WO2006136116A1 - Use of interferon-alpha in order to obtain a compound for the treatment of optical neuromyelitis - Google Patents

Abstract

The invention relates to the use of interferon-alpha in order to obtain a pharmaceutical compound for the treatment of neuromyelitis optica (NMO) or Devic's syndrome. Interferon-alpha (IFN α) can be used as a treatment for NMO in both the monophase form and the relapsing form. In addition, IFN α can be combined with other growth factors such as recombinant erythropoietin (rEPO), thereby increasing the rationale behind its use in relation to said disease.

Description

USE OF THE ALFA INTERFERON TO OBTAIN A COMPOUND FOR THE TREATMENT OF OPTICAL NEUROMYELITIS.

Field of the Technique The present invention relates to the biological sciences, biotechnology and medical sciences, and is based on a new use of interferon alpha (IFN α) which due to its antiviral, immunomodulatory, regulatory and preventive T-cell inductors demyelination is able to stop the progression of optic neuromyelitis disease (NMO) in the single phase form, reduce the number of outbreaks and prolong the time between relapses in patients suffering from the recurrent form of NMO.

Prior art

NMO is characterized by attacks of optic neuritis and myelitis (Devic E. Myelitis follows complications of neurite optique. (1894) BuII Med 8: 1033-1034; Devic E. Myelite aigue dorse-lombaire de neurite optique, autopsy. (1895 ) Congress Francais Medicine (Premiere Session, Lyon) 1: 434-9; Gault F. De la neuromyelite optique aigue. (Thesis) Lyon; (1894)). These clinical events can also occur frequently in Multiple Sclerosis (MS), however, both the epidemiology, clinical characteristics, laboratory, etiopathogenesis and non-response to the accepted conventional treatments for MS, allow to consider the NMO as an entity nosological independent of MS. In the NMO, outbreaks or crises are more acute (sometimes fulminant) and severe, mainly affects young adults and has been reported in childhood. The reported mean age of onset is later than in MS, between 35 and 47 years (Mandler RN, Davis LE, Jeffery DR, Komfeld M. Devic's optic neuromyelitis: a clinicopathological study of 8 patients. (1993) Ann Neurol 34: 162-8), fundamentally affects the female sex and non-white races unlike the MS that predominates in the white race (Weinshenker BG, Sibley WA, Natural history and treatment of multiple sclerosis. Curr Neurol Opinion Neurosurg 1992, 5,203-211) . The incidence or prevalence of NMO is unknown. In Europe, where MS has a prevalence between 100-200 / 100,000 inhabitants, NMO is considered a rare disease. The NMO seems to be common in non-Caucasians such as Africans, Americans, Japanese and other Pacific islands. More than 6% of cases of demyelinating diseases in India are NMO (Singhal BS. Multiple sclerosis-Indian experience. (1985) Annals of the Academy of Medicine, Singapore 14: 32-6). In Cuba the prevalence is unknown but has been increasing in recent years. The role of genetic factors is unknown. There are reports of identical twins with NMO. Certain alleles of human leukocyte antigens (HLA) are associated with the NMO such as the HLA-DPB1 * 0501 while in the MS the HLA allele that is most frequently associated is the HLADR2B. In the NMO the paraclinical measurements such as Nuclear Magnetic Resonance (NMR) of the brain and spinal cord, as well as the analysis of the cerebrospinal fluid (CSF) also differ with MS. In NMO, no or few lesions in the white matter are detected in the brain, however the spinal cord images show distinctive elements: the majority of patients have extensive lesions that extend longitudinally over 3 or more vertebral segments. In addition, patients with NMO have a pleocytosis of more than 50 leukocytes with or without the presence of neutrophils. The NMO tends to follow a single-phase or outbreak or relapse course (more than 70% of cases have a recurrent course) (Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of optic neuromyelitis (Devic's syndrome ). (1999) Neurology 53: 1107-14). In monophasic NMO, patients experience unilateral or bilateral optic neuritis (NO) with a simple episode of myelitis, typically, although not always within a short period of time from each other, but do not have subsequent relapses unlike patients with a relapsing course that continue to have discrete exacerbations of NO and / or myelitis.

The cause of the NMO is unknown. In fact, systemic autoimmune diseases have been associated with NMO suggesting that a single cause of this disease is unlikely. In the pathogenesis of MS, the cellular immune response has an important role, unlike the NMO where the humoral component seems to be predominant.

Different mechanisms have been involved in the pathogenesis of NMO. The pronounced reactivity to lnmunoglobulins (Ig) co-localizing with complement activation at sites of vascular damage suggests that the peri-vascular space It may be the primary site of damage in the NMO. This may be due to antibodies specific to vascular antigens.

