Two compounds with potential for myelin repair in MS identified
Study: Experimental medications showed promise in animal, cell models
Researchers have identified two experimental medications that may promote myelin repair in people with multiple sclerosis (MS).
The two compounds have shown promise in cell and animal models, and preclinical work is ongoing to bring them into clinical testing. The compounds were identified by academic researchers, but the program has now been picked up by Cadenza Bio, which will lead further development.
“We are committed to rapidly advancing these drug candidates, with the goal of halting progression, promoting repair, and ultimately improving quality of life for patients with MS,” Carol Curtis, PhD, co-founder and CEO of Cadenza, said in a company press release.
The two new compounds were described in the study, “Chloroindazole based estrogen receptor β ligands with favorable pharmacokinetics promote functional remyelination and visual recovery,” which was published in Scientific Reports.
Available MS therapies have limited effects on myelin repair
MS is a chronic disorder caused by inflammation in the brain and spinal cord that damages the myelin sheath, a fatty coating that helps nerves send electrical signals. Myelin damage disrupts nerve communication and causes nerve cell death, ultimately leading to MS symptoms.
Although there are treatments that can tamp down inflammation and slow MS progression, available therapies have limited effects on myelin repair, known as remyelination.
One protein that has been identified as a potential target for promoting myelin repair in MS is the estrogen receptor beta (ER-beta), which is produced throughout the body, enabling cells to respond to certain hormones. Data suggest that activating ER-beta in the brain can promote the production of new myelin.
With that in mind, the researchers developed and tested a number of compounds that could activate ER-beta. They ultimately identified two promising candidates called K102 and K110. A battery of tests in preclinical lab models showed that both compounds have pharmacological properties that make them well-suited for use as medications.
Compounds promote myelin repair in pair of mouse models
In experiments done using cell models, K102 and K110 were shown to promote the growth and maturation of oligodendrocytes, the cells chiefly responsible for making and repairing myelin in the brain and spinal cord.
The researchers then tested the two compounds in two mouse models of MS, one where the mice are engineered to have a myelin-targeting immune attack, and one where the mice are fed a toxin that causes myelin damage. Data from both models indicated that K102 and K110 promoted myelin repair, while also modulating immune responses.
Our work represents more than a decade of collaboration, with the last four years focused on identifying and optimizing new drug candidates that show strong potential to treat MS and possibly other neurological diseases involving demyelination.
The treatments led to improvements in the health of nerve cells in the eyes, which are often damaged in MS. This is especially important because noninvasive measures of optic nerve health can be used as a proxy of myelin repair in MS patients participating in clinical trials, said Seema Tiwari-Woodruff, PhD, co-author of the study, scientific founder of Cadenza, and a professor at the University of California, Riverside,.
“Our findings demonstrate that [ER-beta] ligand treatment promotes neuroprotection and enhances visual pathway function,” as assessed by measures that “are particularly valuable because they can also be applied noninvasively in patients, allowing direct translation into clinical trials,” Tiwari-Woodruff said.
Although both compounds showed promise, the researchers have identified K102 as the most promising for MS specifically.
“K110 is also a strong candidate,” Tiwari-Woodruff said in a university news story. “It has slightly different central nervous system effects and may be better suited for other conditions like spinal cord injury or traumatic brain injury, so we’re keeping it in the pipeline.”
This study was funded in large part by the National Multiple Sclerosis Society. The National Institutes of Health and Cadenza also contributed funding for the work.
“Our work represents more than a decade of collaboration, with the last four years focused on identifying and optimizing new drug candidates that show strong potential to treat MS and possibly other neurological diseases involving demyelination,” Tiwari-Woodruff said.
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