Multiple sclerosis

Multiple sclerosis (MS) is a potentially disabling autoimmune disease of the brain and spinal cord (central nervous system). In patients with multiple sclerosis, the immune system attacks the protective sheath (myelin) that covers nerve fibers. The scaring and destruction of the protective layers of neurones, and potentially the underlying nerves, means that messages travelling along the nerves become slowed or disrupted. This causes incorrect transmission of nerve impulses between neurons, and communication problems between the brain and the rest of your body.

Because different nerve cells can be affected from one patient to the next, patients with MS experience a wide range of potential symptoms, including fatigue, muscle weakness, problems with vision, speech, arm or leg movement, sensation or balance. Sufferers usually begin by entering a relapsing-remitting phase of 10-15 years, during which they experience periods of symptoms followed by apparent recovery. However, as the disease progresses into the primary and secondary phase, the individual experiences worsening symptoms with no remission. 

MS is one of the most common causes of disability in younger adults in particular women. It is most commonly diagnosed in people in their 20s, 30s and 40s - although it can develop at any age – and is about 2 to 3 times more common in women than men. Research even suggests the proportion of women with MS is increasing. An estimated 2,500,000 people in the world have multiple sclerosis. The distribution of MS around the world is uneven. Generally, the prevalence increases as you travel further north or south from the equator. An estimated 130,000 patients, most of whom are women, live with MS in the UK. Nearly 7,000 people are newly diagnosed each year. This means that around one in every 500 people in the UK has MS, and that each week, 130 people are diagnosed with the disease.

Exactly what causes the immune system to act in this way is unclear, but most experts think a combination of genetic and environmental factors is involved. Although some forms of treatments exist that slow the progression of multiple sclerosis, currently, there is no cure.

Existing treatments 

Animal models 

Stem cells and transplants

Harnessing the body's own repair mechanisms

Targeting the immune system

Genetic aspects

Drug treatments

Existing treatments

There's currently no cure for multiple sclerosis, but a number of treatments can help control the condition and ease symptoms. A large body of research on the immunobiology of MS, which include studies in animals, has resulted in a variety of anti-inflammatory therapies that are highly effective at reducing brain inflammation and clinical/radiological relapses. However, despite potent suppression of inflammation, benefit in the more important and disabling progressive phase is extremely limited; thus, progressive MS has emerged as the greatest challenge for the MS research and clinical communities.  

 Choice of treatment depends on specific symptoms and difficulties. It may include: 

• treating relapses with short courses of steroid medicine to speed up recovery
• specific treatments for individual MS symptoms
• treatment to reduce the number of relapses using medicines called disease-modifying therapies

Disease-modifying therapies may also help to slow or reduce the overall worsening of disability in people with a type of MS called relapsing remitting MS, and in some people with types called primary and secondary progressive MS, who have relapses. The majority of DMTs approved by the Food and Drug Administration (FDA) since the early 1990s are effective at helping to manage relapsing-remitting MS, which affects between 85% and 90% of people diagnosed with this disease.

Unfortunately, there's currently no treatment that can slow the progress of primary progressive MS, or secondary progressive MS, where there are no relapses.

            - Natalizumab

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It was been licensed in the UK and the US for rapidly evolving, severe, relapsing remitting MS. It is a recombinant humanised monoclonal antibody produced in murine myeloma cells and targeted against the cell adhesion molecule α4-integrin. It inhibits the transmigration of immune cells into the inflamed parenchyma of lymphatic organs and the central nervous system (CNS). 

Natalizumab was the first mAb approved for therapeutic trials in MS and now it represents a second-line drug for treating MS.

In 1994 antibodies targeting immune system cells were shown to halt the development of disease in mouse models of MS, specifically mice with experimental autoimmune encephalomyelitis (EAE) 6. The antibodies used were mouse antibodies and couldn’t be transferred and used in humans without causing an immune response. Researchers then went on to producing humanised antibodies that would work in human patients, today known as Natalizumab. It was shown to be effective in preventing EAE. 

