Tadpole model could be launchpad to test therapies for remyelination

A newly developed laboratory model using tadpoles can help determine the remyelinating potential of new multiple sclerosis (MS) therapies via specific changes in behavior and vision tests, a new study suggests.

The model may help accelerate the discovery of potential MS remyelinating therapies, and reduce the use of resources on compounds that fail to show an effect.

“This model is … ideal for testing the remyelination potential of new drugs before launching long and costly clinical trials,” Bernard Zalc, MD, of the Paris Brain Institute at Sorbonne Université in France, said in a press release.

The new model was described in the study, “Monitoring recovery after CNS demyelination, a novel tool to de-risk pro-remyelinating strategies,” published in Brain.

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MS is caused by inflammation in the brain and spinal cord, collectively called the central nervous system or CNS. This inflammation causes damage to the fatty covering around axons (nerve fibers) known as the myelin sheath.

“Myelin protects nerve fibers, guarantees the good conduction of nerve impulses, and provides nutrients to the axons,” Zalc said. “This protective sheath envelops nerve fibers and is essential for their proper functioning. Its disappearance, called demyelination, causes sensory and motor symptoms: weakness of the lower or upper limbs, loss of balance, sensitivity, and vision disorders.”

While many treatments for MS have been approved, all of the available therapies work by reducing inflammation. To date, no approved therapy has been proven to promote myelin repair (remyelination), and only a few experimental treatments have shown promising remyelinating effects in clinical tests.

Other experimental therapies have shown promise in early laboratory work, but testing these therapies in clinical trials of people with MS has had disappointing results.

According to Zalc, one potential explanation is that in laboratory models  compounds are generally assessed on their ability to promote the growth and activity of oligodendrocytes, which are the cells chiefly responsible for making and repairing myelin in the CNS. However, laboratory models generally haven’t investigated whether changes in oligodendrocyte activity are accompanied by objective evidence of better nerve function.

“Why do candidate molecules systematically disappoint us when tested in humans? One possible explanation: at the preclinical stage, they are evaluated on their ability to generate new myelin-producing cells. This criterion, based on tissue observation, is not sufficient,” Zalc said. “For the drug to be effective, it must also improve the symptoms of the disease or even completely restore sensory and motor capacities.”

African clawed frog tadpoles

Here, Zalc and colleagues developed a new model to study remyelination using Xenopus laevis, the African clawed frog. When these frogs are born as tadpoles, their bodies are transparent, so researchers are able to view the CNS and other internal structures without hurting the animal.

The scientists particularly focused their studies around the optic nerve — the main nerve that connects the eyes to the brain — as this part of the CNS is easily viewed in the tadpoles.

For this model, the tadpoles were engineered so that their oligodendrocytes would express two new proteins: one, a fluorescent marker to allow easier visualization of these myelin-making cells, and two, a bacterial enzyme called nitroreductase. The researchers then treated the tadpoles with the chemical metronidazole.

This chemical is harmless on its own, but the nitroreductase enzyme converts metronidazole into a cellular toxin. As such, in this model, the researchers could give metronidazole to induce oligodendrocyte damage and, consequently, myelin loss. They then could stop giving the chemical to allow oligodendrocytes to recover and remyelination to take place.

The researchers showed that metronidazole-induced myelin damage led to a significant reduction in swimming speed and distance travelled, and poorer performance on a test of visual avoidance (the tadpoles’ tendency to avoid an image that looks like an obstacle in the water, a measure of sight in these animals).

When the drug was withdrawn and remyelination occurred, swimming speed and visual avoidance abilities increased again to normal levels.

“Our results show that variation in motor and sensory performance is perfectly correlated with the level of demyelination and tissue remyelination,” Zalc noted.

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Testing the effects of two molecules, siponimod and clemastine

The team then used this animal model to test the effects of two molecules that have previously shown the ability to promote remyelination in laboratory models: siponimod, the active agent in the approved MS therapy Mayzent; or clemastine, an antihistamine that’s currently being tested in MS clinical trials.

Results showed these compounds led to an increase in oligodendrocyte levels, but only clemastine treatment was accompanied by better performance on swimming speed, distance travelled, and visual avoidance tests. Two other compounds known to have no impact on remyelination also did not significantly affect performance on the functional behavior tests.

“Altogether these data confirm the usefulness of our conditional demyelination model to screen drugs for their potency to promote functional remyelination,” the scientists concluded.

“This new tool … has the potential to advance our knowledge of the link between visual disorders – one of the most common symptoms of multiple sclerosis – and associated demyelination lesions,” Zalc said. “This is a real launchpad for future therapeutic success.”