Alternatively, antigens released into the CNS during the destructive process can reach the peri-vascular space and be recognized there by antibodies from the circulation. Finally, a non-specific inflammatory reaction initiated by the deposition of circulating immune complexes may be involved. In this scenario, the classical complement pathway is activated, allowing the recruitment of activated macrophages to these peri-vascular sites where they bind via a receptor for complement components or Ig / Fc receptors. Activated macrophages, together with eosinophils and neutrophils, locally generate cytokines, proteases and free radicals of oxygen / nitrogen which can contribute to both vascular and parenchymal damage, resulting in non-selective destruction of white and gray matter, including axons and oligodendrocytes Increased vascular permeability and edema can contribute to parenchymal damage via secondary ischemia or favor the typical central location of NMO plaques within the spinal cord (Prineas JW, McDonald Wl. Demyelinating diseases (1997) In: Graham Dl, Lantos PL , editors, Greenfield's neuropathology, 6 ^th ed. London: Arnold; p. 813-96). A similar central location was found in severe cases of experimental autoimmune encephalomyelitis (EAE) induced by myelinic oligodendrocyte protein (MOG) and this phenomenon is probably due to edema induced ischemia. (Lassmann H. Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis. (1983) Schriftenr Neurol 25: 1- 135). New antigens released during the destructive process can amplify the destructive immune response in NMO. The complement may not be specifically activated in response to tissue necrosis. One of the most novel features described in the histopathology of active NMO lesions is the intensity of the meningeal and perivascular infiltration of the spinal cord with eosinophils and neutrophils. Activated eosinophils release proteins with basic granules such as Myelin Basic Protein (MBP), eosinophil-derived neurotoxin, cationic protein from eosinophils and eosinophil peroxidase (Kaneko M, Kita H, Gleich GJ. Eosinophil basic proteins. In: Barnes PJ, Grunstein MM, Leff AR ₁ Woolcock AJ, editors. Asthma. (1997) Philadelphia: Lippincott-Raven p 593-607) . These granules have cytotoxic properties and serve as eosinophil activation markers (Venge P. Monitoring of asthma inflammation by serum measurements of eosinophil cationic protein (ECP): a new clinical approach to asthma management. (1995) Resp Med 89: 1- 2 ). In addition to the high number of eosinophils in NMO lesions, the presence of eosinophil degranulation in the spinal cord tissue of patients with NMO has been confirmed. Evidence of CCR3 expression has been demonstrated in NMO lesions. CCR3 is the main receptor for chemokine eotaxin, a potent chemo-attractant for eosinophils. CCR3 is expressed primarily in human eosinophils (Ponath PD, Qin S, Post TW, Wang J, Wu L, Gerard NP, et al. Molecular cloning and characterization of human eotaxin receptor expressed selectively on eosinophils. (1996) J Exp. Med 183 : 2437-48). Eotaxin signaling through CCR3 is an important index of eosinophil recruitment (Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz I, Sirotina A, Springer MS. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. (1996 ) J Exp Med 183: 2349-54). CCR3 is selectively expressed in T helper 2 (Th2) cells and is therefore associated with the Th2 response (Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokines receptors expression on human polarized T helper 1 and 2 lymphocytes. (1998) J Exp Med 187: 875-83). There is morphological evidence that they are increased in number and are functionally active and probably contribute to the destructive inflammatory process in NMO. The cytotoxicity of eosinophil granule proteins has been well established (Corrigan CJ, Kay AB. T cell / eosinophils interactions in the induction of asthma. (Review) (1996) Eur Respr J Suppl 22: 72s-8s). Eosinophils are an important source of IL-4, which can cause a change in the cytokine profile from Th 1 to Th2 (Rumbley CA, Sugaya H, Zekavat SA, El Refaei M, Perrin PJ, Phillips SM. Activated eosinophils are the major source of Th2- associated cytokines in the schistosome granuloma. (1999) J Immunol 162: 1003-9). Patients with NMO often have circulating auto-antibodies with a frequency that exceeds that view in MS (Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of optic neuromyelitis (Devic's syndrome). (1999 ) Neurology 53: 1107-14). The pathogenicity of these autoantibodies is unknown: they can cause damage directly through the recognition of epitopes on normal cells, or indirectly through the formation of immune complexes that are deposited in normal tissue and activate the complement cascade. Their presence in Devic may also reflect the greater spectrum of the response to B cells. Prominent antibody response can also be found with respect to endogenous myelin antigens, such as MOG. A recent study analyzed the response to antibodies to MOG, MBP and Calcium-binding protein of astroglia (SIOOb) in the serum of 4 cases of Devic's Disease (Haase CG, Schmidt S. Detection of brain-specific autoantibodies to myelin oligodendrocyte glycoprotein , SiOObeta and myelin basic protein in patients with Devic's optic neuromyelitis. (2001) Neurosci Lett 307: 131-3). The authors reported a pronounced antiMOG response, specifically to epitope 63-87 of the amino acid sequence in all patients, antiMBP antibodies in two patients and antiSIOOb antibodies in one patient. In the NMO, the spinal cord and optic nerve are preferentially affected. It is possible, although unlikely that these sites have a restricted vascular or CNS antigen or it may be that both sites have a particular vulnerability to antibody-mediated damage due to the inherent weakness of the blood-brain barrier at these sites. BHE is highly impermeable to circulating plasma proteins and leukocytes and therefore can protect the CNS from an immune reaction. However, in some areas where BHE is not effective, such as spinal nerve roots, it may happen that circulating pathogenic antibodies can access the CNS via these structures and spread to the immediate vicinity. In EAE models, active lesions predominantly affect the spinal cord (Lassmann H. Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis. (1983) Schriftenr Neurol 25: 1- 135). NO in EAE also tends predominantly to occur in the retrobulbar optic nerve (Guy J, Rao NA. Acute and chronic experimental optic neuritis. Alteration ¡n the blood-optic nerve barrier. (1984) Arch Ophthalmol 102: 450-4). The lesions in these two sites are a reflection of the highest degree of permeability of BHE in these regions compared to the brain (Guy J ₁ Rao NA. Acute and chronic experimental optic neuritis. Alteration in the blood-optic nerve barrier. (1984 ) Arch Ophthalmol 102: 450-4; Rao NA. Chronic experimental allergic optic neuritis. (1981) Invest Ophthalmol Vis Sci 20: 159-72; Butter C, Baker D, O'Neill JK ₁ Turk JL. Mononuclear cell trafficking and plasma protein extravasation into the CNS during chronic relapsing experimental allergic encephalomyelitis in Biozzi AB / H mice. (1991) J Neurol Sci 104: 9-12). The permeability of the increased BHE in the spinal cord may be due to vascular properties inherent in this region where the capillaries are longer than in the brain. Therefore, with a background inflammatory process, in the presence of extremely high antibody titres, the lesions may preferentially but not exclusively affect the spinal cord and the optic nerve. This hypothesis is compatible with the observation that in late stages of NMO, lesions often spread to other CNS regions (Wingerchuk DM, Hogancamp WF ₁ O'Brien PC, Weinshenker BG. The clinical course of optic neuromyelitis (Devic's syndrome) (1999) Neurology 53: 1107-14). There is extensive demyelination at the level of the spinal cord and it was associated with cavitation, necrosis and acute axonal pathology (spheroids) in both gray matter and white matter. There is pronounced loss of oligodendrocytes within the lesions. Inflammatory infiltrate within active lesions was characterized by pronounced macrophage infiltration associated with large numbers of granulocytes and eosinophils and rarely CD3 + CD8 + T cells. There is a marked perivascular deposition of immunoglobulins (mainly IgM) and the complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The important activation of complement, eosinophilic infiltration and vascular fibrosis observed in cases of Devic NMO is more prominent compared to MS, and supports the role of humoral immunity in the pathogenesis of NMO (Lucchinetti CF, Mandler RN, McGavem D , Bruck W, Gleich G, Ransohoff RM ₁ Trebst C ₁ Weinshenker B, Wingerchuk D, Parisi JE, Lassman H. (2002) A role for humoral mechanism in the pathogenesis of Devic's optic neuromyelitis. Brain 125: 1450-61).

