ES2541145T3 - Evaluación del riesgo potencial de alteración del estado de ánimo y suicidio inducidos farmacológicamente: utilización de una plataforma dedicada - Google Patents
Evaluación del riesgo potencial de alteración del estado de ánimo y suicidio inducidos farmacológicamente: utilización de una plataforma dedicada Download PDFInfo
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- ES2541145T3 ES2541145T3 ES09775225.7T ES09775225T ES2541145T3 ES 2541145 T3 ES2541145 T3 ES 2541145T3 ES 09775225 T ES09775225 T ES 09775225T ES 2541145 T3 ES2541145 T3 ES 2541145T3
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- 206010010144 Completed suicide Diseases 0.000 title 1
- 238000011156 evaluation Methods 0.000 title 1
- 230000036651 mood Effects 0.000 title 1
- 102000001708 Protein Isoforms Human genes 0.000 abstract description 15
- 108010029485 Protein Isoforms Proteins 0.000 abstract description 15
- 210000004027 cell Anatomy 0.000 abstract description 14
- 210000004962 mammalian cell Anatomy 0.000 abstract description 14
- 101000742223 Homo sapiens Double-stranded RNA-specific editase 1 Proteins 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 108090000790 Enzymes Proteins 0.000 abstract description 8
- 102000004190 Enzymes Human genes 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 108020004999 messenger RNA Proteins 0.000 abstract description 3
- 206010029260 Neuroblastoma Diseases 0.000 abstract description 2
- 108091092328 cellular RNA Proteins 0.000 abstract description 2
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 abstract 2
- 102100025372 Nuclear pore complex protein Nup98-Nup96 Human genes 0.000 abstract 2
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 abstract 1
- 101000761348 Homo sapiens 5-hydroxytryptamine receptor 2C Proteins 0.000 abstract 1
- 239000012472 biological sample Substances 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 101000865408 Homo sapiens Double-stranded RNA-specific adenosine deaminase Proteins 0.000 description 8
- 102100029791 Double-stranded RNA-specific adenosine deaminase Human genes 0.000 description 6
- 102100038191 Double-stranded RNA-specific editase 1 Human genes 0.000 description 6
- 230000004075 alteration Effects 0.000 description 5
- -1 ABCDE Chemical compound 0.000 description 2
- 231100000683 possible toxicity Toxicity 0.000 description 2
- PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
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- G01N33/5058—Neurological cells
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
- G01N33/942—Serotonin, i.e. 5-hydroxy-tryptamine
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Abstract
Método in vitro para la determinación de la toxicidad o los efectos secundarios potenciales de un compuesto de ensayo después de su administración en un paciente, que comprende las etapas siguientes: a) obtener una muestra biológica que contiene células de mamífero, en el que dichas células de mamífero son estirpes celulares de origen humano que presentan una expresión regular y constitutiva de los enzimas de edición ADAR1a, ADAR1b y ADAR2 y del receptor de serotonina 2C (5HTR2C); b) poner en contacto dichas células de mamífero con el compuesto que debe someterse a ensayo; c) determinar en el mismo extracto celular: - el perfil de edición que proporciona la proporción media de cada isoforma identificada del ARNm de 5-HT2CR medido en el extracto celular de ARN, y - la expresión cuantitativa de dichos enzimas de edición ADAR1a, ADAR1b y ADAR2; d) comparar los resultados obtenidos en la etapa c) entre dichas células tratadas con el compuesto que debe someterse a ensayo y las células de control no tratadas, en el que en la etapa a) dichas células de mamífero proceden de la estirpe celular de neuroblastoma humano SHSY5Y.
Description
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-el perfil de edición que proporciona la proporción media de cada isoforma identificada del ARNm de 5-HT2CR medido en el extracto celular de ARN, y
-la expresión cuantitativa de dichos enzimas de edición ADAR1a, ADAR1b y ADAR2.
