$373K Grant to Support Discovery of Remyelinating Compounds for MS

The National Multiple Sclerosis Society has awarded a two-year, $373,000 Fast Forward grant to researchers at the University of California Riverside School of Medicine to identify compounds best able to replace myelin lost over the course of multiple sclerosis (MS), according to a press release.

Seema Tiwari-Woodruff, PhD, a professor of biomedical sciences at Riverside, will lead the project, which builds upon her past research showing that a molecule called chloroindazole, along with structurally similar compounds (analogues), can add new myelin to damaged axons in neurons — a process known as remyelination.

Myelin insulates electrical pulses as they travel along axons, ensuring that they reach their target.

In MS, the immune system attacks and degrades myelin, which cannot easily be replaced. According to the researchers, if chloroindazole and similar compounds can accelerate remyelination, they may lead to new ways of treating MS.

In the awarded project, “Remyelination and Immunomodulation with analogues of Chloroindazole,” Tiwari-Woodruff and colleagues will analyze the ability of chloroindazole analogues to remyelinate axons in mouse models of MS. The team also will evaluate these compounds’ effectiveness, potency, and frequency of dosing.

“Eventually, we will evaluate the safety pharmacology of two compounds with the best efficacy, pharmacokinetics and central nervous system exposure,” Tiwari-Woodruff said in the release.

“Our overall goals through this Fast Forward grant, organized together with our commercial partner, Frequency Therapeutics, are tightly focused on obtaining critical safety and efficacy information on a set of verified candidates needed to identify the best of [chloroindazole] analogues,” she said.

Chloroindazole’s remyelinating effect comes by specifically stimulating a receptor found on oligodendrocytes, which are the cells that produce myelin.

This receptor, called estrogen receptor beta, or ERbeta, also is present on other cells of the nervous and immune systems, such as microglia, neurons, and T-cells. Because of this, chloroindazole also may provide therapeutic benefits for other autoimmune and demyelinating disorders.

Although this makes estrogens — which bind to estrogen receptors like ERbeta — attractive therapeutic candidates, they also have certain harmful effects that researchers will have to overcome to develop them as medicines.

“Accumulating evidence indicates that estrogens are both neuroprotective and immunomodulatory. However, although estrogens display immense potential for treating multiple sclerosis, they possess several deleterious side effects, including male feminization and increasing risk of breast and endometrial cancers,” Tiwari-Woodruff said.

“Our research has focused on the development of ERbeta-selective compounds for the treatment of multiple sclerosis that would be most suitable for commercial development,” she added.