Different clinical associations with NMO suggest that this disease is different from MS. Unlike EM _1, there are numerous reports of optic-spinal disease associated with connective tissue diseases and other autoimmune diseases (April RS, Vansonnenberg E. A case of optic neuromyelitis (Devic's syndrome) in systemic lupus erythematosus: clinical-pathologic report and review of the literature (1976) Neurology 26: 1066-70; Kinney EL, Berdoff RL ₁ Rao NS, Fox LM. Devic's syndrome and systemic lupus erythematosus: a case report with necropsy. (1979) Arch Neurol 36: 643-4; Goldman M, Herode A, Borenstein S, Zanen A. Optic neuritis, transverse myelitis, and anti-DNA antibodies nine years after thymectomy for myasthenia gravis. (1984) Arthritis Rheum 27: 701-3; Nambu M, Hayakawa Y, lto T , Takeda Z, Sakamoto Y, Mikawa H. Hypergammaglobulinemic purple associated with multiple sclerosis. (1988) J Pediatric 113: 331-3; Lindsey LW, Albers GW, Steinman L. Recurrent transverse myelitis, myasthenia gravis, and áutoantibodies. (1992) Ann Neurol 32: 407-9; Sim eon-Aznar CP, Tolosa-Vilella C, Cuenca-Luque R, Jordana-Comajuncosa R, Ordi-Ros J, Bosch-Gil JA. Transverse myelitis in systemis lupus erythematosus: two cases with magnetic resonance imaging. (1992) Br J Rheumatol 31: 555-8; Bonnet F, Mercie P, Morlat P, Hocke C, Vergnes C, Ellie E, et al. Devic's optic neuromyelitis during pregnancy in a patient with systemic lupus erythematosus. (1999) Lupus 8: 244-7; Mochizuki A, Hayashi A, Hisahara S, Shoji S. Steroid-responsive Devic's variant in Sjogren's syndrome. Neurology 2000; 54: 1391-2). Unlike MS, there is a racial predilection for NMOs in non-whites (O'Riordan Jl, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and MRI findings Devic's optic neuromyelitis. (1996) J Neurol Neurosurg Psychiatr 60: 382-7). Aboriginal people in Manitoba have an increased risk for different diseases that have been more implicated in the pathogenesis of NMO including Mycobacterium Tuberculosis infection (Arvanitakis Z, Long RL, Hershfield ES, et al. M. Molecular tuberculosis variation in CNS infection: evidence for strain -dependent neurovirulence. (1998) Neurology 50: 1827-1832), other infectious causes (Young TK. The health of native Americans: toward a bioculturalepidemiology. Toronto: Oxford University Press, (1994)), autoimmune diseases (Oen K, El-Gabalawy HS, Canvin JM, et al. HLA associations of seropositive rheumathoid arthritis in a Cree and Ojibway population. (1998) J Rheumatol 25: 2319-2323) than in MS. NMO has been associated with several systemic diseases including vascular diseases of collagen, autoantibody syndromes, infections and exposures to toxic agents.

The NMO has also been associated with infectious diseases, for example, viral, frequently the NMO has an infectious prodrome characterized by headache, myalgias and high respiratory symptoms, in few cases an infectious agent is identified, there are reports of NMO after acute infectious mononucleosis (Williamson PM. Optic neuromyelitis following infectious mononucleosis. (1975) Proc Aust Assoc Neurol 12: 153-155), Varicella-zoster (Williamson PM. Optic neuromyelitis following infectious mononucleosis. (1975) Proc Aust Assoc Neurol 12: 153-155) . There is also a high frequency of NMR alterations in the hypothalamus-pituitary axis in patients with NMO and associated endocrinopathies. Vernant et al. (Vernart JC, Cabré P, Smadja D, et al. Recurrent optic neuromyelitis with endocrinopathies: a new syndrome (1997) Neurology 48: 58-64) described a series of 8 women from Martinique and Guadeloupe who suffered from NMO and Endocrinopathies, 7 of the 8 patients had a secondary amenorrhea that coincided with exacerbations of NMO. One postmenopausal patient and 2 others had galactorrhea with hyperprolactinemia. 4 patients had hypothyroidism and one patient had diabetes insipidus. The authors reported that 3 patients who had hyperphagia and obesity suffered from hypothalamic dysfunction. In one patient, a thyrotropin-releasing hormone stimulation test indicated hypothalamic dysfunction as a cause of hyperprolactinemia. In 3 patients, lesions with Gadolinium were found in the hypothalamic-pituitary region in the NMR. All patients suffered from recurrent NO and myelitis that was resistant to immunosuppressive therapy and finally caused blindness and paraplegia. The oligoclonal bands in the CSF were found only in one patient. In this study, the neuropathological findings demonstrated pronounced necrosis with limited demyelination, similar to that reported in the NMO (Baudoin D, Gambarelli D, Gayraud D, et al. Devic's optic neuromyelitis: a clinicopathological review of the literature in connection with a case showing fatal dysautonomia. (1998) Clin Neuropathol 17: 175-183; Filippi M, Rocca MA, Moiola L ₁ et al. MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic's optic neuromyelitis. Neurology 1999; 53: 1705-1710) Which could explain the absence of benefit observed with Glucocorticoids and treatment with Interferon beta.

