At the American Academy of Neurology Annual Meeting (AAN 2023), results from the VISIONARY-MS trial (NCT03536559) were presented. This trial investigated CNM-Au8, an agent that has demonstrated neuroprotective and remyelinating qualities in preclinical models . Remyelination is a topic that is gaining more attention in the field of multiple sclerosis (MS). Therefore, Medicom Medical Publishers spoke with Dr Bernard Zalc (Sorbonne University, Inserm, Paris, France) about his recently published new model of MS, and how his team could correlate demyelination with the decline of cognitive and motor abilities . This new tool, which allows in vivo monitoring, has the potential to advance our knowledge of the link between visual disorders—one of the most common symptoms of MS—and associated demyelination lesions.
Medicom: could you start off by explaining the demyelination process in MS?
“The demyelination process is still quite mysterious,” answered Dr Zalc. “There are two types of immune cells, the innate and adaptive immune cells. In MS, the adaptive immune cells enter the brain and start to destroy myelin. However, this does not really explain what is happening inside the brain. As a fact, the destruction of myelin in the brain is not a homogenous process, but a process that is characterised by the formation of plaques. It is currently unknown why lymphocytes destroy myelin in some areas of the brain but not in others.” Dr Zalc stressed that it is important to understand the function of myelin before the clinical consequences of demyelination can be interpreted correctly. “Myelin is a membrane, which, in the central nervous system (CNS), is produced by oligodendrocytes. In addition to increasing conduction speed and protection of axons, myelin also has a metabolic function. “It’s through myelin that axons receive the lactic that they need to survive,” mentioned Dr Zalc. “This important function has only been discovered about 10 years ago. Taking these functions of myelin into account it is understandable that, if myelin is destroyed, the speed of conduction will be slowed down or even blocked completely.”
Medicom: clinical approaches to treat MS have mainly focused on the inflammatory aspect of MS. Can you discuss what the current and perhaps near future remyelinating options are going to be?
“Since 1995 we have made tremendous progress with regard to therapeutic approaches in MS, but we still do not know how to cure MS,” continued Dr Zalc. “The progress that has been made is focused on dealing with immune defects. However, MS is a disease with three main aspects. The first is the inflammatory aspect, the second aspect is demyelination, and the final aspect is that demyelinated axons may be fragile and vulnerable to destruction. At this final degenerative stage there is no hope for recovery. But for the two previous stages, function may be restored with a swift intervention.” Dr Zalc said that the inflammatory aspect of the disease is quite well taken care of with the medicine that are available today. “This started, as I mentioned, in 1995 with the introduction of interferon beta-1a, followed by the development of effective immunomodulators and immunosuppressive agents. These agents have demonstrated to improve the quality of life of the patients and to reduce the number of relapses per year. The next step is to remyelinate the axons of patients with MS. In this way we can cure patients and avoid the degenerative stage of the disease, leaving patients with a permanent handicap. How can we remyelinate?”, asked Dr Zalc.
According to Dr Zalc, remyelination of axons in an MS brain was demonstrated for the first time in 1965. “In experimental models, mostly in rats and mice, we know that endogenous remyelination is possible,” said Dr Zalc. He added that this new myelin is thinner than the initial myelin. “Furthermore, there have been many attempts to remyelinate axons in deceased patients with MS and there are drugs that displayed remyelination in in vitro studies.” Hereafter, Dr Zalc outlined that the current clinical trials aiming to remyelinate axons in patients with MS have not been very successful so far. “There have been 4 large clinical trials assessing the remyelination of axons. One of these trials is still ongoing, but the other 3 have not shown very encouraging results. Does this mean that the whole idea of remyelination is wrong? I still think that it is a good idea to aim for remyelination of axons. However, I think that the trials failed to show remyelination of axons because they have not been using a functional test.” Dr Zalc explained that the research teams conducting these trials focused too much on the increase in oligodendrocytes, instead of on the myelinating cells in the CNS. “This approach is surpassing the fact that we have plenty of oligodendrocytes present in the brain,” he argued. “It has been shown in rat studies that between 5-8% of the total cells are oligodendrocyte precursor cells. These cells turn into oligodendrocytes if the right signal is being provided.” Translating this to humans, this means that about 8 billion cells with the potential to myelinate axons are waiting. Therefore, the idea’s not to increase the number of cells, but to stimulate the present cells to produce myelin.
“In our research, we have been trying to develop a functional test of assessing remyelination. We demyelinated the axons of clawed frogs and tried to remyelinate the axons by administering drugs. Our goal was to test whether the remyelination of axons leads to an improved functional status of the assessed animals,” clarified Dr Zalc. “In addition, the tadpoles are transparent, which means we can follow all the stages of remyelination and develop a functional test without killing the animal.” Dr Zalc explained that the vision was the target of the experiment. “If the animal is blind and you remyelinate its axons and it is no longer blind, then you know that you are remyelinating the optic nerve,” he added.
“Currently we have 2,000 clawed frog eggs per laying,” responded Dr Zalc. “This means that we can run tests on 30 to 60 animals for one molecule at one dosage and that we can thus run a dose curve for the molecule that we are testing. I will not say it’s a high throughput. The high throughput should be done in vitro because then you can have plenty of culture. This is a medium throughput, aiming to screen for molecules that could improve remyelination with a functional test. That’s our strategy,” decided Dr Zalc.
- Barnett M, et al. VISIONARY-MS Top-line Results: A Phase 2, Randomized, Double-Blind, Parallel Group, Placebo-controlled Study to Assess the Safety and Efficacy of CNM-Au8, a Catalytically Active Gold Nanocrystal Suspension in Relapsing Multiple Sclerosis. PL5.005, AAN 2023 Annual Meeting, Boston (MA, USA), 22-27 April.
- Henriet E, et al. Brain. 2023; awad051
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