A new study has found a potential treatment that may be able to reverse nerve damage in individuals with MS, improving motor control and cognitive functions. The treatment, called ESI1, showed promising results in mice with MS symptoms and human brain cells in the lab, allowing for the regeneration of important myelin coatings that protect healthy axon function.
The findings of this breakthrough study were published on May 2, 2024, in Cell. This research offers hope for addressing the challenges associated with MS and nerve damage.
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.
“Currently, there are no effective therapies to reverse myelin damage in devastating demyelinating diseases such as MS,” says corresponding author Q. Richard Lu, PhD, a top brain research expert at Cincinnati Children’s. “These findings are significant as they offer new pathways for treatment that potentially shift the therapeutic focus from just managing symptoms to actively promoting repair and regeneration of myelin.”
PA crucial discovery behind the new research was the recognition that brain regions affected by MS still contained a certain type of cell necessary for repairing myelin damage. However, the disease triggers other cell types and signals to work together, ultimately suppressing the repair function. These cells, known as oligodendrocytes, play a key role in producing myelin sheaths that surround nerve cell axons. Think of it like the plastic insulation around a wire. When this protective myelin becomes damaged, whether due to disease or aging, nerve signaling is disrupted.The research team has discovered a method to activate the stalled repair process by freeing the oligodendrocytes (OLs) to perform their functions. Identifying the genetic modifications and signals responsible for the silencing of repair and locating a compound that can reverse this process was a challenging task. The project took over five years to complete and involved four co-first authors and 29 contributing co-authors from Cincinnati Children’s and the University of Cincinnati. Damaged nerves can disrupt various bodily functions such as movement, vision, and cognitive abilities, depending on where the damage occurs.ati, and 14 other institutions including universities in Australia, China, Germany, India, Singapore, and the United Kingdom.
Among the team’s main discoveries:
Understanding why myelin production is hindered in MS
Examination of stored autopsy tissues revealed that OLs within MS lesions lacked a activating histone mark called H3K27ac, while expressing high levels of two other repressive histone marks H3K27me3 and H3K9me3 associated with silencing gene activity.
Discovering a compound that can reverse the silencing
The research team searched through a library of hundreds of small molecules.lesser-known compounds have been found to target enzymes that can alter gene expression and affect the silenced OLs. The researchers discovered that a compound called ESI1 (epigenetic-silencing-inhibitor-1) was almost five times more potent than other compounds they looked at.
ESI1 tripled the levels of the desired H3K27ac histone mark in OLs while significantly reducing levels of the two repressive histone marks. Furthermore, the study uncovers a new mechanism through which ESI1 promotes the formation of specialized membrane-less regulatory hubs, known as ”biomolecular condensates,” within the cell nucleus that regulate fat and cholesterol levels.Levels. These centralized points help increase the production of necessary fats and cholesterol that are important for creating myelin, which is a crucial part of nerve fibers.
Showing benefits in mice and human tissue grown in a lab
When tested on aging mice and mice with MS-like symptoms, the ESI1 treatment stimulated the production of myelin sheaths and improved lost neurological function. The testing involved monitoring gene activation, measuring the microscopic new myelin sheaths around axons, and observing that treated mice were faster at navigating a water maze.
The treatment was then tested on lab-grown human brain cells. The team utilized
a type of brain organoid, known as myelin organoids, has been discovered to be simpler than a full brain, yet is still able to generate complex myelinating cells. According to the study, when these organoids were treated with ESI1, the myelin sheath of myelinating cells was extended.
Implications and next steps
MS is the most prevalent and well-recognized of several major neurodegenerative diseases. As a result of the new findings, there may be a new method for halting the degenerative effects of these conditions, as stated by Lu.
Treatment for myelin regeneration may also be beneficial for individuals recovering from brain and spinal cord injuries.
However, the most significant implication is The study suggests that ESI1, or similar compounds, could potentially slow down or reverse cognitive declines that occur with aging. Research has indicated that myelin loss is involved in age-related cognitive decline, according to Lu.
However, further research is necessary to determine if human clinical trials can be conducted to assess ESI1 as a potential treatment. This may involve adjusting the dosage, duration of treatment, or using “pulsed therapy” during specific time periods. Additional research is also needed to explore whether there are even more effective compounds available.ESI1 can be built from scratch.
“This research is just the beginning,” Lu explains. “Before the discovery of ESI1, most scientists believed that the failure of remyelination in MS was caused by the halted development of precursors. Now we have demonstrated the concept that reversing the silencing activity in OLs found in the damaged brain can promote myelin regeneration.”
