ES2675579T3 - Dianas moleculares para el tratamiento de heridas, en particular heridas crónicas - Google Patents
Dianas moleculares para el tratamiento de heridas, en particular heridas crónicas Download PDFInfo
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- ES2675579T3 ES2675579T3 ES14744578.7T ES14744578T ES2675579T3 ES 2675579 T3 ES2675579 T3 ES 2675579T3 ES 14744578 T ES14744578 T ES 14744578T ES 2675579 T3 ES2675579 T3 ES 2675579T3
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- 230000001684 chronic effect Effects 0.000 title abstract description 6
- 238000011282 treatment Methods 0.000 title abstract description 5
- 108020004459 Small interfering RNA Proteins 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 2
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- 230000001225 therapeutic effect Effects 0.000 abstract 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 abstract 1
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
Un compuesto terapéutico que comprende un agente que inhibe la actividad del gen del factor de transcripción MAF, donde dicho agente se selecciona del grupo que consiste en ADN o ARN no codificante, ARNip, ARNhc, TALENS o ribozimas, ya sea desnudos o en forma de vectores plasmídicos o víricos, anticuerpos y trametinib, para su uso en el tratamiento de heridas crónicas.
Description
directos e inversos para αSMA por Eurofins (MWG, αSMA directo: CTGTTTTCCCATCCATTGTG (SEC ID NO: 9), αSMA inverso: CCATGTTCTATCGGGTACTT (SEC ID NO: 10)) y se almacenó una solución madre de 100 μM a 20ºC. Se usaron los pares de cebadores directos e inversos para cada reacción RT-qPCR. Las condiciones de ciclo fueron las siguientes: una temperatura inicial de 95°C durante 10 minutos, seguida de 45 ciclos de 95°C durante 15 5 segundos, 58°C durante 30 segundos, 72°C durante 20 segundos. Se usó LightCycler 480 SW 1.5 para evaluar las curvas de TM, para determinar la Cp y para aproximar la concentración relativa para cada reacción de amplificación.
Inmunofluorescencia de α Actina de Músculo Liso
Las células cultivadas en placas de cultivo recubiertas de colágeno y tratadas como se describe previamente, se fijaron con paraformaldehído al 4 % (PFA) en PBS durante 15 minutos y se permeabilizaron con Triton X-100 al 2,5 % (Euromedex, 2000-B) en PBS durante 3 minutos. Después de la saturación con BSA al 5 % en PBS, las
15 células se tiñeron para α-SMA (Abcam, ab5694) y para ADN (DAPI). Como anticuerpo secundario, se usó anticonejo conjugado con CyTM3 (GE Healthcare, PA43004). Se observaron las muestras con un objetivo de inmersión en aceite (Plan Fluor 40X / 1.30 Oil, Nikon) en una Nikon ECLIPSE Ti (Nikon). Se tomaron imágenes digitales con una cámara digital (Cool SNAPHQ2, Photometrics) y software (MetaMorf 7.5.4.0). Para estimar el porcentaje de diferenciación de fibroblastos debido a los diferentes tratamientos, se determinó el número total de células por campo mediante DAPI y se contaron los miofibroblastos, fibroblastos diferenciados, usando la tinción de α-SMA. A continuación, se realizaron ensayos t de STUDENT y de χ2 para evaluar la expresión diferencial de αSMA entre los fibroblastos no tratados (T-E-) y los tratados.
25 Preparación de muestra de ARN total y síntesis de ADNc
Después de cuatro días de experimento, los fibroblastos tratados se separaron con reactivo de TRIzol (Invitrogen (Life Technologies), 15596-018) y se almacenaron a -80°C. A continuación, se purificó el ARN utilizando cloroformo y se precipitó con isopropanol. Se cuantificó el ARN total en el espectrofotómetro NanoDrop 2000c (Thermo Scientific) y se evaluó su calidad en el ARN Nano Chips (bioanalizador Agilent 2100, Agilent, 5067-1511). La transcripción inversa de 500 ng de ARN total a ADNc se realizó con oligot dT (Invitrogen (Life technologies), 18418-020) usando SuperScript III RT (Invitrogen (Life technologies), 18080-085) y RNasa OUT (Invitrogen (Life technologies), 10777019). El ADNc se almacenó a -20°C. Solo se usaron las muestras con un buen perfil de bioanalizador para el análisis
35 por qPCR.
