DK1633189T3 - Trunkerede fragmenter af alfa-synuklein i lewy body-sygdom - Google Patents
Trunkerede fragmenter af alfa-synuklein i lewy body-sygdom Download PDFInfo
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- DK1633189T3 DK1633189T3 DK04776059.0T DK04776059T DK1633189T3 DK 1633189 T3 DK1633189 T3 DK 1633189T3 DK 04776059 T DK04776059 T DK 04776059T DK 1633189 T3 DK1633189 T3 DK 1633189T3
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Claims (23)
1. En in vitro-fremgangsmåde til screening af et middel der har farmakologisk aktivitet der er anvendelig til behandling af LBD omfattende: bringe midlet i kontakt med et fragment af alfa-synuklein der er til stede hos patienter med Lewy Body Disease som er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein; og bestemme raten eller graden af aggregation af fragmentet af alfa-synuklein, hvor en reduktion i raten eller graden af aggregation i forhold til en kontrol der mangler midlet indikerer at midlet har farmakologisk aktivitet.
2. In vitro-fremgangsmåde til screening af et middel for en farmakologisk aktivitet anvendelig i behandling af LBD, omfattende: bringe en celle der udtrykker alfa-synuklein og bearbejder alfa-synukleinet i et fragment i kontakt med dette middel, hvor fragmentet er til stede hos patienter med Lewy Body Disease og er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein; og bestemme et niveau af fragmentet i cellen i forhold til et basislinjeniveau i den samme celletype i fraværet af midlet, en reduktion i niveauet af fragmentet i forhold til basislinjen indikerer at midlet har farmakologisk aktivitet anvendelig i behandling af LBD hvor cellen fortrinsvis er en human celle, mere fortrinsvis en neuronal celle eller en dopaminerg celle.
3. Fremgangsmåde til screening af et middel der har farmakologisk aktivitet der er anvendelig til behandling af LBD, omfattende at bringe et ikke-humant transgent dyr der udtrykker et fragment af alfa-synuklein der er til stede hos patienter med Lewy Body Disease i kontakt med midlet, hvor fragmentet er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein; og bestemme et niveau af aggregerede former af fragmentet i hjernen af det transgene dyr i forhold til et basislinjeniveau af aggregerede former af fragmentet i et sammenligneligt transgent dyr i fraværet af midlet, en reduktion i niveauet af de aggregerede former af fragmentet i forhold til basislinjen indikerer at midlet har en farmakologisk aktivitet anvendelig i behandling af LBD, hvor det transgene dyr fortrinsvis er en mus eller en Drosophila.
4. Fremgangsmåde til screening af et middel for en farmakologisk aktivitet der er anvendelig til behandling af LBD, omfattende at bringe et ikke-humant transgent dyr med et transgen der udtrykker alfa-synuklein og bearbejdning af alfa-synukleinet i et fragment i kontakt med midlet, hvor fragmentet der er til stede hos patienter med Lewy Body Disease og er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein; og bestemme et niveau af fragmentet i en neuronal celle i forhold til et basislinjeniveau i fraværet af midlet, en reduktion i niveauet af fragmenter i forhold til basislinjen indikerer at midlet har farmakologisk aktivitet anvendelig til behandling af LBD.
5. Transgent ikke-humant dyr, fortrinsvis en mus eller Drosophila, med et genom omfattende et transgen omfattende: en promoter operabelt bundet til et nukleinsyresegment der koder for et fragment af alfa-synuklein der er til stede hos patienter med Lewy Body Disease som er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein, hvor ekspression af fragmentet i det transgene dyr disponerer dyret til at udvikle mindst et karakteristika af en LBD, hvor promotoren fortrinsvis er en PDGF promoter, eller hvor det mindst ene karakteristika fortrinsvis er en svækkelse af motorisk funktion eller en svækkelse af kognitiv funktion.
6. In v/fro-fremgangsmåde til påvisning af tilstedeværelsen eller modtageligheden for LBD hos en patient, omfattende: påvise et niveau af et fragment af alfa-synuklein i en prøve af rygmarvsvæske, hvor fragmentet er til stede hos patienter med Lewy Body Disease og er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein, et niveau større end et basislinjeniveau i ikke-sygdomsramte individer indikerer tilstedeværelsen eller modtageligheden for LBD.