Once natalizumab had been proved to be effective in this model system in animals, it was tested on humans in several clinical studies in the 1990s. The antibody reduced the frequency of permanent damage to the brain by almost 45 percent, and the frequency of flare-ups declined by almost 70 percent.

Natalizumab came onto the market in the USA in 2004. Following its temporary withdrawal due to a fatal complication, natalizumab was licensed again in the USA in 2006 and, finally also in Germany for the treatment of highly active, relapsing multiple sclerosis. 

            - interferon betas

Interferons are medicines that "interfere" with diseases that attack the body. They may work by decreasing inflammation and increasing nerve growth. There are many interferon drugs.

Drugs called interferon betas are common treatments for multiple sclerosis (MS), reducing relapses and slowing motor function decline. Interferon beta has been approved for the treatment of relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis. Interferon beta, a protein known to contain a zinc binding pocket, is thought to reduce proinflammatory molecules and even increase production of anti-inflammatory species in MS patients. Numerous animal studies have led to the understanding of this molecule and the drug today used to treat MS. Studies are still ongoing to understand how it works. 

Over the years, an increasing number of interferons have been discovered along with their many different biological activities. Interferons have become part of an interacting family of biological response-modifying proteins. Because of the complexity of these systems, animal experiments are the only way to assess the clinical potential of interferons(and interferon-like molecules).

These molecules have benefitted human, but also animal health. A number of studies have evaluated the use of human, canine and feline Interferons as treatments for infectious, inflammatory and neoplastic disease in dogs and cats. 

- monoclonal antibody ofatumumab

The monoclonal antibody ofatumumab (Kesimpta, Arzerra), approved by the FDA in 2020, targets cells that damage the nervous system. These cells are called B cells. Ofatumumab, which is given as an injection under the skin, decreases multiple sclerosis brain lesions and worsening symptoms. 

It was extensively vetted in animal models, particularly mouse models. More information here: https://www.ema.europa.eu/en/documents/assessment-report/kesimpta-epar-public-assessment-report_en.pdf 

            - glatiramer acetate

The glatiramer acetate preparation is a random polymer consisting of repeated sequences of four amino acids, which has been shown to suppress EAE progression in mice, probably through the stimulation of Th2-mediated anti-MBP immune response or by inducing killing of antigen-presenting cells (APCs) and generation of Treg cells. 

            - Mitoxantrone

Mitoxantrone was first proven to be a powerful immunosuppressive drug in EAE in mice, and it is now a second-line component of MS therapy. Cytotoxic effects on lymphocytes and induction of apoptosis of APC have been proposed as the major mechanism of action of this drug.  

For more information on treatments against MS : https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/expert-answers/emerging-treatments-for-ms/faq-20096786

Animal models of multiple sclerosis

Understanding the brain & harnessing the body’s repair system

Repairing nerve cells 

In order to treat the disease properly, it is important to understand it. Dr Anna Williams from the Centre of Regenerative Medicine in Manchester is particularly interested in trying to understand how the brains of patients with MS repair. Indeed, the brain has the possibility to put myelin sheaths back onto nerves, which has the potential to restore nerve function in MS. However, this process is generally inefficient, and often forms scars which can cause long-term problems for patients.  Cells that have this repair function are called oligodendrocytes. The research team has looked into how these cells work and whether they could get them to repair myelin damage more effectively.

By growing oligodendrocytes in dishes, it is possible to monitor whether they make more or less myelin depending on different conditions or drugs. The team does a lot of experiments using cells from mice, rats and humans and slices of brain from mice and rats. “Ultimately, the work moved to live animals. As humans are the only animals that get MS naturally, we therefore tried to model part of the disease in mice. We’re interested in myelin repair, so we caused a small amount of demyelination in the animals by chemical-injection in the brain. The mice don’t seem to be affected by this. Mice repair their brains much better than humans do. So within 4 weeks, basically all signs that myelin damage goes away,” explains Dr Anna Williams. “The mice don’t develop symptoms but imaging of the brains can give us a before/after treatment picture to see how well oligodendrocytes are repairing myelin. We measure the pathology rather than the pain.”

