Despite being one of the most common and well-known neurodegenerative diseases, multiple sclerosis (MS) remains difficult to treat. However, new research from scientists at Cincinnati Children’s Hospital Medical Center and elsewhere points to a potential therapeutic approach that appears to overcome difficulties faced by other attempts. Their work is described in a new Cell paper titled, “Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.”

According to the paper, the researchers treated mouse models of multiple sclerosis and myelin organoids with an inhibitor molecule called epigenetic-silencing-inhibitor-1 (ESI1) that appears to improve both myelin production and poor cognitive function associated with MS and similar demyelinating diseases. It works at the epigenetic level to essentially restart myelin production by oligodendrocytes present in the MS lesions.

“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,” said Qing Richard Lu, PhD, scientific director of the Brain Tumor Center at Cincinnati Children’s and the study’s corresponding author. “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 [oligodendrocytes] present in the damaged brain can enable myelin regeneration.” 

At the core of the findings is the observation that MS works by activating various cell types and signaling pathways that work together to silence the myelin repair process and prevent oligodendrocytes from doing their job. Analysis of stored autopsy tissues revealed that oligodendrocytes 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.

Armed with this information, the researchers searched small molecule libraries for compounds that could target enzymes responsible for modifying gene expression and influencing silenced oligodendrocytes. Of all the compounds considered, ESI1 proved nearly five times more powerful. In tests, it tripled the levels of the desired H3K27ac histone mark while sharply reducing levels of the two repressive histone marks. The compound also promotes the formation of biomolecular condensates in the nucleus that serve as regulatory hubs for controlling the essential fats and cholesterol needed to make myelin. 

When tested in both aging mice and mouse models of MS, treatment with ESI1 prompted myelin sheath production and improved lost neurological function. These results were based on tests tracking gene activation, measuring microscopic sheaths surrounding axons, and observing the behavior of treated mice. Similarly, when the organoid cultures were exposed to ESI1, the treatment extended the myelin sheath of myelinating cells. 

Myelin regeneration treatment could be a boon for people living with MS as well as people recovering from brain and spinal cord injuries. But the most far-reaching implication of the study is the possibility of using ESI1, or similar compounds, to help slow or even reverse cognitive losses that often occur during aging. 

However, more research is needed to determine whether human clinical trials can be launched to evaluate ESI1 as a potential treatment. For example, the effects of ESI1 may need to be modulated by adjusting the dose, treatment duration, or using “pulsed therapy” during specific time windows. More research is also needed to determine the feasibility of designing compounds even more effective than ESI1 from scratch. 

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