En una forma de realización preferida, en la etapa a) de los métodos de la presente exposición, dichas células de mamífero son capaces de expresar un número significativo de isoformas editadas de ARNm de 5HT2CR, demostrando que dichos enzimas ADAR1a, ADAR1b y ADAR2 son activos en el control de la producción de varias isoformas editadas del receptor en dichas células.
Más preferentemente, dichas células de mamífero son capaces de presentar por lo menos los sitios A, B y también C y E editados, también más preferentemente son células de mamífero que pueden presentar por lo menos 1, preferentemente 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 y 12 isoformas ADAR 1 editadas seleccionadas de entre el grupo que consiste en las isoformas editadas A, AB, ABC, ABCE, ABE, AC, ACE, AE, B, BC, BCE, BE, conjuntamente con por lo menos 1, preferentemente 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 y 15 isoformas que presentan también el sitio D editado seleccionadas de entre el grupo de las isoformas editadas ABCD, ABCDE, ABD, ABDE, ACD, ACDE, AD, ADE, BCD, BCDE, BD, BDE, C, CE y E.
En una forma de realización preferida de los métodos de la presente exposición en la etapa a), dichas células de mamífero son estirpes celulares, particularmente de ser humano, ratón o rata.
En una forma de realización más preferida de los métodos de la presente exposición en la etapa a), dichas células de mamífero son estirpes celulares de mamífero, particularmente de ser humano, ratón o rata, que muestran una expresión constante y constitutiva de los enzimas ADAR1 y ADAR2 de 5HT2CR, preferentemente de los enzimas ADAR1a, ADAR1b y ADAR2.
La característica "muestra una expresión constante y constitutiva de los enzimas ADAR1 y ADAR2 de 5HT2CR, preferentemente de los enzimas ADAR1a, ADAR1b y ADAR2", resulta muy importante en el sentido de que la expresión del contenido de los enzimas ADAR1 y ADAR2 de 5HT2CR debe ser constante (regular) en el caso de que las células se encuentren en cultivo y no sean tratadas (células de control) con el fin de disponer de datos fiables para comparar con las células tratadas (robustez y fiabilidad del ensayo).
Por ejemplo, los inventores han demostrado inesperadamente (ver la Tabla 5 del Ejemplo 5, que las células HTB-14 (línea celular de glioma) no expresan suficiente 5HT2CR de manera constante y constitutiva y no pueden utilizarse como estirpe celular de mamífero en el método de la presente invención.
La expresión de los enzimas de edición ADAR por sí sola no resulta suficiente para predecir la potencial toxicidad o los efectos secundarios de un compuesto de ensayo o para seleccionar un compuesto terapéutico según la presente invención o para encontrar un nuevo compuesto de referencia (tal como interferón alfa) para comparar el efecto de un compuesto sometido a ensayo sobre la alteración de la edición de 5HT2CR y para predecir la potencial toxicidad
o efectos secundarios en vista de la alteración y toxicidad/efectos secundarios conocidos de dichos compuestos de referencia (panel de compuestos de referencia en el que sus efectos sobre la alteración de la edición de 5HT2CR han sido estudiados sobre estirpes celulares de mamífero utilizadas en el método de la presente invención (tal como la estirpe celular de neuroblastoma (es decir SH-SY5Y) y en el que se conocen la toxicidad o efectos secundarios potenciales) en vista de la alteración y toxicidad/efectos secundarios conocidos de dichos compuestos de referencia.
De hecho, la expresión cuantitativa de los ADAR no resulta suficiente para predecir su efecto combinado sobre la edición de 5HT2C. El ensayo de cuantificación de ADAR no es un ensayo de actividad y los inventores han demostrado que sólo la determinación de la distribución de todas las isoformas de 5HT2C resulta significativa en el caso de una alteración real de la edición de 5HT2C. Por este motivo resulta preferente determinar la distribución de todas las isoformas de 5HT2C en relación con la acción de los enzimas de edición.
