WO2002076492A1 - Nouveaux agents pour soigner les troubles moteur - Google Patents
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- WO2002076492A1 WO2002076492A1 PCT/JP2001/007525 JP0107525W WO02076492A1 WO 2002076492 A1 WO2002076492 A1 WO 2002076492A1 JP 0107525 W JP0107525 W JP 0107525W WO 02076492 A1 WO02076492 A1 WO 02076492A1
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- amino acid
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- selenoprotein
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a new use of plasma proteins belonging to the field of prescription pharmaceuticals. More specifically, neurodegeneration caused by cell death or cell degeneration of cells constituting the nervous system, such as aging, traumatic, cerebrovascular disorders, immunological disorders, ataxia, epilepsy, and motor neuron diseases. About pharmaceuticals. More specifically, a therapeutic agent for neurodegenerative diseases containing selenoprotein p, which is a kind of plasma protein, preferably a C-terminal peptide of the selenoprotein P or the peptide group as a main active ingredient, particularly movement disorders It relates to an improving agent.
- selenoprotein p which is a kind of plasma protein, preferably a C-terminal peptide of the selenoprotein P or the peptide group as a main active ingredient, particularly movement disorders It relates to an improving agent.
- Neurological diseases in which cell death or cell degeneration of cells that make up the nervous system are recognized. Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, multiple cerebral infarction dementia, Binswanger's leukoencephalopathy , Cerebrovascular disorders such as chronic subdural hematoma, autoimmune diseases such as multiple sclerosis, Guillain-Barre syndrome, collagen disease, spinocerebellar degeneration, Scheidrager syndrome, amyotrophic lateral sclerosis, Alzheimer's Neurodegenerative diseases such as sickness, Pick's disease, Huntington's chorea, Parkinson's disease, progressive supranuclear palsy, epilepsy, prion disease, and traumatic spinal cord caused by aging-related dementia, gait disorders, and traffic accidents Damage and brain damage are also known. In most of these diseases, the main symptom is decreased motor function (dyskinesia).
- Movement disorders include muscular disorders, nerve disorders, bone and joint disorders, etc.Of these, nervous central disorders causing movement disorders are classified and categorized according to site, cerebral (frontal lobe), cerebellum Gender, vestibular tract) and myelopathy.
- cerebral dyskinesia cerebral cortex, especially frontal lobe disorder, is considered, and cerebrovascular disorder is often a problem in lesions, cerebral atrophy, trauma, tumors, Pick's disease, and chronic subdural hematoma. It also shows ataxic gait as well as a decline in mental function.
- Cerebellar dysmotility is an important symptom associated with cerebellar disorders, i.e., cerebellar tumors, vascular disorders, degenerative diseases, cerebellar atrophy, malformations, etc.
- Obstacles of 'Kin Jin walking showing large walking, generally holding posture and posture Difficult to balance.
- hemispheric cerebellar disorders show abnormalities in the muscular tonus of the extremities, decreased muscle tone, eccentric walking toward the affected side, impaired coordination, false indications (finger-to-finger, finger-to-nose tests), and movement measurements
- it is accompanied by intentional tremor and cerebellar language (intermittent and explosive).
- Vestibular (maze) ataxia results from vestibular dysfunction and is often caused by the presence or sequelae of otological or inner ear disorders. Examples include Meniere's disease, sudden deafness, damage to the balance nerve due to addiction to drugs such as streptomycin and kanamycin, trauma, syphilis, acoustic trauma, otosclerosis, and otitis media (and their sequelae).
- Spinal dyskinesia which is also called retrograde ataxia, is a disorder of deep sensation caused by spinal cord injury, that is, ataxia caused by impaired position, joint, and grip. It is characteristically seen in Friedreich's ataxia, subacute spinal cord association degeneration, spinal cord phlegm, and others.
- the neurodegenerative diseases presenting with these movement disorders are closely related to neuronal cell death and cell degeneration.
