The VISIONARY-MS trial showed that CNM-Au8, an oral liquid suspension of gold nanoparticles, significantly improved low-contrast letter acuity over placebo.

At the American Academy of Neurology Annual Meeting, results from the VISIONARY-MS trial were presented. The trial investigated CNM-Au8, an oral liquid suspension of gold nanoparticles that has demonstrated neuroprotective and remyelinating qualities in preclinical models. The trial enrolled people with relapsing-remitting MS (RRMS) with chronic optic neuropathy who had stable disease, or no relapse for at least 6 months, before being randomized to receive one of two doses of CNM-Au8—15 mg or 30 mg daily—or placebo daily for 48 weeks. Top-line results from the trial showed CNM-Au8 led to significant improvements in low-contrast letter acuity over placebo.

Remyelination is a topic that is increasingly gaining attention in the field; however, being able to model remyelination has hindered progress. To gain additional insight into remyelination with regard to the optic nerve, Physician’s Weekly spoke with Bernard Zalc, MD, about his recently published new model of MS and how his team could correlate demyelination with evolution of visual, 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.

Physician’s Weekly: Can you explain the demyelination process in MS?

Dr. Zalc: The demyelination process is still quite mysterious. 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 characterized by the formation of plaques. It is currently unknown why lymphocytes destroy myelin in some areas of the brain but not in others.

Myelin is a membrane that, in the CNS, is produced by oligodendrocytes. There are three recognized functions of myelin sheath. The first function is protecting the axons from the environment. The second function is to increase the speed of conduction. Myelination increased the speed of conduction by a factor of 50 to 100. The third function of myelin is a metabolic function; it’s through myelin that axons receive the lactic that they need to survive. This important function was only 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.

Physician’s Weekly: Clinical approaches to MS have mainly focused on the inflammatory aspect. Can you discuss remyelinating approaches?

Dr. Zalc: Since 1995, we have made tremendous progress to therapeutic approaches in MS, but we still do not know how to cure MS. The progress that has been made is focused on dealing with immune defects. However, MS is a disease with three main aspects. First, there is the inflammatory aspect, with lymphocytes entering the brain and forming plaques. The second aspect is demyelination, which entails the destruction of myelin. 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. In the two previous stages, however, function may be restored with a swift intervention.

The introduction of interferon beta-1a was followed by the development of effective immunomodulators and immunosuppressive agents. These agents have improved QOL for patients and reduced 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, which leaves patients with a permanent handicap. How can we remyelinate? There are two strategies: an exogenous one and an endogenous one. The exogenous strategy means that you add cells to the brain. The endogenous method means that you try to favor the endogenous process of remyelination. I don’t believe the exogenous strategy has any future.

Remyelination of axons in a brain with MS was demonstrated for the first time in 1965. From experimental models, we know that endogenous remyelination is possible, though 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. The current clinical trials aiming to remyelinate axons in patients with MS have not been very successful so far.

There have been four large clinical trials assessing the remyelination of axons. One of these trials is still ongoing, but the other three 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. The research teams conducting these trials focused too much on the increase in oligodendrocytes, the myelinating cells in the CNS. This approach ignores the fact that we have plenty of oligodendrocytes present in the brain.

It has been shown in rat studies that between 5% and 8% of the total cells are oligodendrocyte precursor cells.  These cells turn into oligodendrocytes if the right signal is provided. Translating this to humans, this means that about 8 billion cells with the potential to myelinate axons are waiting. Therefore, the idea is 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 for assessing remyelination. We demyelinated the axons of Xenopus embryos and tried to remyelinate the axons by administering drugs. Our goal is to observe whether there is a functional response. In other words, we tested whether the remyelination of axons leads to an improved functional status of the assessed animals. 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. 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. The functional testing of the animals is being performed in the morning. In the afternoon, we follow the number of oligodendrocytes in the optic nerve using photo microscopy.

Physician’s Weekly: Do you expect that this research will be applicable to clinical situations? 

Dr. Zalc: Currently we have 2,000 Xenopus eggs per laying. This means that we can run tests on 30-60 animals for one molecule at one dosage and, therefore, run a dose curve for the molecule that we are testing. I will not say it’s a high throughput. High throughput should be performed 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 on vision. That’s our strategy.