7. Antistof der specifikt binder til et fragment af alfa-synuklein uden specifikt at binde til fuld-længde-alfa synuklein som defineret i SEQ ID NO.l, hvor fragmentet der er til stede hos patienter med Lewy Body Disease og er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein, hvor antistoffet fortrinsvis er et humant eller humaniseret antistof, mere fortrinsvis af human isotype IgGl, eller et fragment på mindre end 20 aminosyrer af alfa-synuklein der inducerer sådant et antistof, hvor fragmentet der inducerer antistoffet omfatter C-terminus af det trunkerede fragment der er til stede hos patienter med Lewy Body Disease.
8. Antistoffet ifølge krav 7 til anvendelse i diagnosticering af tilstedeværelsen af eller modtageligheden for LBD hvor antistoffet skal administreres til en patient og bindingsniveauet af antistoffet i patienten skal bestemmes, hvor et højere niveau af binding i forhold til et basislinjeniveau i ikke-sygdomsramte individer indikerer tilstedeværelsen eller modtageligheden for LBD.
9. Antistoffet ifølge krav 7, eller fragmentet på mindre end 20 aminosyrer alfa synuklein der inducerer antistoffet ifølge krav 7, til anvendelse i behandlingen eller profylaksen af Lewy Body Disease.
10. Fragment af alfa-synuklein der er til stede hos patienter med Lewy Body Disease som er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein, til anvendelse i behandlingen eller profylaksen af en Lewy Body Disease.
11. Fragment af alfa-synuklein der er til stede hos patienter med Lewy Body Disease som er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein enten i kombination med en adjuvans der forøger et immunrespons omfattende antistoffer til fragmentet, eller bundet til en bærer der danner et fusionsprotein, hvor bæreren forøger et immunrespons omfattende antistoffer til fragmentet.
12. Fremgangsmåde til screening af en protease der spalter intakt alfa-synuklein til at danne et fragment der er til stede hos patienter med Lewy Body Disease som er kendetegnet ved tilstedeværelsen af mindst 100 sammenhængende aminosyrer af intakt alfa-synuklein og en deletion af 1-25 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein omfattende: identificere en inhibitor af proteasen; bringe inhibitoren i kontakt med en celle- eller vævsekstrakt indeholdende proteasen, hvor proteasen binder til inhibitoren; og frigive proteasen fra inhibitoren.
13. Fremgangsmåden ifølge krav 12, hvor inhibitoren er et peptid af alfa-synuklein omfattende et sammenhængende segment på mindst 5 grupper af intakt alfa-synuklein mellem positionerne 115 og 130, fortrinsvis hvor peptidet omfatter et sammenhængende segment på mindst 5 grupper mellem positionerne 118 og 122, mere fortrinsvis hvor mindst en af grupperne er en overgangstilstandsanalog.
14. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, 6, 12 og 13, hvor fragmentet af alfa-synuklein bærer en A53T-mutation.
15. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, 6 og 12 til 14, hvor fragmentet af alfa-synuklein har en deletion på 1-23 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein.
16. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, 5 og 12 til 15, hvor fragmentet af alfa-synuklein er 1-119 eller 1-122.
17. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, 5 og 12 til 15, hvor fragmentet af alfa-synuklein er 1-X, hvor X er 130-139.
18. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, 6 og 12 til 14, hvor fragmentet af alfa-synuklein er intakt alfa-synuklein trunkeret ved C-terminus med 25 aminosyrer.
19. Fragmentet af alfa-synuklein ifølge krav 11, eller fragmentet til anvendelse ifølge krav 10, hvor fragmentet af alfa-synuklein bærer en A53T-mutation.
20. Antistoffet ifølge krav 7, antistoffet til anvendelse ifølge krav 8 eller 9, fragmentet af alfa-synuklein ifølge krav 11 eller 19, eller fragmentet til anvendelse ifølge krav 10 eller 19, hvor fragmentet af alfa-synuklein har en deletion af 1-23 sammenhængende aminosyrer fra C-terminus af intakt alfa-synuklein.
21. Antistoffet ifølge krav 7 eller 20, antistoffet til anvendelse ifølge et hvilket som helst af kravene 8, 9 og 20, fragmentet af alfa-synuklein ifølge krav 11, 19 eller 20, eller fragmentet til anvendelse ifølge krav 10, 19 or 20, hvor fragmentet af alfa-synuklein er 1-119 eller 1-122.
22. Antistoffet ifølge krav 7 eller 20, antistoffet til anvendelse ifølge et hvilket som helst af kravene 8, 9 og 20, fragmentet af alfa-synuklein ifølge krav 11, 19 eller 20, eller fragmentet til anvendelse ifølge kravene 10, 19 eller 20, hvor fragmentet af alfa-synuklein er 1-X, hvor X er 130-139.