- spinocerebellar degeneration Machado's Joseph's disease, Friedreich's ataxia, etc.
- polyglutamine disease found in myotonic dystrophy, etc. ⁇ hen 'I students are recognized.
- Exercise-two euron diseases such as amyotrophic lateral sclerosis, a typical example, include free radical generation, neuronal cell death due to excessive accumulation of glutamate, increased intracellular calcium ion concentration, and NO generation. It is considered the etiology.
- Parkinson's disease degeneration of dendritic dopaminergic neurons is considered to be the main lesion.
- Autoimmune diseases can cause movement disorders.
- the immune system originally exists as a biological defense mechanism against the invasion of harmful foreign substances from the outside world. However, sometimes the function of the immune system can be harmful to the living body. When this condition occurs, it is called an autoimmune disease.
- an autoimmune disease As a disease exhibiting dyskinesia due to this autoimmune reaction, myasthenia gravis, multiple sclerosis, rheumatoid arthritis and the like are known.
- the exemplified multiple sclerosis is a kind of demyelinating disease in which large and small demyelinating lesions are scattered in the white matter of the central nervous system, and the lesions are characterized by a variety of new and old lesions.
- the lesions are most commonly found in white matter around the lateral ventricles, optic nerve, brainstem, and spinal cord. Histologically, it is a disease in which the oligodendrocytes that form the myelin are damaged, and a large number of cells that have undergone apoptosis in the lesion are observed.
- the demyelinating lesion has inflammatory cell infiltration early, but in the chronic phase it is replaced by glial fibrils and hardens.
- Clinical symptoms are various combinations of symptoms such as optic neuritis, diplopia, oculomotor disorders such as nystagmus, spastic paralysis, painful tonic convulsive seizures, Lermit's syndrome, ataxia, speech disorders, and bladder rectal disorders. It is characterized in that it appears together and shows remission.
- the ischemic state of the brain caused by various factors such as cerebral infarction and intracerebral hemorrhage generally causes oxygen and hypoxia in cells and tissues in the ischemic region, resulting in oxygen deficiency.
- ATP production is disrupted through disruption of ATP production, eventually leading to degeneration, necrosis, or atrophy.
- a decrease in the supply of oxygen and glucose due to ischemia triggers the generation of free radicals, an excessive accumulation of glutamate, an increase in intracellular calcium ion concentration, an increase in NO production, and the like.
- Causing death This disorder is dependent on ischemia time, with longer ischemia times during reperfusion Disability also tends to worsen. As a result, motor function is also impaired due to nerve cell death and cell degeneration.
- neurodegenerative diseases presenting with movement disorders are considered to have a common etiology, such as neuronal death and cytodegeneration, although the types of the diseases are different. Therefore, a substance having an effect of suppressing or improving this nerve cell death or degeneration is considered to be a therapeutic drug for the above-mentioned neurodegenerative diseases, particularly, movement disorders. At present, various drugs are being tried to improve these symptoms.
- Examples include superoxide dismutase ⁇ catalase, glutathione peroxidase, and other substances that prevent and control oxidative disorders in many living organisms, trimetazidine hydrochloride, a therapeutic agent for ischemic heart disease that is actually used for treatment, and Ozadarel sodium, a mouthboxane synthase inhibitor, ifenprodil tartrate, a cerebral circulatory metabolism improver, and nizophenone fumarate, an ischemic encephalopathy improver, are also available. It cannot be suppressed.
- Parkinsonism such as hand tremors
- autonomic nervous symptoms such as orthostatic hypotension
- autonomic nervous modulating agents are used for autonomic nervous modulating agents. Therefore, in order to improve the dyskinesia caused by nerve cell death and cell degeneration, as described above, substances that suppress cell death and cell degeneration caused under adverse conditions for nerve cells, in particular, increase intracellular antioxidant capacity There is a long-awaited need for a substance to be used.
- selenoprotein P which is a protein derived from blood components
- C-terminal peptide of selenoprotein P Cell death inhibitory activity was found, and a patent application was filed based on this finding (PCT / JP99 / 063222).
