Multiple sclerosis (MS) is the most common chronic inflammatory disease of the CNS and the major cause of neurological disability in young adults in developed countires. MS is an autoimmune human disease. The diease typically hits people ages 20-40 and is more common in women. MS is a leading cause of nuerologic disability that affects about 400,000 people in the US and 2.5 million worldwide (Ruff, “Identification of peptide mimotope ligands for natalizumab” Scientific Reports (2018) 8, 14473).
Relapsing-remitting multiple sclerosis (RRMS). Multiple sclerosis is a disease in which the immune system (the body’s defences) attacks and damages the protective insulation around the nerves and the nerves themselves in the brain and spinal cord. In RRMS, the patient has flare-ups (relapses) followed by periods with milder or no symptoms (remission).
Risk factors
MS affects about one million people worldwide with 350,000 cases in North America alone. It ranks as a major cause of nervous-system disability in young adults between the ages of 15 and 45 years. Women are affected two times more frequently than men.
Since the 1960s, a possible linke between MS and mercury exposure from amalgam used to fill dental caries has been explored.
Pathology
MS is usually a sporadic disease and is characterized as a variably progressive human disease of the nervous system in which patchy degenerative and inflammatory changes occur within the brain and spinal cord. MS is a chronic inflammatory disease characterized by lymphocyte infiltration and inflammation of the central nervous systen (CNS) white matter. T cells recognizing myelin protein peptides are likely involved in the pathogenesis of the disease. Myelin is a fatty substance which covers the axons of nerve cells and is important for proper nerve conduction. The disease often beings in young adulthood with recurrent inflammatory attacks against the white matter of the brain, producing a myriad of neurological impairments, including blindness, loss of senstation, lack of coordination, bowel and bladder incontinence and diffculty walking.
MS is an autoimmune disease that is characterized by inflammation in parts of the central nervous system, leading to the loss of the myelin sheathing around axonal nuerons (demyelination), loss of axons, and the eventual death of neurons, oligodendrocytes and glial cells. (US Patent No: 8,399,514)
Abnormalities and Causes of MS
Inflammation and autoimmunity: In MS, certain T cells trigger inflammatory processes when they encounter myelin, stimulating other immune cells and soluble factors like cytokines and antibodies. MS is characterized by loss of the myelin sheath around axons, activation of complement, activation of microglia/macrophages, invasion of leukocytes, astrongliosis and finally destruction of oligodendroglial cells and axonal process (Schwab, Exp. Neurology, 174, 2002, 81-89). The inflammatory processes triggered by the T cells creates leaks in the blood brain barrier which causes swelling, activation of macrophages and more activation of cytokines and destructive proteins like matrix metalloproteinases. The final result is demyelination or destruction of myelin.
The hallmark pathology in MS is the plaque- an area of myelin that has been denuded by inflammation and subsequent scarring by non-neural cells in the brain, including bone marrow derived microglia and brain derived star shaped astroglia. The cause of MS is enigmatic, although most investigators believe that immune attack against white matter is paramount, with the resulting degeneration of axons and nyelin being secondary to this inflammatory process.
T Regulatory Cell Dysfuction: There are few reports on functional analysis of CD4+CD25high cells isolated form patients with autoimmune disease. One reports finds no difference in the frequency of these cells between patients and healthy controls but T-reg cells derived form patients as compared to healthy controls did exhibit significantly less suppressive function.
Th1/Th2 Imbalance: MS is believed to be an autoimmune disease in which Th1 immune responses predominant. This response is associated with an increased production of IFNy and IL12 produced by T cells and by cells of the monocyte lineage. An increased expression of costimulatory molecules by T cells and APCs
Experimental Models
Experimental autoimmune encephalomyelitis (EAE), an inflammatory CNS demyelinating disorder which serves as the prime animal model for MS can be induced in a number of species by immunization with myelin components or injection of autoimmune T lymphocytes.
Treatment
Antibodies:
–Anti-Integrins:
—-Natalizumab (marketed as Tysabri): is the top selling biologic drug indicated for MS. It is highly effective in treating MS patientsand was shown to reduce sustained physical disability by 52% relative to placebo. Natalizumab is a huanized recombinant IgG4 mAb that targets the alpah4 chain of alpha4beta1 integrin (also known as very late activation antigen 4; VLA-4) and alpah4beta7 integrin (LPAM-1). It is thought to function by blocking migration of immune cells across the blood-brain barrier into the CNS thus suppressing inflammation in patients with relapsing-remitting MS. (Ruff, “Identification of peptide mimotope ligands for natalizumab” Scientific Reports (2018) 8, 14473).