Análisis de red
Para esclarecer los reguladores principales del destino de fibroblastos después de cada tratamiento diferente, los inventores de la presente invención realizaron un análisis de red de genes que trata las listas de expresión génica determinadas después del análisis de secuenciación profunda de ARNm seq del perfil del gen TE- con el perfil del gen de T+E-, T+E+ y T-E+ 1. En estos análisis y basándose en el supuesto de que la disminución o el aumento de los genes interconectados es de mayor importancia que un Log FC significativo, los inventores de la presente invención han utilizado listas de genes seleccionados solo basándose en su valor P y no en el valor de su Log FC. 45 Los inventores de la presente invención han llevado a cabo dos tipos de análisis: un "análisis de regulador cadena arriba" ingenuity y un análisis DIRE (http://dire.dcode.org/). El "análisis de regulador cadena arriba" Ingenuity, dado el perfil particular de expresión de genes entre dos condiciones, consiste en seleccionar reguladores potenciales cadena arriba. El análisis DIRE se basa en la selección de elementos reguladores comunes potenciales entre genes basándose en la conservación de estos elementos durante la evolución. A partir de estos elementos identificados, DIRE puede proporcionar una lista de reguladores principales para una lista de genes co-regulados. A partir de esos dos análisis, y para cada lista analizada, los inventores de la presente invención han seleccionado factores de transcripción (FT) expresados en al menos una de las dos condiciones consideradas en la lista (es decir, el número de secuenciación es superior a veinte en al menos una de los dos condiciones). A continuación, los inventores de la presente invención compararon profundamente los dos conjuntos de análisis y decidieron mantener en las "listas de
55 reguladores clave" los factores de transcripción que pertenecen a ambos análisis. Debido a la posible parcialidad en estos dos análisis, los inventores de la presente invención también decidieron rescatar los factores de transcripción que pertenecen solo a un análisis y no al otro, pero presentan un patrón de genes diana muy interesante en una u otra lista. En total, estos análisis de redes de genes permitieron proponer una lista de FT que son reguladores clave en uno u otro destino de fibroblastos.
Para el modelo de herida crónica o no cicatrizante, se añadieron exudados de heridas crónicas a cultivos celulares (500 μg/ml de proteínas totales de exudado). Los experimentos que se realizaron se representan en la Figura 1a): las células o no fueron tratadas (T-E -), o fueron tratadas con TGFβ solo (T+E-), o con exudado solo (T-E+) o con TGF-β y exudado (T+E+) durante 4 días. Los ensayos descritos anteriormente se usaron para evaluar el nivel de 65 diferenciación. Los exudados de heridas crónicas disminuyen la expresión de αSMA (ARNm, figura 1b). Esto indicó que los exudados de heridas crónicas inhiben claramente la diferenciación de los fibroblastos. Esto se correlaciona
11
Claims (1)
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imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| WOPCT/IB2013/001990 | 2013-08-05 | ||
| PCT/IB2013/001990 WO2015019125A1 (en) | 2013-08-05 | 2013-08-05 | Molecular targets for the treatment of wounds, in particular chronic wounds |
| PCT/EP2014/066344 WO2015018699A1 (en) | 2013-08-05 | 2014-07-30 | Molecular targets for the treatment of wounds, in particular chronic wounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2675579T3 true ES2675579T3 (es) | 2018-07-11 |
Family