There are 4 separate evidences that support the role of humoral mechanisms in NMO pathogenesis: the pathology of the lesion, the similarity with a selective variant of EAE induced by MOG, the clinical association with vascular disorders of antibody-mediated collagen and Ia response to plasmapheresis. Although complement activation is observed in a population of patients with MS (Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassman H. A role for humoral mechanism in the pathogenesis of Devic's optic neuromyelitis. (2002) Brain 125: 1450-61; Storch MK, Piddlesden S, Haltia M, livanainen M, Morgan P, Lassmann H. Multiple Sclerosis: in situ evidence for antibody-and complement -mediated demyelination. (1998) Ann Neurol 43: 465-71), the pattern and pronounced perivascular distribution of complement activation seen in NMO is unique. Despite the differences in clinical manifestations, imaging findings, pathology and biochemistry of CSF between NMO and MS, the distinction between these diseases remains controversial (Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic's optic neuromyeliris: a clinicopathological study of 8 patients. (1993) Ann Neurol 34: 162-8; Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of optic neuromyelitis (Devic's syndrome). (1999) Neurology 53: 1107-14) . Reduced levels of the MMP-9 neuro-inflammatory metalloproteinase marker in the CSF of patients with NMO support the possibility of a different pathogenic mechanism of lesion production, since MMP-9 is markedly elevated in the CSF of the MS (Mandler RN , Davis LE, Jeffery DR, Kornfeld M. Devic's optic neuromyeliris: a clinicopathological study of 8 patients. (1993) Ann Neurol 34: 162-8). In addition, the tissue metalloproteinase inhibitor (TIMP-1) was significantly reduced in the EMRR CSF but not in the NMO CSF (Mandler RN, Dencoff JD, Midani F, Ford CC, Ahmed W, Rosenberg GA. Matrix Metalloproteinases and tissues inhibitors of metalloproteinases n cerebrospinal fluid differ in multiple sclerosis and Devic's optic neuromyelitis. (2001) Brain 124: 493-498). These biochemical differences in the CSF may be well related to differences in the inflammatory tissue reaction in MS and NMO of Devic. However, due to the complete spectrum of the pathology of MS, including, the optic-spinal disease, it can be reproduced in the MOG-induced EAE rat model using the same MOG antigen but with different sensitization regimes and strains (Storch MK, Stefferl A, Brehm U, Weissert R, Wallstrom E, Kerschensteiner M ₁ et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. (1998) Brain Pathol; 8: 681-94), it is unclear whether The NMO is pathogenetically different from the MS or if it is a greater reflection of immunogenetically different hosts where environmental factors influence.

NMO is an invalidating and aggressive inflammatory demyelinating disease where no effective treatment for this disease has been found.

All therapeutic recommendations represent anecdotal experiences of a small series of uncontrolled cases. In the single-phase form of NMO and by the index of events and crises in the recurrent NMO, the main stage in therapy is the treatment of acute attacks, medical prevention of complications and rehabilitation.

Most patients with NMO with exacerbations receive intravenous corticosteroid therapy, for example, 1000 mg of methylprepnisolone (MP) per day for 5 consecutive days. Plasmapheresis has been reported beneficial in the management of acute crises of patients with NMO with or without associated connective tissue disorders (Konttinen YT, Kinnunen E, von Bonsdorff M, Lillqvist P, lmmonen I, Bergroth V, et al. Acute transverse myelopathy successfully treated with plasmapheresis and prednisone ¡na patient with primary Sjodren's syndrome. (1987) Arthritis Rheum 30: 339-44; Fletchner KM, Baum K. Mixed connective tissue disease: recurrent episodes oh optic neuropathy and transverse myelopathy. Successful treatment with plamapheresis. (1994) J Neurol Sci 126: 146-8; Weinshenker BG, O'Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Didick DW, et al. A randomized trial of plasma exchangein acute central nervous system inflammatory demyelinating disease (1999) Ann Neurol 46: 878-86; Biliciler S ₁ Uygucgil H, Saip S, Altintas A, Soysal T, Ozdemir SE, et al. Plasmapheresis in multiple sclerosis patients with diíferent indications (2001) MuIt Scler 7 Suppl 1: S64). Plasmapheresis reduces the number of circulating autoantibodies and immune complexes (Clark WF, Dan PC, Euler HH ₁ Guillevin L, Harstord J, Heer AH, et al. Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: desing of the LPSG trial (1991) J Clin Apheresis 6: 40-7J Which may explain some improvement in some NMO patients Intravenous immunoglobulin has also been used anecdotally Preventive therapy is required for patients with recurrent disease. NMO patients in North America receive treatment with

Parenteral beta interferon but based on the fact that there is no controlled experience, they believe that this treatment is ineffective.

In the only prospective treatment study published. Mandler et al found that 7 newly diagnosed NMO patients were stabilized for at least 18 months with an oral Azathioprine and Prepnisone regimen (Mandler RN, Ahmed W, Dencoff JE. Devic's optic neuromyelitis: a prospective study of seven patients treated with prednisone and azathioprine . (1998) Neurology 51: 1219-20). There is evidence to suggest a beneficial effect of type I IFNs in the NMO. Type I IFNs have a potent antiviral effect, they are induced after the cells are infected by viruses, causing the synthesis of a large number of enzymes such as 2.5'oligoadenylate synthetase that interferes with RNA or DNA viral replication. This early (non-specific antigen) response is critical to limit the spread of the viral spectrum before the antigen-specific response can completely control the infection. There is evidence for a strong association of NMO followed by a viral infection, mononucleosis (Williamson PM. Optical neuromyelitis following infectious mononucleosis. (1975) Proc Aust Assoc Neurol 12: 153-155), chickenpox zoster (Doutlik S, Sblova O, Kryl R, Novak M. (Optical neuromyelitis as a parainfectious complication of varicella). (1975) Cesk Neurol Neurochir 38: 238-242), HIV-1 infections (Blanche P, Diaz E, Gombert B, Sicard D, Rivoal O, Brezin A. Devic's optic neuromyelitis and HIV-1 infection (2000) J Neurol Neurosurg Psychiatry 68: 795-796), where the symptoms and signs of NMO they were separated by days or weeks of the viral infection by which it is compressible to associate it with a possible infectious etiology and a possible therapeutic with a drug with antiviral properties. On the other hand, it is reported that IFN alpha synergizes with IL-10 to induce differentiation to regulatory T cells (Tr1), suggesting that via the production of large amounts of IFN alpha, dendritic cells 2 (DC2) can be critical for induction of Tr1 in vivo, therefore, under a viral infection, DC2 cells can simultaneously alert the innate and adaptive immune response to produce type I IFNs (Roncarolo MG ₁ Levings MK ₁ Traversari C. Differentiation of T Regulatory cells by immature dendritic cells. (2001) J Exp Med 193: F5-F9).