En una forma de realización todavía más preferida de los métodos de la presente exposición en la etapa a), dichas células de mamífero son estirpes celulares de mamífero, particularmente de ser humano, ratón o rata, que presentan las características siguientes:
1) presentan una expresión constante y constitutiva de los enzimas ADAR1 y ADAR2 de 5HT2CR, preferentemente de los enzimas ADAR1a, ADAR1b y ADAR2,
2) en el caso de que dicha célula de mamífero se trate con un fármaco capaz de alterar la edición de 5HT2CR,
-capaz de expresar un número significativo de isoformas editadas de 5HT2CR,
-preferentemente capaz de expresar por lo menos una isoforma de 5HT2CR que muestra por lo menos el sitio de edición A editado, una isoforma de 5HT2CR que muestra por lo menos el sitio de edición B editado, una isoforma de 5HT2CR que muestra por lo menos el sitio de edición C editado, una isoforma de 5HT2CR que muestra por lo
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Claims (1)
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imagen1 imagen2
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08305963 | 2008-12-17 | ||
| EP08305963A EP2202321A1 (en) | 2008-12-17 | 2008-12-17 | Evaluation of the potential risk of drug induced mood disturbance and suicide:use of a dedicated platform |
| PCT/EP2009/067464 WO2010070074A2 (en) | 2008-12-17 | 2009-12-17 | Evaluation of the potential risk of drug induced mood disturbance and suicide: use of a dedicated platform |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2541145T3 true ES2541145T3 (es) | 2015-07-16 |
Family
ID=40435151
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09775225.7T Active ES2541145T3 (es) | 2008-12-17 | 2009-12-17 | Evaluación del riesgo potencial de alteración del estado de ánimo y suicidio inducidos farmacológicamente: utilización de una plataforma dedicada |
| ES15161987.1T Active ES2688349T3 (es) | 2008-12-17 | 2009-12-17 | Evaluación del riesgo potencial de la alteración del estado de ánimo y el suicidio inducidos farmacológicamente: utilización de una plataforma específica |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES15161987.1T Active ES2688349T3 (es) | 2008-12-17 | 2009-12-17 | Evaluación del riesgo potencial de la alteración del estado de ánimo y el suicidio inducidos farmacológicamente: utilización de una plataforma específica |
Country Status (9)
| Country | Link |
|---|---|
| US (3) | US8771953B2 (es) |
| EP (3) | EP2202321A1 (es) |
| JP (2) | JP6169317B2 (es) |
| CA (1) | CA2747322C (es) |
| DK (2) | DK2924128T3 (es) |
| ES (2) | ES2541145T3 (es) |
| HU (2) | HUE024990T2 (es) |
| PT (1) | PT2924128T (es) |
| WO (1) | WO2010070074A2 (es) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3868896A1 (en) | 2010-06-24 | 2021-08-25 | Alcediag | Editing profiling of pde8a pre -mrna : use as specific biomarker of adars activities in human tissues to diagnose and to predict and assess therapeutic efficacy and/or efficiency or potential drug side effects |
| KR20140093347A (ko) * | 2013-01-15 | 2014-07-28 | 삼성전자주식회사 | 항 ｃ-Ｍｅｔ 항체 처리에 의해 부작용을 유발하는 유전자 및 이를 이용한 약물 스크리닝 방법 |
| CA3016657A1 (en) * | 2016-03-11 | 2017-09-14 | Alcediag | Algorithm and an in vitro method based on rna editing to select particular effect induced by active compounds |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040142325A1 (en) * | 2001-09-14 | 2004-07-22 | Liat Mintz | Methods and systems for annotating biomolecular sequences |
