Flavonoids are chemicals in fruits and vegetables that have been used in some consumer health products such as nutritional supplements and cosmetics. Scientists at the Oregon Health & Science University (OSHU) have modified a flavonoid to create a drug they say might treat multiple sclerosis (MS) by regrowing the protective sheath around neurons called myelin.
The drug, called S3, reverses a mechanism that blocks the growth of myelin-producing glial cells called oligodendrocytes. That helped create new myelin sheaths in mice, the team reported in the journal Glia.
Back in 2005, Larry Sherman, Ph.D., and scientists at his lab found that the accumulation of a molecule called hyaluronic acid (HA) in the brain inhibits oligodendrocyte progenitors from maturing into myelin-forming cells. The phenomenon can be seen in myelin lesions from individuals with MS and in mice with a similar condition.
A family of enzymes called hyaluronidases can degrade HA. The scientists later found that the HA fragments are responsible for instructing immature oligodendrocytes’ myelin genes to stay inactive. They hypothesized that blocking hyaluronidase could promote remyelination.
Guided by that clue, researchers led by OHSU selected the modified flavonoid S3. In mice studies, the drug helped lift HA’s restrictive influence and triggered precursor cells to form functional myelin sheaths.
“It’s not only showing that the myelin is coming back, but it’s causing the axons to fire at a much higher speed,” Sherman said in a statement. “That’s exactly what you want functionally.”
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Damage to myelin is a hallmark of MS, so healing it has become a popular strategy among scientists trying to treat the neurodegenerative condition. A research team led by the University of Maryland School of Medicine recently found that stem cells in hair follicles with the CD34 surface protein could repair myelin in mice. Scientists at the University of Chicago showed that a derivative of the hypertension drug Wytensin (guanabenz) might be repurposed to protect oligodendrocytes from inflammatory damage and prevent myelin loss.
On the industry side, Convelo Therapeutics recently partnered with Roche’s Genentech to discover novel remyelinating therapies against neurological disorders such as MS. The startup’s target circles around inhibiting CYP51, TM7SF2 and EBP, which are enzymes in the brain that help produce cholesterol. Blocking these enzymes has been shown to drive oligodendrocyte formation and remyelination.
Sherman and colleagues at OHSU have now started to use S3 on macaque monkeys who have a naturally occurring MS-like disease called Japanese macaque encephalomyelitis.
"I think we'll know in about a year if this is the exact right drug to try in human clinical trials," Sherman said. “If it's not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains?”