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