Researchers Find ONX-0914 Halts Progression of Myasthenia Gravis in Animal Study

Researchers have found that the drug ONX-0914 halts disease progression in an animal model of myasthenia gravis by altering immune responses.

The study, “ONX-0914, a selective inhibitor of immunoproteasome, ameliorates experimental autoimmune myasthenia gravis by modulating humoral response,” was published in the Journal of Neuroimmunology.

The buildup of abnormal proteins is detrimental to the normal functioning of our cells. One of the pathways cells use to get rid of these high-risk proteins is through degradation in a structure called the proteasome.

Certain cells of our immune system, however, have a special proteasome, called immunoproteasome. This structure plays a critical role in our immune system response to pathogens, but also may influence the development of several inflammatory diseases.

In fact, a newly developed selective inhibitor of the immunoproteasome – ONX-0914 – showed therapeutic effects in animal models of several inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Hashimoto’s thyroiditis, and inflammatory bowel disease.

Now, researchers investigated the effects of ONX-0914 on the experimental autoimmune myasthenia gravis (EAMG) rat model, an animal model for human disease. The results showed that IV administration of ONX-0914 in rats stopped ongoing EAMG.

To understand how the drug stopped disease progression, researchers looked at its effects on the immune system’s antibody response. They looked specifically to autoantibody production (harmful antibodies that attack the body’s own tissues) and antibody affinity for the acetylcholine receptor (AChR), which underlies myasthenia gravis.

They found that ONX-0914 improved the severity of ongoing EAMG by reducing the autoantibody affinity. Additionally, the drug also decreased the follicular helper T (Tfh) cells, special cells that stimulate the production of high-affinity antibody by another class of immune cells called B-cells, and antigen presenting cells (vital cells that help start the body’s immune response).

Another subtype of T-cells – the Th17 cells – involved in the development of many autoimmune diseases was also reduced.

These results suggest that the immunoproteasome inhibitor ONX-0914 may halt the progression of EAMG by affecting several mechanisms, including inhibition of antibody affinity and decreasing the levels of cells involved in autoimmunity.

Overall, “these data suggest that the immunoproteasome inhibitor ONX-0914 may be a choice for the myasthenia gravis therapy, but more studies would be needed,” the study concluded.