New Therapy Candidates Could Provide Basis for Regenerative Medicines to Treat MS, Study Suggests

Therapy candidates that block enzymes responsible for making cholesterol can promote myelin regeneration, a discovery that could lead to new regenerative medicines capable of treating multiple sclerosis (MS) and other neurological diseases, according to a study.

In fact, Convelo Therapeutics plans to do just that, announcing its intention to use the breakthrough research as the foundation for its new drug discovery platform, according to a company press release.

The study, “Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination,” was published in the journal Nature.

MS is a chronic progressive disease caused by the rapid breakdown and insufficient regeneration of myelin — the protective covering surrounding nerve cells in the brain and spinal cord.

“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,” Drew Adams, PhD, assistant professor of genetics and genome sciences at Case Western Reserve University School of Medicine, said in press release from the university.

A type of stem cell — called oligodendrocyte progenitor cells (OPCs) — develops into oligodendrocytes, the cells responsible for the regeneration of myelin. Previous studies have identified several small molecules that promote myelin regeneration in mice by enhancing the conversion of OPCs to oligodendrocytes.

Now a research team led by scientists from Case Western Reserve University has found that many of these small molecules trigger the development of oligodendrocytes and myelin regeneration by blocking specific enzymes — namely CYP51, TM7SF2, or EBP — needed for the production of cholesterol.

Blocking these enzymes results in the buildup of a molecule called 8,9-unsaturated sterol, which acts as a trigger for the conversion of OPCs to oligodendrocytes, the team reported.

“We were shocked to find that almost all of these previously identified molecules share the ability to inhibit specific enzymes that help to make cholesterol. This insight reorients drug discovery efforts onto these novel, druggable targets,” Adams said.

The team found more than 20 new therapy candidates that regenerated myelin in the same manner.

“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,” said Paul Tesar, PhD, associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine.

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Using a new 3D nerve cell culture model that resembles human brain tissue, the researchers confirmed their findings in the laboratory, showing that the therapy candidates promoted myelin formation by blocking enzymes in the cholesterol pathway.

“Together, these studies provide new drug targets, new drug candidates, and new cholesterol pathway biomarkers to propel the development of medicines that can replenish lost myelin in patients with multiple sclerosis and related diseases,” Adams said.

Building on this research, Convelo’s new platform will focus on developing therapies for myelin regeneration in neurological diseases such as MS. Founded in 2016 by Tesar and Adams, the Cleveland-based company focuses on therapies able to unlock the regenerative capacity of the central nervous system.

“In the case of MS, the most prevalent chronic neurological disease in young adults, patients have been limited to immunomodulatory drugs. These 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,” Derrick Rossi, PhD, president and CEO of Convelo, said in the company’s release.

“I am thrilled to lead the team at Convelo as we translate these remarkable findings of Drs. Tesar and Adams into tangible, life-altering therapies for people living with demyelinating disorders,” he said.

In addition to MS, remyelination can be a useful therapeutic strategy for conditions such as stroke, spinal cord and traumatic brain injury, and age disorders like Alzheimer’s disease.