, changes in a gene called WNK2 underlie the disease’s progression. For these families, WNK2 overactivity in joint cells triggers processes associated with inflammation, which suggests that blocking WNK2 could effectively treat arthritis.

The scientists used an AI-based tool to predict the physical structure of the WNK2 protein, and then computationally simulated how hundreds of thousands of individual chemical compounds would interact with it. This gave them a “shortlist” of just over 50 compounds predicted to bind to WNK2 and reduce its activity. Visual inspection of the shortlist narrowed down the candidate pool to six compounds.

Promisingly, one of the candidate drugs, M04, appeared to prevent osteoarthritis-related changes and make cells healthier in an established cell-based model of osteoarthritis, in which human cartilage cells are exposed to conditions that trigger inflammation.

“We treated cells with this new compound we discovered, and it inhibited many, many genes that are associated with osteoarthritis,” Jurynec says. “Not only did it inhibit these inflammatory factors, but it actually increased expression of genes that promote the health of these cells.”

This suggests that the drug or a derivative of it could help treat OA.

Next steps

The new compound is a valuable starting point, but much more work lies ahead to develop it into a safe and effective drug, Jurynec emphasizes. While computational evaluation and in vitro studies suggest that M04 is a promising OA drug, its toxicity and side effects have not been fully tested, and researchers don’t know whether it will be safe to use in people.

The team is working to address these concerns through a collaboration with the University of Utah Therapeutics Accelerator Hub, working together to develop improved derivatives of the drug. M04 will also need to be comprehensively tested for safety and efficacy in animal models before clinical trials are possible. But as early as it is, the new compound provides a crucial starting point for development of better OA drugs.

“This is really the beginning of the study,” Jurynec says. “It’s not the end. We don’t have a drug that’s going to cure OA yet. But this is very promising.”

The results are published in ACS Omega as “Identification and Validation of a Novel WNK2 Inhibitor: A New Genetically Informed Target for Osteoarthritis Drug Development.”

This research was funded by the Skaggs Foundation for Research, the Utah Genome Project, and the Arthritis National Research Foundation. Content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.

Jurynec and first author Shivakumar Veerabhadraiah have filed a U.S. Patent Application (No. 19/672,326) titled ‘Compounds That Inhibit WNK2 Activity And Methods For Osteoarthritis.

(Newswise/AT)