- the inventors of the present application have conducted intensive studies to provide a new agent for improving a neurodegenerative disease, in particular, an agent for improving a movement disorder.
- the present invention relates to a dyskinetic agent comprising selenoproteins P and Z or a C-terminal peptide of the protein or the peptide group as a main component.
- the C-terminal peptide of the protein or the peptide group comprises a deletion, substitution or addition of one or several amino acids at the C-terminal 103 amino acid sequence of selenoprotein P.
- the C-terminal peptide or the peptide group of the protein is represented by the following formula:
- amino acid sequence represented by the following, the amino acid sequence in which one or several amino acids have been deleted, substituted or added, the partial sequence of any of the amino acid sequences, or the amino acid sequence of any one of the amino acid sequences Or a peptide group having an amino acid sequence contained in a part thereof.
- FIG. 1 is a graph showing the improvement effect of selenoprotein P on bilateral carotid artery blockade-induced dyskinesia in gerbils.
- FIG. 2 is a graph showing the effect of selenoprotein P on dyskinesia in mouse AE.
- FIG. 3 is a micrograph of cultured human neurons observed when selenoprotein P was added (SeP (+)) and when selenoprotein P was not added (SeP (-)). When selenoprotein P was added, projections were observed in cultured human neurons.
- selenium-containing protein was identified as a selenium-containing protein, and in 1982 it was revealed that selenium was incorporated in the form of selenocysteine. Furthermore, in 1991, cloning of the cDNA of selenoprotein P revealed the full-length amino acid sequence, which indicated that the protein could contain up to 10 selenocysteines. (Hill KE and Ourk RF, Biomed. Environ. Sci., 10, p. 198-208 (1997)). Although the function of selenoprotein P was almost unknown, recently, it was found that phospholipid hydroperoxide and peroxynitrite act in vitro and act as survival promoting factors for neurons in in vitro systems.
- the present invention relates to a new drug effect based on the above-mentioned findings of selenoprotein P, and the essential feature of the agent for improving neuropathy of the present invention is selenoprotein P. More specifically, selenocysteine, which contains selenium in selenoprotein P, is characterized by this amino acid, and is thought to be the central amino acid in improving neuropathy, especially movement disorders.
- the inventors of the present application have disclosed in a previous patent application that a cell death fragment of selenoprotein P, which is a protein derived from blood components, has a cell death inhibitory activity which has not been reported previously. It is clear that the contained selenocysteine is also involved in this activity. Therefore, proteins and / or peptides containing selenocysteine and having cell death inhibitory activity can be candidates for the dyskinetic ameliorating agent.
- selenium related to the present invention is one of the trace essential elements, and if it is deficient, severe deficiency accompanied by cardiomyopathy is known.
- selenium is essential for maintaining and proliferating at the cell level.
- the range of effective and dangerous doses that is, the concentration range of the safety zone is narrow, and selenium conjugates with an appropriate amount or more are generally used. Is toxic to cells and induces cell death. For example, selenium sudden and sexually toxic symptoms include facial pallor, neurological symptoms, neuropathy, dermatitis, and gastrointestinal disorders.
- the insects are quite toxic.
- the C-terminal fragment of selenoprotein or tin selenoprotein P which is a preferred embodiment of the present invention, has a strong poison despite its structure containing 9 to 10 selenocysteines. From the above, it is considered important that selenoprotein P exhibiting a medicinal effect according to the present invention contains selenocysteine and has reduced cathodotoxicity.
- the peptide or the peptide group of the present invention not only overcomes the selenium compound's proposition of reducing toxicity, but also makes it possible to bring about an unexpected improving effect on dyskinesia.
