Research Sheds Light on New Drug Targets for Regenerative MS Therapies

In a groundbreaking new study, researchers have identified a molecular pathway for stimulating the regeneration of new myelinating cells and repairing the damage of debilitating neurological diseases. The findings could pave the way for potential new regenerative therapy candidates for neurological conditions such as multiple sclerosis (MS).

The degeneration of myelin—the protective covering that surrounds nerve cells in the brain and spinal cord—causes disease progression in MS. Previous research has identified several small molecules that promote myelin repair in mice by enhancing the conversion of a type of stem cell called oligodendrocyte progenitor cells (OPCs) to oligodendrocytes.

“Many labs, including at Case Western Reserve, had identified drug candidates that kickstart the formation of new myelin, but exactly how each of these molecules affected brain cell function wasn’t clear,” study author Drew Adams, PhD, professor of novel therapeutics and assistant professor of genetics and genome sciences at Case Western Reserve University School of Medicine, said in a press release.

In the study, researchers from Case Western Reserve University found that many of the previously identified molecules trigger myelin regeneration by blocking specific enzymes, known as CYP51, TM7SF2, or EBP, which are used by brain cells to produce cholesterol.

Miconazole, a drug typically used to treat athlete’s foot, enhances myelin formation by inhibiting these cholesterol-producing enzymes, according to the study. The team found 20 additional therapies that also enhance myelin formation in this way. The researchers were able to pinpoint which enzymes were being blocked by which drugs from the accumulation of metabolites in the cholesterol pathway.

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“The idea that almost all drug candidates that promote myelin repair inhibit the same enzyme targets represents a bold new paradigm for the field and may redirect the course of ongoing drug discovery efforts,” study author Paul Tesar, PhD, said in the press release.

To confirm their findings, the researchers measured the formation of human myelin in the laboratory by using a new 3-dimensional nerve cell culture model that closely resembles human brain tissue. The investigated drug candidates promoted human myelin regeneration by blocking the cholesterol pathway enzymes.

In a press release, Convelo Therapeutics announced its intention to use the new research as a foundation for its drug discovery platform.

“In the case of MS, the most prevalent chronic neurological disease in young adults, patients have been limited to immunomodulatory drugs,” Derrick Rossi, PhD, president and chief executive officer of Convelo Therapeutics, said in a statement. “These drugs can be effective in slowing the progression of disease, but do not halt it. Our thesis is that therapeutics that act directly within the central nervous system to stimulate myelin regeneration may be what is needed to stop or reverse the progressive nature of these types of diseases altogether.”

Although clinical candidates based on this research are not expected to enter trials until 2019, the researchers concluded that the findings provide an enhanced understanding of myelin repair that can enable the development of novel regenerative MS therapies.

References

Hubler Z, Allimuthu D, Bederman I, et al. Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Nature. 2018. https://www.nature.com/articles/s41586-018-0360-3

A New Roadmap for Repairing the Damage of Multiple Sclerosis [news release]. Case Western Reserve University’s website. http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=1375&news_category=8. Accessed July 30, 2018.