AI and genetics identify WNK2 inhibitor for osteoarthritis treatment

Researchers at University of Utah Health have identified an early-stage drug candidate that could form the basis of disease-modifying treatments for osteoarthritis (OA), using artificial intelligence and human genetics to accelerate the drug discovery process.

The preclinical study describes how researchers combined genetic data from Utah families with AI-based molecular modelling to identify compounds that inhibit WNK2, a protein linked to inherited forms of osteoarthritis. One candidate, known as M04, reduced inflammatory gene activity and promoted cartilage cell health in a laboratory model of the disease.

Although the compound is only at an early stage of development and has yet to undergo animal testing, the findings provide a potential starting point for therapies designed to slow disease progression rather than simply manage symptoms.

AI narrows drug candidates

Osteoarthritis is one of the leading causes of disability worldwide, with current treatments largely focused on pain relief or joint replacement surgery once the disease has advanced.

Building on previous genetic studies, the researchers investigated WNK2 after identifying mutations in the gene as a driver of several highly hereditary forms of osteoarthritis. Increased WNK2 activity in joint cells is thought to trigger inflammatory processes associated with disease progression, suggesting that inhibiting the protein could offer a new therapeutic approach.

The team used AI tools to predict the three-dimensional structure of the WNK2 protein before carrying out virtual screening of around 500,000 chemical compounds. Computational modelling identified just over 50 molecules predicted to bind to WNK2, with researchers manually narrowing the shortlist to six candidates for laboratory testing.

One compound, M04, demonstrated the greatest potential in an established cell-based model of osteoarthritis, where human cartilage cells were exposed to inflammatory conditions.

“We treated cells with this new compound we discovered and it inhibited many, many genes that are associated with osteoarthritis,” says Dr Michael Jurynec, Associate Professor of Orthopaedic Surgery at University of Utah Health and a senior author of the study. “Not only did it inhibit these inflammatory factors, but it actually increased expression of genes that promote the health of these cells.”

Early preclinical findings

The researchers say the results suggest that M04, or an improved derivative, could eventually form the basis of a disease-modifying therapy for osteoarthritis.

“Our goal really comes down to treating patients,” says Jurynec. “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.”

However, the team emphasises that the work remains in the early stages of drug development. While computational analysis and cell-based experiments support M04’s potential, the compound has not yet been evaluated in animal models and its safety profile remains unknown.

Future steps

Researchers are now collaborating with the University of Utah Therapeutics Accelerator Hub to optimise the molecule and develop improved derivatives before progressing to preclinical animal studies. Successful safety and efficacy testing in animals would be needed before any human clinical trials could begin.

“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.”