Researchers are combining genetic studies of Utah families with AI-based molecular biology tools to find new medications that may ultimately help treat osteoarthritis at its source. This approach aims to move beyond current symptom management and joint replacement to find therapies that address the disease process itself.
Using AI tools, the researchers narrowed a pool of half a million drug candidates down to six in a matter of weeks. This work builds on previous human genetics research with Utah families, which found that changes in a gene called WNK2 underlie the progression of several highly hereditary forms of osteoarthritis. In these cases, WNK2 overactivity in joint cells triggers processes associated with inflammation, suggesting that blocking WNK2 could effectively treat the condition.
The scientists used an AI-based tool to predict the physical structure of the WNK2 protein and computationally simulated how hundreds of thousands of individual chemical compounds would interact with it. This process resulted in a shortlist of just over 50 compounds predicted to bind to WNK2 and reduce its activity. After visual inspection, the candidate pool was narrowed down to six compounds.
One candidate drug, M04, appeared to prevent osteoarthritis-related changes and promote cell health in a cell-based model where human cartilage cells were exposed to conditions that trigger inflammation. The compound inhibited many genes associated with osteoarthritis and increased the expression of genes that promote cell health.
Michael Jurynec, PhD, an associate professor of orthopedic surgery at University of Utah Health and the senior author of the study, stated that the goal is to treat patients. He noted that currently, options for osteoarthritis are limited to joint replacement or pain medication, and finding something that slows the disease process could provide people with many extra years of pain-free living.
While the results are promising, the compound has not yet been tested for safety and efficacy in living organisms or humans. The research team is working with the University of Utah Therapeutics Accelerator Hub to develop improved derivatives of the drug. M04 must undergo comprehensive testing in animal models before clinical trials can be considered. The findings were published in ACS Omega.