Although there are conflicting reports that question the Th1 / Th2 paradigm, recent evidence suggests that IFN alpha in humans can directly induce a Th 1 I cell differentiation which would be beneficial in NMO characterized by a Th2 response, which constitutes an additional element that justifies The rationality of the use of interferon alfa in obtaining a pharmaceutical compound for the treatment of optic neuromyelitis. When T lymphocytes were cultured in the presence of IFN-alpha and cloned (Parronchi P, De Carli M, Manetti R, Simonelli C, Sampognaro S, Piccini MP, Macchia D, Maggi E, Del Prate G, Romagnani S. IL-4 and IFN alfa and IFN gamma exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. (1992) J Immunol 149: 2977-2983) or directly stimulated (Brinkmann V, Geiger T, Alkan S, Heusser Interferon alpha increases the frequency of IFN gamma-producing CD4 + T cells. (1993) J Exp Med 178: 1655-1663) via the TCR / CD3 complex, the proportion of IFN gamma producing cells (Th1 type cells) increased. In addition, it was demonstrated that the addition of IFN alpha to human umbilical cord leukocytes stimulated under Th2 inducing conditions (IL-4 and anti-IL-12 monoclonal antibody) resulted in the development of IFN gamma-producing Th1 cells (Rogge L, Barberis- Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F. Selective expression of an interleukin-12 receptor component by human T helper 1 cells. (1997) J Exp Med 185: 825-832). Type I IFNs act directly on virgin cells inducing Th1 differentiation of CD45RA + cells stimulated with anti-CD3 (Rogge L ₁ D'Ambrosio D ₁ Biffi M ₁ Penna G, Minetti LJ, Presky DH, Adorini L, Sinigaglia F. The role of stat4 in species-specific regulation of Th cell development by type I IFNs. (1998) J Immunol 161: 12: 6567-6574). There is evidence in vivo that the administration of type I IFNs can favor the development of human Th 1 cells. IFN gamma producing cells of patients with MS increase in number when patients are treated with IFN beta (Dayal A, Jensen MA, Lledo A, Arnason BGW. Interferon-gamma-secreting cells in multiple sclerosis patients treated with interferon beta -1b. (1995) Neurology 45: 2173-2177). Therapy with recombinant IFN alpha has been used in diseases considered to be mainly mediated by the over-expression of Th2 cytokines such as hlpereosinophilic syndrome (Zielinskl RM, Lawrence WD. Interferon alpha for the hyper-eosinophilic syndrome. (1990) Ann Int Med 113: 716-718; Butterfield JH, Gleich GJ. Interferon alpha treatment of 6 patients with the idiopathic hypereosinophilic syndrome. (1994) Ann Int Med 121: 648-653) and atopic dermatitis (Mackie RM. Interferon alpha for atopic dermatitis. ( 1990) Lancet 335: 1282-1283). IFN alpha induces activation of Stat4 and therefore Th1 response (Cho SS, Bacon CM ₁ Sudarshan C, Rees RC, Finbloom D, Pine R, O'Shea JJ. Activation of Stat4 by IL-12 and IFN alpha. Evidence for the involvement of ligand-induced tyrosine and serine phosphorilation. (1996) J Immunol 157: 4781-4789). In the pathogenesis of the NMO as in the case of MS, demyelination plays an important pathological role and it has been observed that gamma IFN is not involved in demyelination. IFN alpha has been shown to induce gamma IFN. In IFN gamma knockout mice, an increase in inflammation and demyelination has been observed (Tran EH, Prince EN, Owens T. IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines. (2000) J Immunol 164 : 2759-2768) suggesting that an independent IFN gamma pathway is the one that mediates the destruction of myelin. IFN gamma prevents the accumulation of neutrophils in the CNS of patients with NMO. Two recent reports (Tran EH, Prince EN, Owens T. IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines. (2000) J Immunol 164: 2759-2768; Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA. IFN-gamma plays a critical down- regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. (1996) J Immunol 157: 3223-3227) have shown that large numbers of neutrophils accumulate in the IFN gamma_nockout mice or their receptor and that these mice express chemokines in the CNS that attract neutrophils. According to the arguments expressed above, the use of a pharmaceutical compound characterized by containing components with remyelinating, immunomodulating and / or inducing regulatory T cell activity would be helpful for the treatment of the NMO. Another protein whose properties could explain a beneficial action in the CNS is Erythropoietin (EPO), the observation that EPO and its receptor are expressed in the brain tissue of humans and rodents (Juul, SE, Anderson, DK, Li , Y. & Christensen, RD (1998) Pediatr. Res. 43, 40-49; Marti, HH, Wenger, RH, Rivas, L A., Straumann, U., Digicaylioglu, M., Henn, V., Yonekawa , Y., Bauer, C. & Gassmann, M. (1996) Eur. J. Neurosci. 8, 666-676; Sirén, A.