There are currently three drugs that have entered human trials for trying to improve myelin repair in MS after studies in animals. Dr Anna Williams worked on one of them called Baroxatine.

Fibrin 

Looking into the repair system of nerves, researchers have also identified a molecule of interest. Fibrin, a protein that helps form blood clots, may inhibit the repair of damaged nerves. Previous research had shown that fibrin accumulates in the damaged nerves of MS patients, but research in mice has recently shown that fibrin-free mice regenerate myelin faster than normal mice after damage to the sciatic nerve in the leg5. In 2004 researchers found that EAE mice that were bred without fibrin showed a later disease onset and lived longer that normal EAE mice6.

CNTF & TNF- α
Researchers also found that EAE mice had a more severe form of the disease if they lacked a chemical messenger known as CNTF. They proposed that CNTF protects oligodendrocytes against programmed cell death through a mechanism that involves a substance called tumour necrosis factor alpha (TNF-α)7 8. Other scientists found that administration of another messenger, LIF, can reverse this loss of oligodendrocytes normally seen in EAE. This compound is well-tolerated in humans9.

Paradoxically, MS does not respond to TNF-α, and it has now been shown that TNF-α has two opposite effects in mice, first accelerating damage to nerves and later accelerating its repair. This finding may help the development of more effective treatments for the disease. In MS, cells have some capacity for self-repair, so a promising treatment approach is to increase the body’s ability to repair itself10. 

Stem cells and transplants 

Lymphocyte transplants

An emerging potential treatment removes the ‘self-reactive’ lymphocytes, replacing them with lymphocytes developed from the patient’s own stem cells. In effect, this is a recalibration of the person’s immune system which removes the abnormal aspects and transplants their own immune cells back into the body. Because the replenishing white cells are developed from the patient’s own stem cells, they do not induce the usual problems of rejection.1

Glial cell transplants
A new study shows that when specific human brain cells are transplanted into animal models of multiple sclerosisand other white matter diseases, the cells repair damage and restore function. The findings are the culmination of more than 15 years of research understanding support cells found in the brain called glia, how the cells develop and function, and their role in neurological disorders. 

When human glia progenitor cells are transplanted into adult mouse models of progressive multiple sclerosis, the cells migrated to where needed in the brain, created new oligodendrocytes, and replaced the lost myelin.  The study also showed that this process of remyelination restored motor function in the mice. The findings, which appear in the journal Cell Reports, are the culmination of more than 15 years of research at URMC understanding support cells found in the brain called glia, how the cells develop and function, and their role in neurological disorders. 

Bone marrow transplants

HSCT (haematopoietic stem cell transplantation) is an intense chemotherapy treatment for MS. It aims to 'reset' the immune system by wiping it out and then regrowing it, using your stem cells. The use of HSCT to treat autoimmune disorders was first considered following observations of autoimmune disease remission when bone marrow tissue was destroyed during cancer therapy. 

Researchers found that bone marrow transplants could induce either resistance or susceptibility to autoimmune diseases, and realised that the bone marrow cells were key to the development of such diseases. However, the destruction of bone marrow was an aggressive treatment regime which severely depleted the patient’s immune system. Using animal models, researchers were able to conclude that bone marrow transplants were a viable treatment for MS, but that severe depletion of lymphocytes also raised the mortality risk.2 These results led to the development of less aggressive conditioning regimes which would be safer for human patients. Researchers are also using animal models to further investigate whether the source of the HSCT should be the individual concerned, or a donor.3

Targeting the immune system

In 2004 scientists reported that inhibiting a protein called Nogo A in EAE mice significantly delays the onset of the condition11 12 13. It may therefore play a role in the human disease.

Two immune proteins found in mouse brains raise the possibility that autoimmune diseases such as MS may be the result of a misguided attack by the immune system on the nerve cells that carry 'genetic fingerprints'14. Such attacks are carried out by subset of white blood cells called T cells.

A specially engineered CD28 molecule blocks interactions between immune-system and suppresses EAE disease in mice. It interferes with the interaction that prompts T-cells to attack nerve cells in MS15. Researchers have found a way of using normal T-cells to recognise misdirected T-cells in EAE mice. Mice treated in this way survived, whereas 50% of the untreated EAE mice died16.