The immunosuppressive activity of natalizumab has been associated with opportunistic infection by John Cunningham (JC) virus which may lead to progressive multifocal leukoencephalopathy (PML), a serious and often fatal opportunistic brain infection. (Ruff, “Identification of peptide mimotope ligands for natalizumab” Scientific Reports (2018) 8, 14473).
Inteferons: Three treatment for MS are interferons: Interferon beta-1a (Avonex and Rebif) or beta-1b (Betaseron). Part of there mechanism may be to reduce MO CD86 and CD40L expression as well as IL-12 secretion. IFN-B induces IL-10 secretion and suppresses IFN-y-inducible MHC class II up regulation an APC.
Glatiramer acetate (COPXONE): A fourth approved medication is glatiramer acetate (Copaxone), a mixture of polypeptides which may protect important meylin proteins by substituting itself as the target of immune system attack. Yeda Research Development Co is the assignee of US Patent Nos: 8,232,250, 8,399,413, 8,969,302 and 9,155,776 which describe and claim COPAXONE 40 mg/mL for treating relapsing remitting multiple sclerosis (“RRMS). The active ingredient is glatiramer acetate (“GA”), a synthetic mixture of polypeptides. The treatment consists of inection of 40 mg of GA three times a week. These patents were latter found invalid for obviousness (see Tevan Pharmaceuticals v. Sandoz Inc, Fed. Cir, 2017).
Mitoxantrone: A fifth medication, mitoxantrone is effective but is limited by cardiac toxicity. All of the medications cited require frequent injections and are expensive.
Ocrelizumab: The newest and most promising treatment is a drug called ocrelizumab manufactured by Roche (RHHBY) which blocks B cells The FDA has approved ocrelizumab for treatment of primary progressive MS, making it the first drg ever approved for the most aggressive form of the disease. The drug was originally approved for non-Hodgkin lymphoma. In one study, the drug cut annualized repalse rate almost in half compared with a commonly used treatment Rebif. The formation of new lesions in the brain and spinal cord, the key marker of inflammation was reduced by more than 94% compared to patients on Rebif.
Corticosteroid: MS patients are usually given high doses of intravenous corticosteroids, such as methylprednisolone to end the attack sooner. This corticosteroid treatment however does not appear to have a significant impact on long term recovery. During symptomatic attacks, patients may be hospitalized.
4-AP (AKA “dalfampridine” and “fampridine”) belong to a class of compounds that function as potassium channel blockers and have been found to slow the potassium flow in nerve impulse transmission and by doing so help restore conduction in blocked and demyelinated nevers. MS caues demyelnations (loss of myelin) of ncerves in the CNS and results in a wide vareity of symptoms, including walking impariment, tingling or pain, brain scarring, cognitive changes, visual impairments and fatiuge. The FDA has approved Amprya, a 10 milligram 4-AP sustained release tablet for twice daily oral administration. .
Bone marrow transplant and total lymphoid irradiation have been studied and are currently reserved for the most dire cases.
Dimethyl fumarate (DMF, Tecfidera) was approved by the US FDA in March 2013 as an oral disease modifying treatment for relapsing forms of MS. Combined data from a Phase II study and two Phase III trials showed that DMF reduces relapses, disability progression, MRI lesion activity.
The exact mechanism of action of DMF is not known but may include direct inhibition of proinflammatory pathways and effects on dendritic cell differentiation. DMF may also act through the nuclear factor (erythroid-derived 2) like 2 (Nrf2) antioxidant response pathway.
Sphingosine-1-phosphate receptor inhibitors: Zeposia by Bristol Myers contains an active substance, ozanimod, which blocks the action of sphingosine-1-phosphate receptors on lymphocytes (cells of the immune system that can attack the body’s own tissues in diseases such as multiple sclerosis or ulcerative colitis). By attaching to these receptors, ozanimod stops lymphocytes from travelling from the lymph nodes towards the brain, spinal cord or intestine, thus limiting the damage they cause in multiple sclerosis and ulcerative colitis.
Natural products: Among natural products, a recent study found that women who took vitamin D supplments were 40% less likely to develop MS than women who did not take supplements. There were, however, some controversy regarding whether or not the beneficial effects were due to vitamin D or multivitamin supplments including vitamin E and various B vitamins, which may also exert a protective effect.