23. Antistoffet ifølge krav 7, antistoffet til anvendelse ifølge krav 8 eller 9, fragmentet af alfa-synuklein ifølge krav 11 or 19, eller fragmentet til anvendelse ifølge krav 10 eller 19, hvor fragmentet af alfa-synuklein er intakt alfa-synuklein trunkeret ved C-terminus med 25 aminosyrer.
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| US47192903P | 2003-05-19 | 2003-05-19 | |
| PCT/US2004/015836 WO2005013889A2 (en) | 2003-05-19 | 2004-05-19 | Truncated fragments of alpha-synuclein in lewy body disease |
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| DK04776059.0T DK1633189T3 (da) | 2003-05-19 | 2004-05-19 | Trunkerede fragmenter af alfa-synuklein i lewy body-sygdom |
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| US20040146521A1 (en) * | 1999-06-01 | 2004-07-29 | Schenk Dale B. | Prevention and treatment of synucleinopathic disease |
| US20080014194A1 (en) | 2003-10-31 | 2008-01-17 | Elan Pharmaceuticals, Inc. | Prevention and Treatment of Synucleinopathic and Amyloidogenic Disease |
| US8697082B2 (en) | 2002-11-01 | 2014-04-15 | Neotope Biosciences Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
| US8506959B2 (en) * | 2002-11-01 | 2013-08-13 | Neotope Biosciences Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
| US9034337B2 (en) | 2003-10-31 | 2015-05-19 | Prothena Biosciences Limited | Treatment and delay of outset of synucleinopathic and amyloidogenic disease |
| TW200509968A (en) * | 2002-11-01 | 2005-03-16 | Elan Pharm Inc | Prevention and treatment of synucleinopathic disease |
| US7358331B2 (en) * | 2003-05-19 | 2008-04-15 | Elan Pharmaceuticals, Inc. | Truncated fragments of alpha-synuclein in Lewy body disease |
| US7550649B2 (en) | 2003-10-30 | 2009-06-23 | Taisho Pharmaceutical Co., Ltd. | Transgenic non-human mammal |
| WO2005047860A2 (en) | 2003-11-08 | 2005-05-26 | Elan Pharmaceuticals, Inc. | Antibodies to alpha-synuclein |
| MX2007001679A (es) | 2004-08-09 | 2007-05-23 | Elan Pharm Inc | Prevencion y tratamiento de la enfermedad sinucleinopatica y amiloidogenica. |
| US20070214509A1 (en) * | 2005-12-23 | 2007-09-13 | The Parkinson's Institute | Methods and systems for identifying compounds that modulate alpha-synuclein aggregation |
| US20090010894A1 (en) * | 2005-12-23 | 2009-01-08 | The Parkinson's Institute | Methods and systems for identifying compounds that modulate alpha-synuclein aggregation |
| PL2583978T3 (pl) | 2007-02-23 | 2016-07-29 | Prothena Biosciences Ltd Co | Profilaktyka i leczenie chorób synukleinopatycznych i amyloidogennych |
| LT3067066T (lt) | 2007-02-23 | 2019-06-25 | Prothena Biosciences Limited | Sinukleopatinių ir amiloidogeninių ligų prevencija ir gydymas |
| US8147833B2 (en) | 2007-02-23 | 2012-04-03 | Neotope Biosciences Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
| AT506535B1 (de) * | 2008-02-22 | 2010-04-15 | Affiris Forschungs & Entwicklungs Gmbh | Vaccine enthaltend alpha-synuclein-mimotope auf basis von peptiden |
| WO2009128948A1 (en) * | 2008-04-17 | 2009-10-22 | Peptimmune, Inc. | Design and synthesis of directed sequence polymer compositions and antibodies thereof for the treatment of protein conformational disorders |
| ES2709048T3 (es) | 2008-04-29 | 2019-04-15 | Bioarctic Ab | Anticuerpos y vacunas para su uso en métodos terapéuticos y diagnósticos para trastornos relacionados con alfasinucleína |
| AT508638B1 (de) | 2009-08-21 | 2011-08-15 | Affiris Ag | Verwendung von peptiden und polypeptiden zur behandlung und/oder prävention von synukleinopathien |
| JP6006908B2 (ja) * | 2010-11-05 | 2016-10-12 | ブランダイス ユニバーシティＢｒａｎｄｅｉｓ Ｕｎｉｖｅｒｓｉｔｙ | Ｉｃｅ阻害化合物およびその使用 |
| EP2659906A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
| EP2659908A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
