Russian Researchers Discover New Approach to Combatting Osteoarthritis

A team of researchers from HSE University, the Russian Academy of Sciences Zelinsky Institute of Organic Chemistry, and Molecular Technologies, LLC have jointly proposed a new treatment for osteoarthritis. This is currently the first disease-modifying osteoarthritis drug to act simultaneously on bone and cartilage tissue metabolism and on inflammation. The study findings are published in Scientific Reports.

Osteoarthritis (OA) is one of the most common diseases affecting adults over the age of 40 worldwide. It begins with acute inflammation, usually accompanied by pain and discomfort in the knee joint. Gradually, as synovial inflammation progresses, the cartilages covering the ends of the bones in the affected joint degenerate, causing the bones to come into contact with each other. Eventually, the joint can degenerate to a point where it loses its function. 

Thus, the disease is driven by two pathological processes: tissue degradation and inflammation. An effective treatment must address both aspects of OA, but most treatments available today only act on inflammation, often partially. Most drugs can only alleviate the symptoms, such as pain and swelling, but are unable to slow down the joint degeneration. In addition, many such medicines tend to have serious side effects.

Another worrying aspect of OA is that over time, it usually progresses into a chronic condition. The body begins to recruit additional inflammatory cells and activate its own, causing the joints to degenerate even faster and more severely. Certain enzymes—kinases—play a key role in this process. In particular, SYK and cSrc kinases are part of the signalling pathways that recruit and activate inflammatory cells.

Researchers from HSE University and the RAS Zelinsky Institute of Organic Chemistry, together with colleagues from Molecular Technologies, LLC, hypothesised that 'turning off' and inhibiting SYK and cSrc kinases could slow down or stop joint deterioration. For this purpose, they proposed using MT-SYK-03 , a small-molecule multikinase inhibitor originally developed for the treatment of rheumatoid arthritis, a more severe autoimmune disease. Both SYK and cSrc kinases have been found to play a key role in the pathogenesis of both diseases. 

Originally, we were developing a treatment for rheumatoid arthritis and testing how the MT-SYK-03 molecule works. During that study, we found that this molecule inhibits two targeted kinases involved in the pathogenesis of both rheumatoid arthritis and osteoarthritis. As for other kinases, this molecule hardly affects them at all. We were really lucky, because designing a drug capable of inhibiting only a certain kinase is impossible: there is a huge number of enzymes in this category—more than 450 types, and all very similar to each other.

Victor Stroylov
Study co-author, Associate Professor, Joint Department of Organic Chemistry with the RAS Zelinsky Institute of Organic Chemistry

Based on the MT-SYK-03 molecule, a drug candidate has been developed and successfully tested in a phase-one trial on healthy volunteers to confirm its safety for humans. Before the clinical trial, experiments on mice and rats with osteoarthritis or rheumatoid arthritis demonstrated that the molecule made it possible to slow down bone degradation and even to reverse cartilage degeneration, causing cartilage tissue to regenerate.

As far as we know, this is the first drug to act on bone and cartilage tissue metabolism and to fight the inflammatory process simultaneously. Results from the phase-one trial offer hope for effective treatment of this debilitating condition. Now we are waiting for the next, phase-two trial on patients, which is expected to take about a year.

Victor Stroylov
Study co-author, Associate Professor, Joint Department of Organic Chemistry with the RAS Zelinsky Institute of Organic Chemistry

IQ

 

Text author: Elena Shchur

June 02, 2023