- selenoprotein P used here. Any molecule having a good activity is included. That is, various molecular forms such as complete molecular selenoprotein P can be targeted. Among them, a preferred embodiment is a peptide at the C-terminal side of selenoprotein P or the peptide group, and among them, 103 at the C-terminal side (from 260 to 362: 260Lys Arg Cyslie Asn Gin Leu Leu Cys Lys Leu Pro Thr Asp Ser Glu Leu Ala Pro
- the term "the peptide group” refers to a peptide derived from the amino acid sequence of selenoprotein P and containing at least one selenocystin, and one or several amino acids in the amino acid sequence. Means an aggregate of peptides having different microstructures due to the presence or absence of sugar chains, differences in charge, diversity of fragmentation, etc., including amino acid sequences that have been deleted, substituted or added. That is, the selenoprotein P and peptides of the present invention are derived from the amino acid sequence of selenoprotein P and have no particular restriction on the molecular form as long as they have cytotoxicity-inhibiting activity.
- Such a peptide of the present invention can be prepared according to a conventional method using a peptide synthesizer, and a peptide compound of the present invention can be used as a lead substance to design a synthetic compound. .
- the method for producing selenoprotein P or a peptide or peptide group derived from the protein used in the present invention is not particularly limited.For example, a method for separating human blood from human blood, or a method using genetic recombination technology Can be manufactured You.
- the protein or peptide or peptide group as an active ingredient can be combined with a suitable known excipient to obtain the dyskinetic agent of the present invention by a known method.
- the effective dose of the dyskinesia-improving agent of the present invention varies depending on the age, symptoms and severity of the administration subject, and ultimately varies according to the intention of the physician. Although the efficacy does not depend on the method of administration, it is optimal to administer it subcutaneously, intradermally, intraperitoneally, single intravenously (bolus) or intravenously. In the case of peptides having a small molecular weight, oral administration and transdermal administration are also possible.
- the subject to which the agent for improving a neurological disorder of the present invention is administered is not particularly limited as long as it is a disease that exhibits neurological symptoms due to nerve cell death or cell degeneration thereof, particularly a disease in which motor function is reduced.
- a drug containing the selenoprotein P of the present invention or a peptide or peptide group derived therefrom as a main component is used as an agent for improving a neurological disorder such as a movement disorder, the drug may be administered alone.
- co-administration with other therapeutic agents can also be expected as an effective means for increasing the effect.
- an effect can be expected in either prophylactic or therapeutic administration.
- the present invention provides an agent for improving a neuropathy suitable for a neurodegenerative disease caused by various etiologies, in particular, a disease having reduced motor function.
- the heparin-sepharose-bound fraction in plasma was precipitated with 2 M ammonium sulfate, and the precipitate was dissolved with 5 times or more of 2 OmM Tris (pH 8.0) with respect to the precipitated fraction.
- Selenoprotein P present in this solution was bound to the anti-SeP antibody column and washed with PBS. Thereafter, selenoprotein P was eluted with 20 mM citrate buffer containing 4 M urea, and bound to a cation exchanger (Macroprep High S: BioRad) equilibrated with 20 mM citrate buffer. This was subjected to salt concentration gradient elution with sodium chloride, and a fraction showing cell death inhibitory activity was collected.
- an Atsey medium (50% PBS / SA / 0.03% HSA (manufactured by SI GMA)) or SA / 0.05% defatty acid BSA (WAKO) / 4 M Long-chain polyvalent fatty acid (such as arachidonic acid, linoleic acid or linolenic acid) is washed twice to obtain 3 ⁇ 10 4
- the obtained cell suspension was dispensed into a 96-well 11 plate, with 200 1 only for the sample addition and 100 1 for the serial dilution.
- a peptide purified from the fragment in a reduced state (Lys Arg Cyslie Asn Gin Leu Leu Cys Lys Leu Pro Thr Asp Ser Glu Leu Ala Pro Arg Ser Xaa Cys Cys His Cys Arg His Leu lie Phe Glu Lys (SEQ ID NO: 4) was also confirmed to have cytotoxicity-suppressing activity, while selenocysteine-free peptide derived from selenoprotein P (Lys Arg Cys lie Asn Gin Leu Leu Cys Lys Leu Pro Thr Asp Ser Glu Leu Ala Pro Arg Ser) (SEQ ID NO: 5) was found to have no activity, indicating that selenocystine is important for -selenoprotein P activity.
