THE METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS
|発明の名称 （英語）||THE METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS|
|発明の概要（英語）||Problem: An object of the present invention is to provide a drug effective for the treatment of ALS, or a method for treating ALS. Solution: The present invention provides an ALS treatment method that improves clinical symptoms of ALS or suppresses the progression of ALS by administering an anti-TNFalfa monoclonal antibody to an ALS patient; an anti-ALS drug containing an anti-TNFalfa monoclonal antibody; an anti-TNFalfa monoclonal antibody for use as an anti-ALS drug; and use of an anti-TNFalfa monoclonal antibody for the treatment of ALS and for the manufacture of a medicament.|
ALS is a rapidly progressive disease that shows symptoms such as muscle atrophy and muscle weakness. About 3 to 5 years after the onset of ALS, the symptoms occur in the
respiratory muscles, causing death due to respiratory failure, unless a mechanical ventilation system is provided. Muscle atrophy seen in ALS patients characteristically shows abnormal excitation (muscle spasticity or fasciculation) of muscles and motor neurons. Further, ALS patients are characteristically free from the following symptoms: atrophy of the muscles controlled by sensory nerves, autonomic nerves, and the like; abnormality in eye movement; and disorder in the functions of rectum, bladder, and the like.
According to the epidemiological investigation, there is no significant difference in the incidence of ALS among ethnic groups. The annual incidence of ALS is known to be about two per 100,000 people. Further, although some patients develop ALS in their teens, the peak age of onset of ALS is 40 to 69. Among ALS patients, about 5 to 10% are patients with familial ALS, and the remaining majority of patients have sporadic ALS.
Among familial ALS patients, 20 to 30% of the patients carry a point mutation of superoxide dismutase 1 (SODl) gene. It has been clear that SODl transgenic mice present a phenotype in which motor neurons are altered (NPL 1). The death of motor neurons is not recognized in SODl knockout mice .
Based on such findings, clinical conditions of motor neurons of ALS patients have been examined. Release of a
significant amount of glutamic acid, which is considered to be a possible cause of muscle spasticity, is identified in motor neurons of patients with early ALS. Based on such a finding, an anti-ALS drug that prevents the death of motor neurons has been developed. Specifically, a drug that inhibits the action of glutamic acid on motor neurons has been developed. Specific examples include Rilutek (registered trademark, Aventis Pharma) that works as a glutamic acid release inhibitor, and the like. There is also a method, as one of the ALS treatment methods, in which a large amount of methylcobalamin (a vitamin B12
derivative) is administered to an ALS patient. However, these drugs, and a treatment method that administers these drugs, are not considered to sufficiently and effectively treat ALS.
As shown in NPL 2, the present inventors found, in a patient with familial ALS, a mutation of optineurin (OPTN) gene that inhibits NFKB function, which has an important role in nerve cell death. It has been also reported that a significant amount of OPTN is accumulated in motor neurons of patients with sporadic ALS. The present inventors also found that the accumulation of mutant OPTN in motor neurons is induced by overexpression of mutant OPTN by activated NFKB. Therefore, it was found that while wild-type OPTN can inhibit NFKB function, mutant OPTN found in ALS patients does not have the ability to inhibit NFKB function. This suggested that inhibition of activation of NFKB function would lead to an ALS treatment.
Conventionally, inhibitors of NFKB function have been used in ALS patients. However, among NFKB inhibitors,
immunosuppressive drugs such as steroids have been reported to be ineffective (NPL 3). Thalidomide is one such steroid.
Thalidomide was effective in SOD1 transgenic mice, but not in ALS patients (NPL 4). It has also been reported that simply knocking out the TNF locus of SOD1 transgenic mice does not show a
treatment effect in ALS (NPL 5). Citation List
PTL 1: Patent No. 3861118
PTL 2: Patent No. 4404181
NPL 1: Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY,
Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. , "Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation". Science, 1994 Jun 17; 264 (5166): 1772-5.
NPL 2: Maruyama H, Morino H, Ito H, Izumi Y, Kato H, atanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure 0, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H, "Mutations of optineurin in amyotrophic lateral sclerosis," Nature; 465: 223-226.
NPL 3: Tan E, Lynn DJ, Amato AA, Kissel JT, Rammohan KW, Sahenk Z, Warmolts JR, Jackson CE, Barohn RJ, Mendell JR,
"Immunosuppressive treatment of motor neuron syndromes: Attempts to distinguish a treatable disorder," Arch Neurol, 1994
NPL 4: Stommel EW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, Mackenzie T, Channon Smith JY, Harris BT, "Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial," Amyotroph Lateral Scler. , 2009 Oct-Dec; 10 (5-6): 393-404.
NPL 5: Gowing et al, "Absence of tumor necrosis factor-alpha does not affect motor neuron disease caused by superoxide
dismutase 1 mutations," J Neuroscience, 2006 Vol. 26: 11397-11402 NPL 6: de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M. , "Electrodiagnostic criteria for diagnosis of ALS," Clin.
Neurophysiol 2008; 119: 497-503.
NPL 7: "Adult-onset primary open-angle glaucoma caused by mutations in optineurin," Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Science. 2002 Feb 8; 295(5557): 1077-9.
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
『 THE METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS 』に関するお問合せ
- 国立大学法人徳島大学 産学官連携推進部
- URL: http://www.tokushima-u.ac.jp/ccr/
- Address: 〒770-8506 徳島市南常三島町２丁目１番地
- TEL: 088-656-7592
- FAX: 088-656-7593