Paper #1: Promoting remyelination in multiple sclerosis
Nick Cunniffe and Alasdair Coles
Journal of Neurology (2021) 268:30–44
Paper #2: Identification of novel myelin repair drugs by modulation of
oligodendroglial differentiation competence
Anastasia Manousia, Peter GÖttlea, Laura Reichea et al
EBioMedicine 65 (2021) 103276
Bottom Line:
In the past several decades there has been great success in discovering drugs that decrease central nervous system inflammation in persons with MS. Why hasn’t there been success in finding drugs that promote lesion healing and restore lost myelin (remyelination)? The reasons are multiple, but the bottom line is that remyelination is a complex process, involving not only the cells that make myelin (oligodendrocytes) but many other brain and blood cells. In addition, there are strong genetic factors as well as environmental factors and the effects of associated illnesses that persons with MS may have.
Paper #1 provides an excellent overview of the complex issues involved in central nervous system remyelination and summarizes past and current clinical trials of potential remyelinating agents.
Paper #2 describes an exciting and novel new technique for rapidly identifying drugs with potential to induce remyelination. The authors propose that this new method will greatly accelerate the search for remyelinating agents. Two drugs in particular are discussed based on their ability to induce new myelin both in tissue cultures of human cerebellum and in an experimental animal model of myelin loss (demyelination).
Several conclusions can be drawn from the above papers. It is unlikely that any single agent will be sufficient to restore lost myelin. Most likely persons with MS will require cocktails of drugs, given concurrently with anti-inflammatory agents to minimize tissue destruction. Given the diversity of disease processes in MS “cocktails” will need to be personalized and administered early in the disease before irreversible damage has occurred. Despite multiple frustrating failures to date, research into finding remyelinating agents and techniques is accelerating, offering hope for a breakthrough in the not-too-distant future.
Key Questions:
1. Myelin in the central nervous system is produced by cells called oligodendrocytes. Mature oligodendrocytes can repair myelin. Most new myelin is made by immature oligodendrocytes that must first mature to acquire the ability to form new myelin.
2. Immature oligodendrocytes are called oligodendrocyte progenitor or precursor cells (OPCs). They must undergo a complex series of changes to move to sites of tissue damage and produce new myelin. Disruption of any stage in this pathway, either from lack of cells or the presence of inhibitors of OPC maturation results in loss of ability to remyelinate.
3. Surprisingly, adequate numbers of OPCs are present at sites of chronic myelin loss but are prevented from maturing. To further complicate the issue, there are activated populations of brain cells called astrocytes in areas of tissue damage that release substances toxic to OPCs, resulting in their death. Most importantly, OPCs in persons with MS may have genes that are different than genes in OPCs from persons without MS, potentially reducing their ability to make new proteins. This issue was discussed in a previous blog (“Is there brain susceptibility to MS”; June 4, 2020).
4. Persons with MS vary greatly in their ability to form new myelin. About 20% of persons with MS have an excellent ability to restore damaged myelin. As a result, these individuals also have less disability. Unfortunately, most persons with MS don’t have this ability. Reasons for these differences are not known but a genetic basis is most likely.
5. An additional variable is that different parts of the central nervous system have different abilities to remyelinate. Lesions next to the ventricles are least likely to remyelinate while lesions next to the cortex tend to remyelinate more. These observations suggest that the local tissue environment of OPCs is critical for their ability to restore myelin.
6. Age and disease duration affect the ability to remyelinate. The ability to remyelinate decreases with increasing age and with disease duration. with OPCs from older individuals have less ability to differentiate to mature cells. New data suggests such changes may be reversible, at least in rats, after treatment with the diabetes drug metformin. This is being studied in humans.
7. Another critical factor in remyelination is the immune system, especially the more “basic” innate immune system. The presence of myelin debris in areas of inflammation and tissue loss impairs OPC maturation. Cells of the innate immune system, in particular microglia and macrophages, are needed to remove myelin debris, allowing OPC maturation. In addition, microglia and macrophages release nutrient substances that nurture OPCs, fostering their maturation.
8. The myelin formed around nerve fibers (axons) serves multiple purposes. It is needed for axon nutrition as well as to permit rapid electrical conduction. Unfortunately, axons are destroyed early during MS inflammation with limited ability to regenerate. Thus, any treatments meant to induce remyelination must be administered early in the course of the illness, most probably in conjunction with drugs that suppress central nervous system inflammation. Given the different pathways required for remyelination, it is most likely that multiple drugs will be needed to have an effect.
