When treated with a novel protein function inhibitor called ESI1, mice that mimic the symptoms of multiple sclerosis (MS) and lab-prepared human brain cells both demonstrated the ability to regenerate vital myelin coatings that protect healthy axon function.
This breakthrough, published , in Cell, appears to overcome difficulties that have long frustrated previous attempts to reverse a form of nerve damage that robs people with MS of motor control and gradually blunts cognitive functions for many people as they age.
Analysis of stored autopsy tissues revealed that OLs within MS lesions lacked an activating histone mark called H3K27ac while expressing high levels of two other repressive histone marks H3K27me3 and H3K9me3 associated with silencing gene activity.
The research team scoured a library of hundreds of small molecules known to target enzymes that could modify gene expression and influence the silenced OLs. The team determined that the compound ESI1 (epigenetic-silencing-inhibitor-1) was nearly five times more powerful than any other compounds they considered.
Then, the team tested the treatment on lab-grown human brain cells. The team used a type of brain organoid, myelin organoids, that is far more simplified than a full brain but still produces complex myelinating cells. When the organoids were exposed to ESI1, the treatment extended the myelin sheath of myelinating cells, the study reports.
“This study is a beginning,” Lu says. “Prior to finding ESI1, most scientists believed that remyelination failure in MS was due to the stalled development of precursors. Now we show a proof of concept that reversing the silencing activity in OLs present in the damaged brain can enable myelin regeneration.”
Views: 105