ID=49447578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES14744578.7T Active ES2675579T3 (es) | 2013-08-05 | 2014-07-30 | Dianas moleculares para el tratamiento de heridas, en particular heridas crónicas |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US10071097B2 (es) |
| EP (2) | EP3354659A3 (es) |
| JP (2) | JP6473155B2 (es) |
| CN (1) | CN105829338A (es) |
| BR (1) | BR112016002570A2 (es) |
| CA (1) | CA2919600A1 (es) |
| ES (1) | ES2675579T3 (es) |
| WO (2) | WO2015019125A1 (es) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170082611A1 (en) * | 2015-09-21 | 2017-03-23 | Regenerative Research Foundation | Methods for Inhibiting Epithelial to Mesenchymal Transition by Inhibition of FOXS1 |
| RU2708302C1 (ru) * | 2016-01-11 | 2019-12-05 | Тюркие Шише Ве Джам Фабрикалары А.Ш. | Стекло с низкоэмиссионным покрытием, устойчивое к термической обработке |
| CN106868006B (zh) * | 2017-03-29 | 2019-12-17 | 华中科技大学同济医学院附属协和医院 | 一种e2f1蛋白可结合dna片段及在e2f1活性检测中的应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000510333A (ja) | 1996-04-23 | 2000-08-15 | プレジデント アンド フェロウズ オブ ハーバード カレッジ | 因子活性を調節することによりｔ細胞サブセットを制御するための方法及び組成物 |
| DE10235624A1 (de) | 2002-08-02 | 2004-02-19 | Aventis Pharma Deutschland Gmbh | Endiandric acid H und ihre Derivate, Verfahren zu ihrer Herstellung und Verwendung derselben |
| EP1944361A1 (en) * | 2007-01-11 | 2008-07-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A method for expanding monocytes |
| JP5641388B2 (ja) * | 2009-05-01 | 2014-12-17 | 独立行政法人理化学研究所 | 創傷治療剤及びそのスクリーニング方法 |
| EP2322163A1 (en) * | 2009-11-03 | 2011-05-18 | Pharnext | New therapeutics approaches for treating alzheimer disease |
| TWI505828B (zh) * | 2010-12-20 | 2015-11-01 | 葛蘭素史克智慧財產（第二）有限公司 | 新穎醫藥組成物 |
| CN102146411B (zh) * | 2011-01-06 | 2013-01-02 | 中国人民解放军第三军医大学第三附属医院 | 新型双功能抗瘢痕和组织纤维化寡聚核苷酸药物 |
| GB201103898D0 (en) * | 2011-03-08 | 2011-04-20 | Univ Cardiff | Molecular targets for healing or treating wounds |
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2013
- 2013-08-05 WO PCT/IB2013/001990 patent/WO2015019125A1/en active Application Filing
-
2014
- 2014-07-30 ES ES14744578.7T patent/ES2675579T3/es active Active
- 2014-07-30 BR BR112016002570A patent/BR112016002570A2/pt not_active Application Discontinuation
- 2014-07-30 CN CN201480043897.4A patent/CN105829338A/zh active Pending
- 2014-07-30 US US14/909,669 patent/US10071097B2/en not_active Expired - Fee Related
- 2014-07-30 EP EP18156497.2A patent/EP3354659A3/en not_active Withdrawn
- 2014-07-30 JP JP2016532316A patent/JP6473155B2/ja not_active Expired - Fee Related
- 2014-07-30 CA CA2919600A patent/CA2919600A1/en not_active Abandoned
- 2014-07-30 WO PCT/EP2014/066344 patent/WO2015018699A1/en active Application Filing
- 2014-07-30 EP EP14744578.7A patent/EP3030574B1/en not_active Not-in-force
-
2018
- 2018-08-06 US US16/055,571 patent/US20190022097A1/en not_active Abandoned
- 2018-11-15 JP JP2018214549A patent/JP2019038847A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016527290A (ja) | 2016-09-08 |
| CA2919600A1 (en) | 2015-02-12 |
| EP3030574A1 (en) | 2016-06-15 |
| JP2019038847A (ja) | 2019-03-14 |
| WO2015019125A1 (en) | 2015-02-12 |
| US20170281628A1 (en) | 2017-10-05 |
| US20190022097A1 (en) | 2019-01-24 |
| US10071097B2 (en) | 2018-09-11 |
| JP6473155B2 (ja) | 2019-02-20 |
| CN105829338A (zh) | 2016-08-03 |
| EP3354659A2 (en) | 2018-08-01 |
| EP3354659A3 (en) | 2018-09-12 |
| BR112016002570A2 (pt) | 2017-09-12 |
| EP3030574B1 (en) | 2018-03-28 |
| WO2015018699A1 (en) | 2015-02-12 |
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