-L, Knerlich, F., Poser, W., Gleiter, C, Brück , W. & Ehrenreich, H. (2001) Acta Neuropathol) as well as by neuronal cultures (Morishita, E., Masuda, S., Nagao, M., Yasuda, Y. & Sasaki, R. (1997) Neuroscience 76, 105-116; Konishi, Y., Chui, DH, Hirose, H., Kunishita, T. & Tabira, T. (1993) Brain Res. 609, 29-35; Lewczuk, P., Hasselblatt, M., Kamrowski -Kruck, H., Heyer, A., Unzicker, C, Siren, AL & Ehrenreich, H. (2000) NeuroReport 11, 3485-3488) and astrocytes (Lewczuk, P., Hasselblatt, M., Kamrowski-Kruck, H., Heyer, A., A zicker, C, Siren, AL & Ehrenreich, H. (2000) NeuroReport 11, 3485-3488; Marti, HH, Wenger, RH, Rivas, LA, Straumann, U., Digicaylioglu, M., Henn, V., Yonekawa, Y., Bauer, C. & Gassmann, M. (1996) Eur. J. Neurosci. 8, 666-676) and which has effects on neurons (Konishi, Y., Chui, DH, Hirose, H., Kunishita, T. & Tabira, T. (1993) Brain Res. 609, 29-35) expanding its biological effects beyond that hematopoiesis could explain some of its benefits taking into account the pathogenesis of NMO. The neutral protective effect has been well documented in cell cultures (Bemaudin, M., Bellail, A., Marti, HH, Yvon, A., Vivien, D., Duchatelle, I., Mackenzie, ET & Petit, E. (2000 ) GHa 30, 271-278; Lewczuk, P., Hasselblatt, M., Kamrowski-Kruck, H., Heyer, A., Unzicker, C, Siren, AL & Ehrenreich, H. (2000) NeuroReport 11, 3485- 3488; Morishita, E., Masuda, S., Nagao, M., Yasuda, Y. & Sasaki, R. (1997) Neuroscience 76, 105-116) and in rodent infarction models (Bernaudin, M., Marti , HH, Roussel, S., Divoux, D., Nouvelot, A., MacKenzie, ET & Petit, E. (1999) J. Cereb. Blood Flow Metab. 19, 643-651; Brines, ML, Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N. C ₁ Cerami, C ₁ Itri, LM & Cerami, A. (2000) Proc. Nati Acad. Sci. USA 97, 10526-10531; Sadamoto, Y., Igase, K., Sakanaka, M., Sato, K., Otsuka, H., Sakaki, S., Masuda, S. & Sasaki, R. (1998) Biochem. Biophys Res. Commun. 253, 26-32; Sakanaka, M., Wen, T. C ₁ Matsuda, S., Masuda, S., Morishita, E., Nagao, M. & Sasaki, R. (1998) Proc. Nati Acad. Sci. USA 95, 4635-4640). There is evidence that signaling cascades that have been well characterized in hematopoietic cell lines (IhIe, JN (1995) Nature (London) 377, 591-594) are functional in neurons and can be modulated by EPO. The anti-apoptotic effect of BDNF where the signaling cascades referred to above are involved (Hetmán, M., Kanning, K., Cavanaugh, JE & Xia, Z. (1999) J. Biol. Chem. 274, 22569-22580) . Antioxidant effects (Chattopadhyay, A., Choudhury, TD, Bandyopadhyay, D. & Datta, AG (2000) Biochem. Pharmacol. 59, 419-425), angiogenic (Ribatti, D., Presta, M., Vacca, A ., Ria, R., Giuliani, R., Dell'Era, P., Nico, B., Roncali, L. & Dammacco, F. (1999) Blood 93, 2627-2636) and neurotrophic (Campana, WM, Misasi, R. &O'Brien, JS (1998) Int. J. Mol. Med. 1, 235-241) emphasize the regenerative potential of this molecule, in addition to the neuroprotective effect. The anti-inflammatory effect since it reduces the inflammatory infiltrate induced by cortical trauma in mice and improves EAE by what is considered an anti-inflammatory cytokine: A direct anti-inflammatory effect of EPO at the cytokine level cannot be excluded since EPO has been reported to decrease ex vivo production of TNF-alpha and increases the production of IL-10 in cell culture of hemodialyzed patients (Bryl, E., Mysliwska, J., Debska-Slizien, A., Rachon, D., Bullo, B., Lizakowski, S., Mysliwski, A. & Rutkowski, B. (1998) Artif. Organs 22, 177-181). An EPO has been associated with an immunomodulatory effect by demonstrating that it delays the increase in TNF-alpha levels and decreases IL-6 levels in an EAE model in Lewis rats (Agnello D., Bigini P, Villa P, Mennini T, Cerami A, Brines ML, Ghezzi P (2002) Brain Research 952, 128-134). EPO directly affects neuronal excitability in this way can also limit neuronal necrosis (Brines, ML, Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N. C ₁ Cerami, C, Itri, LM & Cerami, A. (2000) Proc. Nati Acad. Sci. USA 97, 10526-10531). It has a cytoprotective effect since different groups have shown that EPO protects neuronal cultures against glutamate toxicity (Bernaudin, M., Bellail, A., Marti, HH, Yvon, A., Vivien, D., Duchatelle, I., Mackenzie, ET & Petit, E. (2000) Glia 30, 271-278; Morishita, E., Masuda, S., Nagao, M., Yasuda, Y. & Sasaki, R. (1997) Neuroscience 76, 105- 116) and reduces ischemic neuronal damage and neurological dysfunction in rodent infarction models (Morishita, E., Masuda, S., Nagao, M., Yasuda, Y. & Sasaki, R. (1997) Neuroscience 76, 105 -116; Bernaudin, M., Marti, HH, Roussel, S., Divoux, D., Nouvelot, A., MacKenzie, ET & Petit, E. (1999) J. Cereb. Blood Flow Metab. 19, 643- 651; Brines, ML, Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N. C ₁ Cerami, C ₁ Itri, LM & Cerami, A. (2000) Proc. Nati. Acad. Sci USA 97, 10526-10531). Systemically administered EPO crosses the BHE (Cerami A, Brines ML, Ghezzi P, Cerami CJ. Effects of epoetin alfa on central nervous system. Semin Oncol 2001 Apr; 28 (2 Suppl 8): 66-70).

