6:46 PM
Aug 16, 2018
 |  BC Innovations  |  Targets & Mechanisms

Unsaturated remyelination

Case Western spins out Convelo to develop remyelination drugs

Editor's Note: This article was updated on Aug 31, 2018 at 12:21 PM PDT

Enzymes downstream in cholesterol biosynthesis could provide new ways to stimulate remyelination that avoid the baggage of previously identified multiple sclerosis targets, according to a group at Case Western. The university is spinning out Convelo Therapeutics Inc. to translate the idea.

Marketed therapies for MS work via immune suppression, which slows disease progression but does not regenerate lost myelin.

High throughput screening systems have identified dozens of compounds capable of inducing remyelination in preclinical models. But the relevant targets of many of those compounds are either unknown, because the small molecules bind to many proteins, or are problematic for drug development.

For example, clemastine is the only remyelinating compound that has produced functional recovery in the clinic to date. In a Phase II trial in MS patients with optic neuropathy, clemastine met the primary endpoint of decreasing latency of evoked visual potentials, indicating a recovery of conduction velocity, one of myelin’s most important functions. Results were published in a 2017 Lancet paper.

But the compound, better known as an antihistamine and antimuscarinic, hits a variety of molecular pathways and likely cannot be used at high enough doses to warrant further development. Its remyelinating properties were discovered in a high throughput screen and licensed by Versant Ventures’ Inception 5 Inc. incubator company, now owned by Roche (see “High Throughput Remyelinaton”).

Remyelination screens have also pointed to kappa opioid agonists, which cause problematic psychotropic side effects, as well as other muscarinic receptor inhibitors, estrogen receptor agonists, EZH2 inhibitors, imidazole antifungals and additional compound classes (see “KOR-recting MS”).

In a Nature paper published on July 25, the Case Western Reserve University team argued that the diverse agents all induce remyelination via a common mechanism -- production of unsaturated sterols.

The researchers, led by Assistant Professor of Genetics and Gene Therapy Drew Adams, showed several remyelinating compounds target enzymes in the cholesterol synthesis pathway in addition to their canonical targets, leading to buildup of myelin-inducing sterols. They propose that two of those enzymes -- EBP and TM7SF2 -- could provide easier and safer paths to drug development than targeting other pathways.

“There’s a central pathway that all therapies from screens converge on -- and it’s a very druggable pathway.”

Derrick Rossi, Convelo Therapeutics

The team’s logic for this is that marketed drugs like statins, used broadly and safely for heart disease, block the pathway further upstream, where the chances of side effects are greater.

Convelo plans to develop small molecule inhibitors of EBP and TM7SF2, and has snagged serial entrepreneur Derrick Rossi as CEO. It has raised $7.8 million in angel funding. Rossi is an assistant professor of stem cell and regenerative biology at Harvard Medical School who previously cofounded Moderna Therapeutics Inc., Intellia Therapeutics Inc. and Magenta Therapeutics Inc. It will be his first time in an executive role.

“Everyone in the clinical community recognizes the next thing we need is remyelination and neural protection,” said Rossi. “The latest Nature work shows there’s a central pathway that all therapies from screens converge on -- and it’s a very druggable pathway.”

However, while at least two other experts in the field agree that the new mechanism holds promise, they aren’t convinced it explains all the previous screening hits so tidily.

They argue data from previous...

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