| FR2842827B1 (fr) * | 2002-07-26 | 2004-10-22 | Biocortech | NOUVELLE METHODE D'ANALYSE D'ACIDE NUCLEIQUE ET SON UTILISATION POUR EVALUER LE DEGRE D'EDITION DE L'ARNm DU RECEPTEUR 5-HT2c |
| JP2004121218A (ja) * | 2002-08-06 | 2004-04-22 | Jenokkusu Soyaku Kenkyusho:Kk | 気管支喘息または慢性閉塞性肺疾患の検査方法 |
| JP2004191368A (ja) * | 2002-11-29 | 2004-07-08 | Institute Of Physical & Chemical Research | ターゲット分子の検出方法 |
| JP2004187545A (ja) * | 2002-12-10 | 2004-07-08 | Hitachi Ltd | 核酸配列の検査方法及び試料調製方法 |
| EP1891241B1 (en) * | 2005-06-16 | 2011-01-12 | EVOTEC Neurosciences GmbH | Diagnostic and therapeutic target adarb2 proteins for neurodegenerative diseases |
| ES2952748T3 (es) | 2007-06-13 | 2023-11-03 | Alcediag | Muestra de tejido periférico que contiene células que expresan el 5HTR2C y/o las ADAR como marcadores de la alteración del mecanismo de edición del ARNm de 5HTR2C y sus aplicaciones |
| US20100184058A1 (en) * | 2007-06-14 | 2010-07-22 | Dinah Weissmann | Peripherical tissue sample containing cells expressing the 5htr2c and/or adars as markers of the alteration of the mechanism of the 5htr2c mrna editing and its applications |
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2008
- 2008-12-17 EP EP08305963A patent/EP2202321A1/en not_active Withdrawn
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2009
- 2009-12-17 PT PT15161987T patent/PT2924128T/pt unknown
- 2009-12-17 ES ES09775225.7T patent/ES2541145T3/es active Active
- 2009-12-17 EP EP15161987.1A patent/EP2924128B1/en active Active
- 2009-12-17 HU HUE09775225A patent/HUE024990T2/en unknown
- 2009-12-17 HU HUE15161987A patent/HUE039723T2/hu unknown
- 2009-12-17 DK DK15161987.1T patent/DK2924128T3/en active
- 2009-12-17 US US13/140,325 patent/US8771953B2/en active Active
- 2009-12-17 CA CA2747322A patent/CA2747322C/en active Active
- 2009-12-17 WO PCT/EP2009/067464 patent/WO2010070074A2/en not_active Ceased
- 2009-12-17 DK DK09775225.7T patent/DK2376649T3/en active
- 2009-12-17 EP EP09775225.7A patent/EP2376649B1/en active Active
- 2009-12-17 JP JP2011541457A patent/JP6169317B2/ja active Active
- 2009-12-17 ES ES15161987.1T patent/ES2688349T3/es active Active
-
2014
- 2014-06-06 US US14/297,933 patent/US20140356875A1/en not_active Abandoned
-
2017
- 2017-02-28 US US15/445,901 patent/US20170253926A1/en not_active Abandoned
- 2017-04-18 JP JP2017082349A patent/JP6644731B2/ja active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2012511923A (ja) | 2012-05-31 |
| JP6169317B2 (ja) | 2017-07-26 |
| WO2010070074A3 (en) | 2010-10-07 |
| EP2924128A1 (en) | 2015-09-30 |
| JP2017169571A (ja) | 2017-09-28 |
| DK2924128T3 (en) | 2018-10-08 |
| US20170253926A1 (en) | 2017-09-07 |
| EP2376649A2 (en) | 2011-10-19 |
| EP2376649B1 (en) | 2015-04-01 |
| CA2747322C (en) | 2021-09-28 |
| US20140356875A1 (en) | 2014-12-04 |
| PT2924128T (pt) | 2018-10-24 |
| EP2924128B1 (en) | 2018-07-04 |
| WO2010070074A2 (en) | 2010-06-24 |
| EP2202321A1 (en) | 2010-06-30 |
| CA2747322A1 (en) | 2010-06-24 |
| US20120129177A1 (en) | 2012-05-24 |
| HUE024990T2 (en) | 2016-01-28 |
| US8771953B2 (en) | 2014-07-08 |
| DK2376649T3 (en) | 2015-07-06 |
| HUE039723T2 (hu) | 2019-01-28 |
| ES2688349T3 (es) | 2018-11-02 |
| JP6644731B2 (ja) | 2020-02-12 |
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