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes the use of interferon alfa for obtaining a pharmaceutical compound that contains more specifically, recombinant interferon alfa 2b, useful in the treatment of patients with NMO, a disease for which an effective treatment has not been described so far.

In a particular embodiment, said compound was used at therapeutic doses of 3 and 10 million Ul, twice a week.

The immunomodulatory, antiviral, remyelinating and inducing properties of regulatory T cells of the pharmaceutical compound of the present invention justify its effectiveness in the NMO.

The results obtained in our invention suggest that IFN alpha in humans can directly induce a Th1 cell differentiation endorsing its immunomodulatory effect, since in the majority of patients treated with the pharmaceutical compound an increase in IFN gene expression was observed. gamma and a decrease in IL-4, which would be beneficial in NMO characterized by a Th2 response. It has been shown that IFN alpha induces gamma IFN, which is corroborated in another embodiment of our invention, but the demyelination observed in the NMO does not involve gamma IFN, suggesting the participation of an independent path to gamma IFN, in fact, In our invention we find high levels after the CNTF recombinant IFN alpha 2b therapy, remyelination marker, which supports the remyelinating effect of the pharmaceutical compound.

In our invention, a greater number of patients are described where there was an increase in natural and induced regulatory (CD25 and Foxp3) T-cell markers (IL-10 and TGF-β) after treatment with recombinant IFN alpha 2b, effect of IFN alpha that had not previously been demonstrated in the absence of synergism with another molecule.

These properties of the pharmaceutical compound justify its therapeutic capabilities in NMO. Most therapeutic recommendations for NMO represent anecdotal experiences of a small uncontrolled case series, reports of use of IFN beta in NMO are not very encouraging, for example, Mirsattari et al, 2001 reported a simple case of autopsy, characterized by Eosinophilic necrosis and infiltrate within the spinal cord injury, which they attributed to chronic treatment with IFN beta. Recently the group of Saida et al, 2005 reported a study with IFN beta with some favorable results but it has the disadvantage that it is not a double blind study like the one referred to in our invention.

The differences between some biological activities of the alpha and beta IFNs, as well as the divergences from the etiopathogenic point of view between the NMO and the MS, refute the fact that the demonstration of the effect of the IFN beta makes the therapeutic effect of the IFN alpha obvious Which should be demonstrated as we have described in our invention.

Our invention is the fact that it is a double-blind, randomized and placebo-controlled clinical trial where it is demonstrated that IFN alfa2brec achieves the reduction of outbreaks and the frequency of relapses in patients with recurrent NMO.

The invention also includes pharmaceutical compositions comprising the combination with Erythropoietin (EPO rec). In our invention, the combination of IFN alfa2brec with EPO rea, showed a decrease in the degree of cerebral atrophy, as well as positively modified molecular markers involved in the pathogenesis of the disease. In our invention, the combination showed a synergistic effect between IFN alfa2brec and EPO rec. in relation to immunomodulatory events and inducers of regulatory T cells, reflected by the proportion of patients who raised the levels of expression CD25, Foxp3, IL-10 and TGF-β demonstrating improvement of the autoimmune context that characterizes the disease, on the other hand, Ia combination was shown to be useful in accelerating neurogenesis processes through its neurotrophic, anti-apoptotic and remyelinating properties, reflected in the synergistic effect of the 2 components of the combination with respect to the independent principles on the increase of the anti-apoptotic marker or BDNF and the remyelination marker CNTF. The pharmaceutical compound referred to in our invention for the treatment of NMO is characterized in that it contains interferon alfa that can be modified by peguylation or fusion to other proteins while maintaining the activities referred to above.

The therapeutic administration of interferon alfa 2b or of the combination IFN alfa with EPO requires repeated administrations. According to what is described in the present invention, both the pharmaceutical compound containing IFN alpha alone or modified by peeling, independently or as part of pharmaceutical compositions that combine it with Growth Factors such as Erythropoietin, could be administered intramuscularly, intravenously , subcutaneous, oral, nasal and intrathecal.

EXAMPLES

Example 1: Characteristics of the compound.

It is a pharmaceutical compound containing recombinant Interferon alpha 2b produced in Escherichia CoIi, where the characteristics of the final formulation are set forth in Table 1.1, said compound can also be modified by adding Polyethylene Glycol (PEG-IFN) Table 1.2 and can contain growth factors such as recombinant erythropoietin produced in CHO cells (chinesse hamster ovary cells), whose characteristics of the final formulation are set forth in Table 1.3. Table 1.1

Recombinant interferon alpha 2b

Each vial contains recombinant Interferon alfa 2b in a range between 3 and 10 x10 ⁶ Ul, 10 mg benzyl alcohol, 0.2mg polysorbate 80, 4.67mg NaCL, 2.96mg NaH ₂ PO ₄ ^ H ₂ O, 14.41 mg Na ₂ HPO ₄ .2H ₂ O and water for injection to complete 1 mL

Table 1.2

PEG-IFN

Each vial contains recombinant PEG-I interferon alfa 2b in a range between 180 and 360 μg, 2,617 mg tri-hydrated sodium acetate, 8 mg NaCL, 10 mg benzyl alcohol, 0.05 mg polysorbate and water for injection at complete 1 mL.

Table 1.3

Recombinant interferon alfa 2b + recombinant Erythropoietin

Each vial contains recombinant Interferon alfa 2b in a range between 3 and 10 x10 ⁶ Ul, recombinant Erythropoietin 2000 Ul, 10 mg benzyl alcohol, 0.2mg polysorbate 80, 4.67mg NaCL, 2.96mg NaH ₂ PO ₄ .2H ₂ O, 14.41 mg Na ₂ HPO ₄ .2H ₂ O and water for injection to complete 1 mL

Example 2: Characteristics of the sample evaluated. Evaluation of the therapeutic effect of IFN α2b rec in NMO.

To evaluate the therapeutic effect of IFN α2brec, a randomized, double-blind, placebo-controlled Phase III Clinical Trial was carried out that included 18 patients presenting with the recurrent form of NMO according to the criteria of Wingerchuck et al. Patients received randomized placebo, IFN α2brec 3 million and 10 million administered intramuscularly, twice a week for 2 years. The clinical evaluation was carried out through the Scripps and EDSS Scales, making the evaluation of the proportion of outbreak-free patients and the comparison of the number of outbreaks between patients under treatment and the same patients the 2 years prior to the start of treatment. As shown in Table 2, the sample was homogeneous in terms of age, sex and race. The fact that all patients were female (100% in each group) is in accordance with the reports in the literature that report a higher incidence of NMO in women. In addition, the uniform distribution of the different racial groups in the sample demonstrating a predominance of the disease in non-white races (75% in the placebo, 62.5% in the IFN α2brec 3 million group and 50% in the IFN α2brec group 10 million) also agrees with the literature reports in this regard. Table 2. Homogeneity of the sample studied.

Example 3: Evaluation of the evolution of the outbreaks.

Outbreaks were considered as worsening and / or the appearance of new symptoms and / or neurological signs that persisted for more than 24 hours. The proportion of patients from the different groups (placebo, IFN α2brec 3 and 10 million) who had outbreaks for 2 years was measured.