| EP2659907A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
| WO2013173827A2 (en) * | 2012-05-18 | 2013-11-21 | Board Of Regents Of The University Of Nebraska | Methods and compositions for inhibiting diseases of the central nervous system |
| US11191832B2 (en) | 2013-11-19 | 2021-12-07 | Prothena Biosciences Limited | Monitoring immunotherapy of Lewy body disease from constipation symptoms |
| JP2017536102A (ja) | 2014-10-16 | 2017-12-07 | ジェネンテック， インコーポレイテッド | 抗アルファ−シヌクレイン抗体及び使用方法 |
| GB201512203D0 (en) | 2015-07-13 | 2015-08-19 | Lundbeck & Co As H | Agents,uses and methods |
| TW202309093A (zh) | 2016-06-02 | 2023-03-01 | 英商梅迪繆思有限公司 | 針對α-突觸核蛋白之抗體及其用途 |
| US20190227082A1 (en) * | 2016-07-06 | 2019-07-25 | Prothena Biosciences Limited | Assay for detecting total and s129 phosphorylated alpha-synuclein |
| RU2019114679A (ru) | 2016-11-15 | 2020-12-17 | Х. Лундбекк А/С | Средства, пути применения и способы лечения синуклеопатии |
| EP3555127B1 (en) | 2016-12-16 | 2024-12-18 | H. Lundbeck A/S | Agents, uses and methods |
| US10364286B2 (en) | 2016-12-22 | 2019-07-30 | H. Lundbeck A/S | Monoclonal anti-alpha-synuclein antibodies for preventing tau aggregation |
| JP7136790B2 (ja) | 2017-02-17 | 2022-09-13 | ブリストル－マイヤーズ スクイブ カンパニー | アルファ－シヌクレインに対する抗体およびその使用 |
| GB201720970D0 (en) | 2017-12-15 | 2018-01-31 | Ucb Biopharma Sprl | Antibodies |
| GB201720975D0 (en) | 2017-12-15 | 2018-01-31 | Ucb Biopharma Sprl | Anti-alpha synuclein antibodies |
| EP3752840A4 (en) * | 2018-02-12 | 2022-08-10 | The Scripps Research Institute | PROCEDURES RELATED TO PARKINSON'S DISEASE AND SYNUCLEINOPATHIES |
| CN112105393A (zh) | 2018-05-16 | 2020-12-18 | 爱默蕾大学 | 苯乙烯基苯并噻唑衍生物及在成像中的用途 |
| MX2021007446A (es) * | 2018-12-19 | 2021-09-08 | United Biomedical Inc | Epítopos artificiales promiscuos de linfocitos t colaboradores como estimuladores inmunes para inmunógenos peptídicos sintéticos. |
| JP7898188B2 (ja) | 2020-08-04 | 2026-07-31 | エイシー イミューン ソシエテ アノニム | 免疫原性化合物 |
| KR102505164B1 (ko) * | 2020-09-29 | 2023-02-28 | 서울대학교산학협력단 | 신경퇴행성 질환의 예방 또는 치료용 펩타이드 및 이를 포함하는 약학 조성물 |
| IL311344A (en) * | 2021-09-16 | 2024-05-01 | H Lundbeck As | Preparations and methods for the treatment of synoclinopathies |
| CN118475836A (zh) | 2021-11-01 | 2024-08-09 | 硝酸酶治疗公司 | 诊断突触核蛋白病的方法 |
| WO2024240186A1 (zh) | 2023-05-22 | 2024-11-28 | 深圳博芮健制药有限公司 | 含硫稠环化合物、含其的药物组合物、其制备方法及其应用 |
| WO2025172592A1 (en) | 2024-02-15 | 2025-08-21 | Ac Immune Sa | Alpha synuclein therapeutic vaccine |
Family Cites Families (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH652145A5 (de) | 1982-01-22 | 1985-10-31 | Sandoz Ag | Verfahren zur in vitro-herstellung von hybridomen welche humane monoklonale antikoerper erzeugen. |
| US4634666A (en) | 1984-01-06 | 1987-01-06 | The Board Of Trustees Of The Leland Stanford Junior University | Human-murine hybridoma fusion partner |
| DE3521994A1 (de) | 1985-06-20 | 1987-01-02 | Bayer Ag | N-(2-aminoacylamido-2-desoxy-hexosyl)-amide-, -carbamate und -harnstoffe, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
| US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
| US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
| US4912094B1 (en) | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
| US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
| IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
| WO1990014837A1 (en) | 1989-05-25 | 1990-12-13 | Chiron Corporation | Adjuvant formulation comprising a submicron oil droplet emulsion |
| EP1690935A3 (en) | 1990-01-12 | 2008-07-30 | Abgenix, Inc. | Generation of xenogeneic antibodies |
| US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
| ES2109945T3 (es) | 1990-06-01 | 1998-02-01 | Chiron Corp | Composiciones y procedimientos para identificar moleculas biologicamente activas. |
| GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
| US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
| US5789650A (en) | 1990-08-29 | 1998-08-04 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
| US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
| US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
| ES2246502T3 (es) | 1990-08-29 | 2006-02-16 | Genpharm International, Inc. | Animales no humanos transgenicos capaces de producir anticuerpos heterologos. |
| US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
| US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
| US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
| US5874299A (en) | 1990-08-29 | 1999-02-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
| US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
| US5871907A (en) | 1991-05-15 | 1999-02-16 | Medical Research Council | Methods for producing members of specific binding pairs |
| US5858657A (en) | 1992-05-15 | 1999-01-12 | Medical Research Council | Methods for producing members of specific binding pairs |
| EP0590058B1 (en) | 1991-06-14 | 2003-11-26 | Genentech, Inc. | HUMANIZED Heregulin ANTIBODy |
| WO1993001222A1 (fr) | 1991-07-03 | 1993-01-21 | Kanebo, Ltd. | Elastomere de polyurethane thermoplastique, procede et dispositif de production, et fibre elastique realisee a partir de cet elastomere |
| EP0604552B1 (en) | 1991-09-18 | 1997-02-12 | Affymax Technologies N.V. | Method of synthesizing diverse collections of oligomers |
| ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
| DE69233109T2 (de) | 1992-01-07 | 2004-05-19 | Elan Pharmaceuticals, Inc., San Francisco | Transgene tiermodelle fur alzheimer-krankheit |
| US5733743A (en) | 1992-03-24 | 1998-03-31 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
| US5604102A (en) * | 1992-04-15 | 1997-02-18 | Athena Neurosciences, Inc. | Methods of screening for β-amyloid peptide production inhibitors |
| HUT72495A (en) | 1992-10-01 | 1996-05-28 | Cold Spring Harbor Lab | Complex combinatorial chemical libraries encoded with tags |
| ATE199392T1 (de) | 1992-12-04 | 2001-03-15 | Medical Res Council | Multivalente und multispezifische bindungsproteine, deren herstellung und verwendung |
| JPH09508353A (ja) | 1993-11-02 | 1997-08-26 | アフィマックス テクノロジーズ ナムローゼ フェンノートシャップ | 分子多様性の合成及びスクリーニング |
| US5914349A (en) | 1994-01-10 | 1999-06-22 | Teva Pharmaceutical Industries, Ltd. | Compositions containing and methods of using 1-aminoindan and derivatives thereof and process for preparing optically active 1-aminoindan derivatives |
| JPH10500112A (ja) | 1994-05-06 | 1998-01-06 | ファーマコピーア，インコーポレイテッド | 組合せ ジヒドロベンゾピラン ライブラリー |
| US5663046A (en) | 1994-06-22 | 1997-09-02 | Pharmacopeia, Inc. | Synthesis of combinatorial libraries |
| AU753688B2 (en) | 1997-03-10 | 2002-10-24 | Ottawa Civic Loeb Research Institute | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
| AU3117799A (en) * | 1998-03-30 | 1999-10-18 | Trustees Of The University Of Pennsylvania, The | Method of identifying, diagnosing and treating synuclein positive neurodegenerative disorders |
| US6184351B1 (en) * | 1998-09-25 | 2001-02-06 | Amgen Inc. | α-synuclein super-mutants accelerate α-synuclein aggregation |
| UA81216C2 (en) | 1999-06-01 | 2007-12-25 | Prevention and treatment of amyloid disease | |
| CN1440420A (zh) * | 2000-07-07 | 2003-09-03 | 万能药制药公司 | 预防神经组织损伤和治疗α－共核蛋白疾病的方法 |
| TW200509968A (en) | 2002-11-01 | 2005-03-16 | Elan Pharm Inc | Prevention and treatment of synucleinopathic disease |
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| WO2005013889A9 (en) | 2005-06-02 |
| PT1633189T (pt) | 2017-10-04 |
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