In MS, T-cells in the immune system are stimulated to attack myelin sheaths when they are exposed to small amounts of myelin protein, while T-cells exposed to large amounts of the same protein will self-destruct. This has led to the development of immunological therapy, which has been tested successfully in marmosets17. T-cells are, however, essential to survival, so researchers have devised a way to eliminate only those T-cells that are causing the problem. A molecule that targets a specific type of T cell delivers a toxic drug called doxorubicin. This might prove useful in several autoimmune diseases18.

Using laboratory cell tissue cultures and mice genetically manipulated to lack two key immune system cells, researchers showed that Mycobacterium leprae, the leprosy bacterium, destroys the protective myelin sheath that surrounds nerve fibres and then hides in Schwann cells, poised to initiate later attacks. This novel bacterial mechanism of inducing demyelination may provide clues to early molecular events in MS19.

Three potential drug treatments

MS patients have toxic levels of glutamate in their spinal fluid. Glutamate can cause extensive brain damage following stroke. Two studies have shown that compounds that block glutamate, which were being tested as stroke treatments, also protected rats and mice with EAE25 26. Similar compounds may prove useful in the treatment of MS.

Two anti-diabetic drugs called TZDs, already approved in the USA for treatment of Type 2 diabetes, prevented MS in mice and treated those already ill. There have already been small scale successful trials of one of these, pioglitazone, in humans. Even if the drugs are only as good as those currently in use, they still offer an advantage because they can be taken orally27.

Many MS patients are adamant that cannabis relieves their tremors and muscle spasms, and research in mice confirms this. When EAE mice were injected with cannabis extracts, these symptoms improved within minutes and did not return for hours. The researchers found that the cannabis stimulated certain receptors on the surface of motor nerve cells and did not have a sedative effect28.

A team managed to reduce chronic inflammation associated with multiple sclerosis in mice thanks to the administration of a type of lipid that mediates inflammation. The team found that these types of mediator substances, responsible for resolving the inflammatory process when it is no longer beneficial, are minimized in people with multiple sclerosis as well as in animal models of the disease. The use of these mediators could become a good strategy for the treatment of this autoimmune disease.

Diagnosis - Finding biomarkers of the disease

MS is a complex disease characterised by important pathophysiological heterogeneity affecting the clinical appearance, progression and therapeutic response for each patient. To date, there is no specific molecular test for the treatment choice, which is based more on risk assessment than on the specific needs of the patients. Therefore, there is a strong unmet need to define specific biomarkers that will reflect the different features of the disease. This will facilitate the prediction of the clinical outcome and the therapeutic choice among the growing number of treatments available for MS.

There are five groups of clinically relevant MS molecular biomarkers, based on the key pathological hallmarks of MS: inflammation, blood–brain barrier disruption, myelin and axonal damage, gliosis and, ultimately, repair mechanisms. In many cases, early-stage biomarkers are first discovered and studied in animal models and then validated in human disease to evaluate their potential for diagnosing, predicting or treating human disease.

Like any disease animal model, EAE models can sometimes fail to mimic the entire spectrum of human disease, but they can nonetheless recapitulate the disease’s primary hallmarks. In fact, the EAE model is a valuable tool for understanding MS physiopathological mechanisms and for identifying biomarkers fundamental for drug development. The different biomarkers recapitulating the main hallmarks of the disease are comparably dysregulated in EAE models and MS. Biomarkers expression between EAE models and MS disease often coincides, making the EAE model a valuable tool for biomarker discovery and it will most likely continue to provide MS drugs.

https://hal.science/hal-04078010v1/preview/islandora_162072.pdf

Diagnosis 

https://www.sciencedaily.com/releases/2022/03/220324122612.htm

A critical gene, osteopontin, is a key factor in the inflammatory immune response and may determine the cycle of relapses and remissions. In rodents, disease severity is proportional to the amount of osteopontin gene expression. Osteopontin-deficient mice have milder disease and more frequent remission. The findings could lead to targeted new therapies for MS. However, more research is needed, especially as other genes are involved in the disease22. Indeed, when researchers analysed brain tissue from four MS patients, they found that the expression of 39 genes was increased, and the expression of 49 other genes was decreased. They selected two of these genes for therapeutic testing in mice with EAE, and found that the disease was less severe in mice deficient in the antibody receptor Fc, and that a naturally-occurring substance called G-CSF improved the condition23.