Two evaluations were performed (per year and 2 years of treatment) and compared with the number of outbreaks that the patients presented the 2 years prior to treatment. As observed in Table 3, the results show that 66.7% of the patients treated with IFN α2brec 10 million were free of outbreaks during the 2 years evaluated. A statistically significant difference was found between the total number of outbreaks of patients receiving placebo and those treated with IFN α2brec (p = 0.013) with respect to the number of outbreaks that had the previous 2 years, stratifying, this difference was observed between the group placebo and the group treated with IFN α2brec 10 million (p = 0.026).

Table 3. Effect of the treatment with IFN α2brec on the evolution of the number of outbreaks in patients with NMO.

Example 4: Characteristics of the sample evaluated. Evaluation of the therapeutic effect of the IFN α2brec / EPO combination in NMO.

To evaluate the therapeutic effect of the IFN α2brec / EPO combination, 9 patients with NMO were selected according to the criteria of Wingerchuck et al., 3 were treated with IFN α2brec, 3 with rec EPO and 3 with the IFN α2brec / EPO combination.

The 3 patients in the first group received IFN α2brec 3 million IM twice a week, the 3 in the second group received EPO rec SC 500U / kg twice a week and 3 in the third group, both treatments combined at the doses referred to above for a period of 1 year. The clinical evaluation was performed at 6 months and 1 year of NMR treatment to measure the evolution of cerebral atrophy. At the beginning and after one year with the different treatments, molecular determinations were made at the level of RNA and protein that included: Determination by RT-PCR in mononuclear cells isolated from peripheral blood of the gene expression for the CCR3 chemokine receptor, cationic protein of eosinophils, CD25, Foxp3, IFN gamma, IL-10 and TGF-beta and determination of serum concentrations of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) by ELISA.

Table 4 shows the characteristics of the patients evaluated. The sample was homogeneous in terms of age, sex and race. The majority of the patients were female and the black race, which is consistent with the literature reports for this disease. Table 4. Homogeneity of the sample studied.

Example 5: Effect of the treatment with the IFN α2brec / EPO combination on cerebral atrophy.

To measure the degree of cerebral atrophy, T1 measurements of the degree of cerebral atrophy were performed by NMR at 6 months and 1 year of treatment. The results are reflected as the% of patients in whom there was a decrease in cerebral atrophy at the time of the evaluation with respect to the onset.

Table 5 shows the result of the evaluation of cerebral atrophy in patients treated with IFN α2brec, EPO rec and the IFN α2brec / EPO combination. As can be seen, the IFN α2brec / EPO combination reduced the degree of cerebral atrophy in 66.6% of patients a year of treatment, demonstrating a greater effect than with independent treatments.

Table 5. Evaluation of the degree of cerebral atrophy in patients with NMO.

Example 6: Modulation of genes involved in the pathogenesis of the NMO.

The evaluation by RT-PCR of the modulation of different genes involved in the pathogenesis of the NMO was performed one year after treatment with IFN α2brec, EPO rec and the IFN α2brec / EPO combination in the patients. The results are reflected as% of patients in whom the relative levels of the evaluated gene increase / decrease with respect to the expression of a constitutive gene.

Table 6 shows the results where it is valid to highlight that in 100% of the patients treated with the IFN α2brec / EPO combination, the expression of CCR3, a chemokine receptor that is expressed exclusively in eosinophils, decreased in accordance with this result also it was found that in the majority of patients treated with the combination the expression of the gene corresponding to the cationic eosinophilic protein decreased, which seems to indicate that the IFN α2brec / EPO combination can have an effect both on the decrease of the characteristic eosinophilic infiltrate of this disease as in the decrease of the degranulation of these cells where one of the fundamental components of these granules is precisely the cationic protein of eosinophils. On the other hand, it is our attention that the treatment with the combination caused an increase in the expression of the IL-10 and TGF-beta gene and may indicate the participation of a mechanism of induced regulatory T cells. A significant fact is that 100% of the patients treated with the combination have an increase in the expression of CD25 and the Foxp3 transcriptional factor, which may indicate the participation of natural regulatory cells. Another relevant data obtained constitutes that 66.6% of the patients present an increase in the levels of IFN gamma, cytokine TH 1 which is beneficial in this disease that when characterized by a TH2 predominance, a polarization of the response to TH 1 would result beneficial

Table 6, Effect of the different treatments and the IFN α2brec / EPO combination on the modulation of some genes involved in the pathogenesis of the NMO.

Example 7: Evaluation of anti-apoptotic (BDNF) and remyelinating (CNTF) factors in patients with NMO treated with independent treatments and the IFN α2brec / EPO combination.

ELISA measurements of anti-apoptotic (BDNF) and remyelinating (CNTF) factors were performed in the serum of patients with NMO at one year of treatment with IFN α2brec, EPO rec and the IFN α2brec / EPO combination. The results are expressed as% of patients in whom the serum concentrations of both factors increased / decreased at one year of treatment with respect to the values before starting treatment. The results are reflected in Table 7, observing how for both factors an increase in the concentrations of these factors is observed with the treatment with the combination that speaks in favor of the anti-apoptotic and remyelinating effect of this molecule.

Table 7. Effect of independent treatments and the IFN α2brec / EPO combination on BDNF and CNTF in patients with NMO.

Claims

REDEMPTIONS

1- Use of interferon alfa to obtain a pharmaceutical compound for the treatment of optic neuromyelitis.

2- Use according to claim 1, characterized in that the interferon is interferon alfa 2b.

3- Use according to claims 1 and 2, characterized in that the interferon is in the compound at a concentration between 3-10 million Ul.

4- Use according to claims 1, 2 and 3, characterized in that the interferon can be modified by peguylation or fusion to other proteins.

5- Use according to claims 1, 2, 3 and 4, characterized in that components with remyelinating, immunomodulating and / or inducing activity of regulatory T cells are co-administered.

6- Use according to the preceding claims, characterized in that co-administration Erythropoietin.

7- Use according to claims 1, 2, 3, 4, 5 and 6 characterized in that the pharmaceutical compound is administered intramuscularly, intravenously, subcutaneously, orally, nasally and intrathecally.

8- Pharmaceutical compound for the treatment of optic neuromyelitis according to claim 1, characterized in that it contains interferon alfa.