Experimental MS therapy safely repairs myelin sheath in animals
Motor function improved in mice, marmosets
An experimental medicine, 2-D08, boosts motor function in mice and primate models of multiple sclerosis (MS) by repairing the myelin sheath, the protective coating on nerve fibers that’s damaged in people with the neurodegenerative condition, a study showed.
2-D08 also outperformed the approved therapy dalfampridine, sold as Ampyra in the U.S., in its ability to repair myelin without inducing seizures, a known fampridine side effect.
“These results indicate significant potential for future clinical application of 2-D08 in MS treatment,” the researchers wrote.
The study, “Activation of Kir4.1 Channels by 2-D08 Promotes Myelin Repair in Multiple Sclerosis,” was published in Advanced Science.
MS is an autoimmune disease marked by progressive damage and loss of the myelin sheath, a fatty coating that surrounds and protects nerve fibers. This is associated with inflammatory attacks that damage myelin, nerve cells, and the cells that produce myelin, called oligodendrocytes, giving rise to neurological symptoms.
Myelin sheath repair in mice
Elevated levels of self-reactive antibodies against the Kir4.1 channel, a protein that controls the flow of potassium ions into cells, have been found in the bloodstreams of MS patients. Kir4.1 channels are widely produced in certain cells that support nerve cells, including astrocytes and oligodendrocytes.
However, it remains unclear whether the self-reactive antibodies against Kir4.1 are a byproduct of the neurodegenerative process in MS or a contributing factor.
“Investigating and clarifying the [disease-associated] role of Kir4.1 is imperative to explore new therapeutic approaches that can benefit a larger proportion of MS patients,” the researchers wrote.
The team of researchers in China started their exploration by investigating Kir4.1 in a mouse model of induced MS.
Blood tests revealed significantly higher levels of self-reactive antibodies against Kir4.1 in MS mice relative to healthy mice. In line with this finding and previous reports, those antibodies were also significantly higher in the blood of MS patients than in healthy individuals.
When researchers examined mouse tissues, they found that Kir4.1 production was substantially reduced in the spinal cords of animals with MS-like disease than in healthy mice.
Moreover, Kir4.1 channel deficits were initially detected in oligodendrocyte precursor cells (OPCs) rather than astrocytes in the spinal cord, and MS mice genetically engineered to have lower levels of Kir4.1 channels in OPCs had more severe symptoms.
Building on these findings, the team searched for small molecules that could activate Kir4.1 and promote myelin repair. One molecule, called 2-D08, strongly bound to and activated Kir4.1 in OPCs but not in astrocytes.
MS mice treated with 2-D08 showed stronger myelin repair compared with untreated animals, as indicated by increases in myelin-related biomarkers. Treated mice also had more myelinated nerve fibers, thicker myelin sheaths, and more motor neurons, the nerve cells responsible for controlling movement.
Treatment was also found to accelerate the maturation of OPCs into mature oligodendrocytes.
When MS mice were placed on an inclined plane with increasing angles, those treated with 2-D08 showed improved motor abilities over untreated mice. In addition, hind limb placement while walking on a grid led to significantly fewer paw slips in treated versus untreated mice.
Comparing efficacy
To investigate 2-D08’s potential as a therapy for MS, the team compared its efficacy to dalfampridine, which is used to improve walking skills in people with MS and is known to block the activity of potassium channels. It’s sold as Ampyra in the U.S. and Fampyra in other countries, with generic versions available.
At the onset of MS symptoms, MS mice received either dalfampridine or 2-D08 for 11 days. While both treatments had similar effects in easing disease severity and improving walking ability, 2-D08 showed a greater effect on myelin repair, as indicated by larger myelin sheath thickness than with fampridine.
While dalfampridine is known to increase the risk of recurrent seizures, 2-D08, was found to promote brain functional recovery on electroencephalogram (EEG) recordings without inducing seizure-like activity.
The researchers also evaluated the efficacy of 2-D08, administered daily starting at symptom onset, in marmosets with induced MS, a valid primate model of the disease.
One month of 2-D08 treatment significantly repaired myelin in the spinal cords of marmosets alongside an increase in the number of mature oligodendrocytes. 2-D08-treated marmosets showed motor coordination recovery, as indicated by an increase in total jumps in the feeding cage. In comparison, untreated animals developed progressively worse disease, with their hind legs becoming almost paralyzed.
“Our findings highlight the potential of targeting the Kir4.1 ion channel in OPCs as an approach for protecting neurons from demyelinating [myelin loss] injuries,” the researchers wrote. “It suggests that 2-D08 treatment holds promise as a therapeutic strategy for demyelinating diseases, including MS.”
About the Author
