Multiple sclerosis (MS) is a chronic, progressive disease of the central nervous system (CNS), which is clinically manifested by multisystemic neurological symptoms and signs, and is pathomorphologically characterized by formation of multiple foci of demyelination in the white matter of the brain and spinal cord (Noseworthy et al. (2000) New Engl. J. Med. 343:938-952). The pathogenetic mechanism of the disease is the activation of autoreactive T cells specifically against components of the myelin, which leads to damage of the myelin sheath of oligodendrocytes and axons and consequently to formation of a persistent neurological deficit in the patient (Comabella et al. (2012) Clin. Immunol. 142:2-8).
Today, drugs used for MS drug therapy can be divided into two groups: drugs for symptomatic treatments, and drugs modifying the course of multiple sclerosis (Goodin, et al. (2002) Neurol. 58:169-178; Menge et al. (2008) Drugs 68:2445-2468). Drugs used for symptomatic treatment of MS include glucocorticoids (e.g., prednisolone, metypred, Solu-Medrol) and immuno-suppressive drugs (e.g., cyclophosphan, azathioprine, and mitoxantrone).
The mechanisms of action of glucocorticoids include both a reduction in the number of activated immunocompetent cells and inhibition of autoantibodies (Tischner et al. (2007) Mol. Cell. Endrocrinol. 275:62-70). The anti-inflammatory effect results in the reduction of the permeability of the blood vessels and the blood-brain barrier, which, in turn, leads to a reduction in the rate of prostaglandin synthesis. Due to reduced permeability of the endothelium of the capillaries, migration of leukocytes and other cells to the inflammatory focus is reduced. Adrenocorticotropic hormone (ACTH) and its synthetic analogs (tetracosactide) have a neurotransmitter effect.
A disadvantage of this group of drugs is the symptomatic nature of the treatment, where the prolonged use of these drugs causes hypercorticism syndrome (Cushing's syndrome), psychiatric disorders, arterial hypertension, and hypertrichosis (Weinstock-Guttman et al. (2004) Multiple Sclerosis 10:170-175).
Along with corticosteroids, drugs used in primary or secondary progressive multiple sclerosis include cytostatics, such as azathiaprine, cladribine, methotrexate, cyclophosphamide, mitoxatrone, etc. These drugs have pronounced side effects associated with poor tolerability and depression of bone marrow hemopoiesis.
Pathogenetic treatment of MS includes the use of a number of drugs, such as interferon beta (IFNβ)-1a and IFNβ-1b. The therapeutic effects of IFNβare associated with the inhibition of antigen presentation and suppression of both the proliferation and the activation of inflammatory cells. IFN-β1 induces anti-inflammatory cytokines and a change in the cytokine profile toward the anti-inflammatory phenotype, and also reduces entry of leukocytes into the central nervous system through the blood-brain barrier (see, e.g., Chofflon (2005) Biodrugs 19:299-308; Schreiner et al. (2004) J. Neuroimmunol. 155:172-182; Leppert et al. (1996) Ann. Neurol. 40:846-852; Finocchiaro et al. (2002) J. Interferon Cytokine Res. 22:1181-1184; Huynh et al. (1995) J. Neuroimmunol. 60:63-73; Liu et al. (2001) J. Neuroimmunol. 112:153-162.
The major disadvantages of IFNβuse are the length of treatment (at least six months, and if a positive effect is observed, potentially lifelong), the high cost of a treatment course, and the side effects, including flu-like symptoms (elevated body temperature, acute muscle and joint pain, weakness, fatigue), as well as the production of neutralizing antibodies. In most patients, these antibodies appear between 6 and 18 months after beginning treatment. The negative effect of neutralizing antibodies has been proven by clinical parameters (frequency of relapse) and by neurovisualization parameters of MS activity, as well as by the progression of disability (Kappos (2005) Neurol. 65:40 and Reder (2007) J. Multiple Sclerosis 13:53-62).
Another drug used for treatment of multiple sclerosis is glatiramer acetate (Copaxone), a synthetic polymer of four amino acids. The mechanism of this drug involves competitive binding with the major histocompatibility complex class II molecule, participating in presentation of antigens with the major myelin protein. This drug also activates Th2 CD4+T cells crossing the blood-brain barrier and induces suppression of the autoimmune response against multiple myelin antigens (Neuhaus et al. (2001) Neurol. 56:702-708).
Direct comparative studies of Copaxone with high doses of beta interferons (Refib, Betaferon) have not shown any significant differences in the ability of the drugs to reduce the relapse frequency, or to reduce the number and volume of lesions on MRI (Mikol et al. (2007) Program and Abstracts of the ECTRIMS: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Oct. 11-14, 2007, Prague, Czech Republic, Poster 119). The disadvantages of treatment with this drug include the need for prolonged use (course of treatment lasts at least 6 months), the high cost, and the presence of side effects both at the injection sites (hyperemia, stinging) and a generalized post-injection reaction (breathlessness, tachycardia, flushed skin, cold sweats, chest pain, and dimming of vision). Furthermore, when the drug is taken for many years, lipoatrophic changes may occur (local atrophy of fatty tissue at the injection sites) (Lebrun et al. (2011) J. Multiple Sclerosis 17:88-94).
Also used for MS treatment is Natalizumab (Tysabri), a preparation of monoclonal antibodies against integrin molecules. In MS patients, the drug blocks molecular interaction between a4-integrin (which can be expressed on autoaggressive lymphocytes), and vascular cell adhesion molecule 1 (VCAM-1) of the vascular endothelium of the blood-brain barrier, and prevents the migration of lymphocytes through the endothelium to the inflammatory foci in the CNS (Von Andrian et al. (2003) New Engl. J. Med. 348:68-72).
The disadvantages of the drug include high frequency (in up to 25% of patients) of side effects (headaches, dizziness, itching, chills, hives, asthenia). Delayed side effects are associated with immunosuppression arising as a result of the action of the drug, which include urinary tract infections, vaginal infections, pneumonia, tonsillitis, and herpes infection. 0.1% of the patients who undergo treatment with Natalizumab develop liver, and accordingly, the European Medicines Agency for registration of drugs (EMA) has recommended routine monitoring of patients with liver damage. However, the most serious side effect of Tysabri treatment is progressive multifocal leukoencephalopathy (PML), a demyelinating disease manifested by headaches, paresis, loss of coordination, vision impairment, speech impairment (aphasia) and pronounced cognitive deficits. Most often, the disease ends with the death of the patient. PML is associated with activation (under immunodeficiency conditions) of the JCV polyomavirus in the CNS.
Thus, what is needed is an improved and efficacious treatment for relapsing-remitting MS with reduced or no side effects.
USPTO Backgrounds
USPTO Backgrounds