Two genes, known as Olig1 and Olig2, control the development of cells that the central nervous system uses to generate muscle movement. Mice bred to lack one or both Olig genes failed to develop the motor nerves needed to control muscle movement and were completely paralysed. Olig genes induce oligodendrocytes to surround and protect the nerves with myelin24. 

Recent discoveries regarding MS : https://www.sciencedaily.com/news/health_medicine/multiple_sclerosis/

https://www.mssociety.org.uk/research/latest-research/latest-research-news-and-blogs

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References

References from the earlier version of this page. Modern references provided as links and within the body of the article.

1. Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol 2009; published online January 30.
2. Burt RK, Traynor AE. Hematopoietic stem cell transplantation: a new therapy for autoimmune disease. Oncologist. 1999;4(1):77-83
3. Sykes M, Nikolic B. Treatment of severe autoimmune disease by stem-cell transplantation. Nature. 2005 Jun 2;435(7042):620-7. Review.
4. MS Society, 2009. Stem cell therapy may halt and even reverse disability in people with relapsing remitting MS. (Research News) [Online] (Updated 30 Jan 09). Available at: http://www.mssociety.org.uk/research/news_in_research/research_news/stem_cell_trial.html
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6. Akassoglou K, Adams RA, Bauer J et al (2004) Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc Nat Acad Sci 101, 6698
7. Akassoglou K, Adams RA, Bauer J et al (2004) Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc Nat Acad Sci 101, 6698
   
   
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9. Butzkueven H, Zhang J-G, Soilu-Hanninen M et al (2002) LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival Nature Medicine 8, 613
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11. Jameson BA, McDonnell JM, Marini JC & Korngold R (1994) A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis Nature 368, 744
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16. Jyothi MD, Flavell RA, Geiger TL (2002) Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes Nature Biotech 2, 1215
17. McFarland HI, Lobito AA, Johnson MM et al (2001) Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis J Immunol 166, 2116
18. Casares S, Stan AC, Bona CA, Brumeanu T-D (2001) Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II-peptide chimera Nature Biotechnology 19, 142
19. Rambukkana A, Zanazzi G, Tapinos N, Salzer JL (2002) Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells Science 296, 927
20. Ebersole TA, Chen Q, Justice MJ, Artzt K (1996) The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins Nature Genetics 12 (3), 260
21. Klein L, Klugmann M, Nave K et al (2000) Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells Nature Med 6, 56
22. Chabas D, Baranzini SE, Mitchell D et al (2002) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease Science 2001 November 23; 294, 1731
23. Lock C, Hermans G, Pedotti R et al (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis Nature Medicine 8, 500
24. Lu R, Tao Sun, Zhu Z, Nan Ma N et al (2002) Common developmental requirement for olig function indicates a motor neuron/oligodendrocyte connection Cell 109, 75
25. Smith T, Groom A, Zhu B et al (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists Nature Med 6, 62
26. Pitt D, Werner P, and Raine C (2000) Glutamate excitotoxicity in a model of multiple sclerosis Nature Med 6, 67
27. Feinstein D, Galea E, Gavrilyuk V et al (2002) Perixisome proliferator-activated receptor- agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 51, 694
28. Baker D, Pryce G, Croxford JL et al (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model Nature 404, 84

 

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• Author(s): Mia Rozenbaum
• Animal(s): Mouse, Mouse (knockout/GM), Primates, Rat
• Research field(s): Biochemistry, Brain and nervous system, Drugs and toxins, Genetics, Infection and Immunity
• Medical application(s): Basic research, Medicine

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Last edited: 31 May 2023 09:48