• Gary Birnbaum, MD

Repairing an injured brain with gold

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis.

Robinson AP, Zhang JZ, Titus HE, et al.

Sci Rep. 2020;10:1936.

https://www.ncbi.nlm.nih.gov/pubmed/32041968

Nanocrystalline Gold to Treat Remyelination Failure in Chronic Optic Neuropathy In Multiple Sclerosis (VISIONARY-MS)

(https://www.clinicaltrials.gov/ct2/show/NCT03536559)

(https://static.coreapps.net/actrims2020/handouts/77a21b66e17bcde7e05ff25c092e4fb8c7421db5.pdf)



Bottom Line:

A major “hole” in current drug therapy of relapsing forms of multiple sclerosis is a lack of treatment for stimulating tissue repair. A recent paper and an ongoing clinical trial use a novel new approach to address this problem. Loss of myelin followed by loss of nerve cells and tissue scarring are the hallmark of relapsing forms of multiple sclerosis. Tissue repair in these areas is limited despite the presence of large numbers of potential myelin-producing cells (oligodendrocytes). One of many reasons for the lack of oligodendrocyte response is a lack of essential energy-providing nutrients. The two studies cited above describe the use of tiny particles of gold (“nanoparticles”), 6-8 thousand times smaller than the diameter of human hair, to stimulate oligodendrocyte-precursor cells to mature and produce myelin. The gold nanocrystals are given orally and act by inducing the expression of genes that provide essential nutrients to oligodendrocytes, allowing them to form new myelin. While the published paper describes work with animal models of myelin loss, preliminary results of the human trial are encouraging.

Key Points:

1. Patches of myelin loss (demyelination) are the hallmark of multiple, associated with loss of nerve cells (neurons) and the formation of dense scars (plaques).

2. Tissue repair in the form of remyelination does occur but only to a very limited extent. This is despite the presence of large numbers of potential myelin-producing cells (oligodendrocytes or OL) and immature oligodendrocytes called oligodendrocyte precursor cells (OPC).

3. While there are multiple reasons for the lack of OL or OPC responses, two major barriers are an impaired energy metabolism of OL and a lack of essential energy nutrients.

4. Researchers of the above-cited paper induced patches of demyelination in mice by administering two compounds, cuprizone and lysolecithin. These compounds cause a loss of myelin and mature oligodendrocytes but with no inflammation and with sparing of oligodendrocyte precursors or OPC.

5. The scientists then studied the effects of adding tiny crystals of pure gold (nanocrystals), 13 nanometers in size, to the drinking water of their mice. To put the size of the crystals in perspective, the width of a human hair is 80,000 to 100,000 nanometers. Gold nanocrystals have been used for years in commercial chemical reactions where the crystals enable or catalyze chemical reactions.

6. Once myelin loss was induced some animals were fed suspensions of the gold nanocrystals in water. Another group of mice was given plain water. Animals were then studied for evidence of myelin repair or remyelination.

7. Mice fed nanocrystals of gold had much greater remyelination than did untreated mice and did much better on multiple tests of strength and motor function, indicating that the restored tissues functioned well. No major toxicity from the gold nanocrystals was noted.

8. The researchers then asked, how did these gold nanocrystals effect OL and OPC? They showed that feeding gold nanocrystals did not stop cuprizone or lysolecithin from killing mature oligodendrocytes. Rather it stimulated immature OPC to become mature OL, to migrate to areas of myelin loss, and to start producing myelin.

9. OPC were then exposed to gold nanocrystals to tissue cultures. Multiple effects were noted. Most prominently, OPC were induced to become mature OL with the activation of genes necessary for the production of myelin. At the same time the activity of genes that blocked the generation of important metabolites was reduced.

10. Most interestingly, there was upregulation of genes involved in stimulating a pathway for coordinating not only energy metabolism, but also myelination and cellular responses to stress. As a result, there were increased amounts of the essential energy-providing compounds, in particular NADH and NAD+. These metabolites are vital for driving reactions in living cells and are essential for energy generation.

11. Of additional potential importance is that levels of NAD+ are reduced in the blood of persons with MS. Indeed, the severity of the reduction of this essential compound correlates with the severity of that person’s MS. Some researchers have even suggested that, administration of NAD+ be considered as a treatment for MS.

12. Based upon these exciting results, a Phase II clinical trial is now in progress, looking to see if there are beneficial effects to drinking gold nanocrystals in persons with stable MS who have chronic changes to their optic nerves. The study, called “Nanocrystalline Gold to Treat Remyelination Failure in Chronic Optic Neuropathy In Multiple Sclerosis (VISIONARY-MS)” is still in progress, but preliminary findings related to improved vision, memory and motor function are encouraging.

13. The above observations, describing an entirely new approach to treatment portend an exciting new era of potential therapy for persons with MS.

Discussion: As noted above, none of the current disease-modifying therapies for relapsing forms of multiple sclerosis and for the inflammatory phase of secondary progressive MS specifically address the issue of tissue repair. True, by reducing central nervous system inflammation the current disease-modifying therapies may facilitate tissue repair, but only indirectly. Several therapies have been tested for their potential to repair areas of demyelination. These include the anti-seizure drug phenytoin, and a monoclonal antibody, opicinumab, that is meant to block LINGO-1, a protein that prevents remyelination. While results in animal studies were encouraging, human trials to date have not shown substantive benefit though some trials are still on-going.

The two references noted at the top of this posting introduce an entirely new approach to the issue of remyelination. The first describes a study in mice where researchers a induced loss of myelin using one of two compounds, cuprizone and lysolethicin. The myelin loss occurs because oligodendrocytes are destroyed. There is no inflammation and no immune response to the tissue loss. Thus, these models are very different from what occurs in relapsing forms of multiple sclerosis. Nevertheless, the data are quite persuasive. Gold nanocrystals, 6-8 thousand times smaller than the width of a human hair, were fed to mice in drinking water. The particles were able to enter the brain and induced oligodendrocyte-precursor cells (OPC) to mature into oligodendrocytes. They also activated genes that were needed for the production of myelin as well as genes that produced nutrients, such as NADH, essential for oligodendrocytes to synthesize myelin. As a result there was substantive myelin repair in the central nervous systems of the mice and this correlated with improved motor activity, indicating that the new myelin allowed neurons to recover function.

On the basis of the results of the above study a Phase II clinical trial is now in progress assessing the benefits of gold nanocrystals in persons with MS that have long-standing (chronic) optic nerve injury due to loss of myelin. The main endpoints are improved vision, but participants are also tested for walking, memory function and upper extremity coordination. The trial is ongoing but preliminary data was presented and results were encouraging.

The ease of administration of gold nanocrystals, their safety, and their potential for major therapeutic benefit, introduces a whole new approach to the goal of inducing myelin repair. If preliminary results are validated in a randomized, placebo-controlled Phase III clinical trial, the use of such agents, in combination with current immune modulating therapy, could significantly alter the course of MS, not only in persons with relapsing forms of multiple sclerosis, but potentially also those individuals with the progressive forms of MS.

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