- Klotho mouse is an aging model mouse created by Dr. Yoichi Nabeshima of Kyoto University graduate School of Medicine in 1997.It has an average lifespan of 60 days and its growth is delayed from around 20 days after birth. Nearly all cases die within 0 days.
- the tail is completely hanging
- the selenoprotein P administration group was found to have an effect of suppressing the onset of the disease and reducing the severity. Furthermore, comparing the incidence rate on day 10, 4 out of 13 selenoprotein P groups showed severe onset in the selenoprotein P administration group, although 12 out of 13 animals in the Saline group were affected. Not. This indicates that selenoprotein P has an inhibitory effect on the onset of immunological disorders and a reduction effect on motor disorders.
- Neurosci. Res. 35: 585-602 is a neural progenitor cell derived from human teratocarcinoma, and can be converted to hNT neurons that show the properties of central nervous system nerves by retinoic acid. (Trojanowski, JQ et al., 1993 Exp. Neurol. 122: 283-294). The effect of selenoprotein P on the projection formation of the hNT cells was examined.
- Both NT2 and hNT cells can be cultured in a CO 2 incubator at 37 ° C, and hNT cells were obtained by the following procedure. First, 10% FCS / D—MEM / F—1
- NT 2 cells that can be subcultured in 2 media are plated with 2.5 x 10 5 cells ml, and D—MEM / F-1 containing 10 M all trans retinoic acid after 24 B
- the medium was changed to 2 and induction was started. After that, the medium was changed every three days, and the cells were cultured for 6 weeks to differentiate NT2 cells into hNT cells. After collecting all the differentiated cells, the cells were subcultured three times in 10% FCS / D-MEM / F-12 medium. After 48 hours, plating was performed so that 3-4 ⁇ 10 6 cells Zm 1 were obtained.
- the medium was replaced with 5% FCS / D-MEMZF-12 plus mitotic inhibitor (10 ⁇ M Fluorodeoxyuridine, Uridine, 1 ⁇ cytosine arabinoside), and culturing was performed for 10 days while changing the medium every 3 days.
- mitotic inhibitor 10 ⁇ M Fluorodeoxyuridine, Uridine, 1 ⁇ cytosine arabinoside
- the released hNT neurons were recovered by light tapping.
- the recovered cells were suspended in a medium containing an equal volume of NT2 culture supernatant (10% FCS / D-MEM / F-12) and fresh 10% FCS / D-MEM / F-12, and then coated with Larainin. After plating on the plate, the cells were maintained.
- the hNT cells thus obtained were used for experiments.
- the obtained hNT cells were collected by trypsinization, washed with a basal medium mixed with RPMI 1640, D-MEM, F-12 at a ratio of 1: 2: 2, suspended in the same medium, and placed in a 96-well plate. Culture at 3000 cells / we11 killed completely on days 5-7. On the other hand, when selenoprotein P was added to 100 ng Zml, cell death was completely suppressed, and it was possible to maintain the cell death for 2 weeks or more. In addition, when the cell morphology was observed on the fourth day of culture, as shown in FIG. 3, the formation of projections was observed when selenoprotein P was added. This indicates that selenoprotein P has an effect on the formation of dendrites and axons of nerve cells.