9. How can one tell if a treatment results in meaningful remyelination? Clinical outcomes are the most important but may take months to years to show benefits. More immediate means of detecting new myelin involve advanced central nervous system MRI techniques, using radioactive markers of myelin, and measures of brain function such as the speed of nerve conduction in the optic nerves and brain.
10. While several drugs were found to induce remyelination in animal models of demyelination translating these benefits to humans has not been successful. One such drug was clemastine, an antihistamine used to treat nasal allergies. The drug was studied in persons with optic nerve inflammation (optic neuritis) and significantly improved the ability of the injured nerve to conduct impulses. However, there was no effect on other MS findings, such as central nervous system MRIs, walking, or the neurologic exam. Studies with clemastine are ongoing.
11. Studies also were done with an antibody that blocked a protein, lingo-1, that prevents OPCs from maturing. This antibody, called opicinumab, was given to persons with optic nerve inflammation who may or may not have had MS. Initial trials were negative. Subsequent trials involving persons with MS also were negative, though some effects were seen in selected individuals and studies are ongoing.
12. Paper #2 describes a novel, new method to quickly identify agents that have the potential to induce remyelination. The researchers studied a protein called “p57kip2.” When p57kip2 is in the nucleus of an OPC it prevents that cell from maturing. When p57kip2 moves out of the nucleus into the cytoplasm it activates a series of genes that enhances OPC maturation.
13. The researchers screened more than 1200 compounds for their ability to move p57kikp2 out of the nuclei of rat oligodendrocytes. They chose compounds already approved for human use that also had the ability to pass through the blood-brain barrier and enter the brain.
14. When compounds were found that resulted in p57kip2 leaving rat OPC nuclei they measured the effects of these agents on their ability to induce rat, mouse and human. OPC’s to mature.
15. Twenty-one promising agents were found. Further screening, based on the compounds ability to induce myelin in tissue cultures of rat OPCs and human cerebellum narrowed the number of promising compounds to four.
16. Three of the four compounds that resulted in OPCs maturing to myelin producing cells were drugs used to treat parasitic infections, bacterial and viral infections, and cancers (nocodazole, parbendazole and methiazole), drugs used mainly in veterinary medicine. The fourth drug, danazol, is a testosterone-like drug, used to treat several inflammatory disorders (e.g., endometriosis).
17. Two of the drugs were felt to be too toxic, so only parbendazole (injected) and danazol (given orally) were tested in mice. Demyelination was induced in mice by feeding the drug cuprizone. Both parbendazole and danazol reduced areas of myelin loss and increased myelin production by mature oligodendrocytes.
18. The authors believe that their system of screening compounds for their ability to induce maturation of OPCs is both faster and more biologically relevant than other techniques (such as those described in Paper #1).
19. They also note that some of the compounds will need modification due to concerns about toxicity and that studies must be done in an inflammatory model of central nervous system demyelination since demyelination caused by cuprizone is non-inflammatory. The authors propose that their technique will allow much greater and rapid testing of potential remyelinating compounds and could accelerate the discovery of new agents.
Discussion:
There are major challenges to studies of remyelination. The most obvious are the multiple processes and cell types involved in remyelination and the differences, not only between humans and research animals, but within persons with MS. These include the effects of a person’s genes, associated illnesses a person with MS may have, such as diabetes, environmental factors such as smoking, the presence of toxins at sites of demyelination that block and kill OPCs, and the observation that persons with MS vary greatly varying in their ability to remyelinate.
Despite major obstacles, frustrating setbacks, and lack of critical insights, efforts to determine means of inducing central nervous system repair in persons with MS continues at a rapid pace. A multitude of factors need to be addressed, almost certainly requiring more than just one drug or treatment. These include ways of inducing OPCs to differentiate and mature, ways to induce cells of the innate immune system to “clean up” areas of myelin loss and to secrete anti-inflammatory “balms,” and ways to prevent the loss of axons so that there continue to be targets for oligodendrocytes to remyelinate. Timing also will be important, with treatment early in the course of illness, most likely in conjunction with drugs to control central nervous system inflammation.
While efforts to date have not succeeded in inducing major structural repair of lost myelin, the gradual unraveling of the complexities of the process, and the development of new techniques, as described in Paper #2, bodes well for the eventual discovery of effective agents.
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