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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EP01961246A EP1374887B1 (en) | 2001-03-23 | 2001-08-31 | Novel agents for ameliorating motor disorder |
DE60135501T DE60135501D1 (de) | 2001-03-23 | 2001-08-31 | Neue mittel zur linderung von motorischen störungen |
CA002441403A CA2441403A1 (en) | 2001-03-23 | 2001-08-31 | Novel agents for ameliorating motor disorder |
JP2002575005A JPWO2002076492A1 (ja) | 2001-03-23 | 2001-08-31 | 新規な運動障害改善剤 |
US10/472,444 US20050037954A1 (en) | 2001-03-23 | 2001-08-31 | Novel agents for ameliorating motor disorder |
US12/081,991 US7704951B2 (en) | 2001-03-23 | 2008-04-24 | Method for ameliorating dyskinesia |
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JP2001084050 | 2001-03-23 |
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US12/081,991 Division US7704951B2 (en) | 2001-03-23 | 2008-04-24 | Method for ameliorating dyskinesia |
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WO2004050114A1 (ja) * | 2002-11-29 | 2004-06-17 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | 新規な神経伝達機能異常疾患改善剤 |
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EP1386963A4 (en) * | 2001-05-11 | 2005-03-23 | Juridical Foundation | PEPTIDES WITH CYTOTOXICITY-RESTRICTIVE ACTIVITY AND METHOD FOR SCREENING THESE PEPTIDES WITH CYTOTOXICITY-HAZARDOUS ACTIVITY |
US20050143310A1 (en) * | 2001-05-11 | 2005-06-30 | Masaki Hirashima | Novel remedies for neurodegenerative disease |
US8754084B2 (en) | 2012-03-27 | 2014-06-17 | The Board Of Trustees Of The University Of Illinois | Therapeutic methods and agents for treating myotonic dystrophy |
US10266520B2 (en) | 2014-08-08 | 2019-04-23 | The Board Of Trustees Of The University Of Illinois | Bisamidinium-based inhibitors for the treatment of myotonic dystrophy |
CA2974988A1 (en) * | 2015-02-06 | 2016-08-11 | The Regents Of The University Of California | Methods and compositions for improved cognition |
US11078236B2 (en) | 2017-05-02 | 2021-08-03 | Burke Neurological Institute | Selenium-based therapies |
US11242326B2 (en) | 2017-08-25 | 2022-02-08 | The Board Of Trustees Of The University Of Illinois | Multivalent ligand for myotonic dystrophy |
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AT397200B (de) * | 1988-06-03 | 1994-02-25 | Birkmayer Joerg Ddr | Verwendung von selenmethionin zur herstellung eines arzneimittels |
EP1386963A4 (en) | 2001-05-11 | 2005-03-23 | Juridical Foundation | PEPTIDES WITH CYTOTOXICITY-RESTRICTIVE ACTIVITY AND METHOD FOR SCREENING THESE PEPTIDES WITH CYTOTOXICITY-HAZARDOUS ACTIVITY |
US20050143310A1 (en) | 2001-05-11 | 2005-06-30 | Masaki Hirashima | Novel remedies for neurodegenerative disease |
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Non-Patent Citations (3)
Title |
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J. YAN ET AL.: "Purification from bovine serum of a survival-promoting factor for cultured central neurons and its identification as selenoprotein-P", vol. 18, no. 21, 1998, pages 8682 - 8691, XP002906334 * |
V. MOSTERT: "Selenoprotein P: Properties, functions and regulation", vol. 376, no. 2, 2000, pages 433 - 438, XP002906333 * |
Y. SAITO ET AL.: "Selenoprotein P: Its structure and function", JOURNAL OF HEALTH SCIENCE, vol. 46, no. 6, 2000, pages 409 - 413, XP002906332 * |
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WO2004050114A1 (ja) * | 2002-11-29 | 2004-06-17 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | 新規な神経伝達機能異常疾患改善剤 |
JP2004182616A (ja) * | 2002-11-29 | 2004-07-02 | Chemo Sero Therapeut Res Inst | 新規な神経伝達機能異常疾患改善剤 |
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US7704951B2 (en) | 2010-04-27 |
ATE405286T1 (de) | 2008-09-15 |
EP1374887B1 (en) | 2008-08-20 |
EP1374887A1 (en) | 2004-01-02 |
CA2441403A1 (en) | 2002-10-03 |
US20050037954A1 (en) | 2005-02-17 |
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