ES2613755T3 - Bacteria probiótica recombinante para la prevención y tratamiento de la Enfermedad Inflamatoria Intestinal (EII) y del Síndrome del Intestino Irritable (SII) - Google Patents

Bacteria probiótica recombinante para la prevención y tratamiento de la Enfermedad Inflamatoria Intestinal (EII) y del Síndrome del Intestino Irritable (SII) Download PDF

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ES2613755T3
ES2613755T3 ES11700274.1T ES11700274T ES2613755T3 ES 2613755 T3 ES2613755 T3 ES 2613755T3 ES 11700274 T ES11700274 T ES 11700274T ES 2613755 T3 ES2613755 T3 ES 2613755T3
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treatment
ibs
ibd
prevention
probiotic bacteria
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Nathalie Vergnolle
Jean-Michel Sallenave
Philippe Langella
Luis Bermudez-Humaran
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Institut Pasteur de Lille
Institut National de la Recherche Agronomique INRA
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
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Institut Pasteur de Lille
Institut National de la Recherche Agronomique INRA
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8121—Serpins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8121—Serpins
    • C07K14/8125—Alpha-1-antitrypsin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
    • C12N15/746—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora for lactic acid bacteria (Streptococcus; Lactococcus; Lactobacillus; Pediococcus; Enterococcus; Leuconostoc; Propionibacterium; Bifidobacterium; Sporolactobacillus)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus

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Abstract

Una Bacteria Ácido Láctica recombinante de calidad alimentaria que comprende un gen recombinante que codifica para la proteína elafina o una fracción activa de la proteína elafina.

Description

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La expresión proteica de la quimioquina RANTES no se aumentó significativamente mediante colitis por DSS en el momento de tiempo observado (7-días después del comienzo del tratamiento DSS). Lb. casei de tipo salvaje o que secreta Elafina fracasó para modificar el nivel de la expresión RANTES en ratones tratados con DSS (Fig. 5A). TNFα, IL-6, MCP1, KC, INFγ y IL-17A estaban todos significativamente aumentados en la colitis por DSS, 7 días después de la inducción (Fig. 5B a G). El tratamiento de los ratones con Lb. casei recombinante que expresa elafina redujo significativamente la expresión proteica de IL-6, MCP1, KC y IL-17 (Fig. 5C, D, E, G), pero falló para reducir el nivel de expresión de otras citoquinas inflamatorias tales como TNFα y INFγ (Fig. 5B y F). Es interesante que, aunque la colitis por DSS no causó ningún incremento de las citoquinas IL-2, IL-4, IL-5, IL-10 y IL-13 (Fig. 6A a E), el tratamiento de los ratones con Lb. casei recombinante para elafina alcanzó significativamente la expresión de estas citoquinas, pero sólo en un contexto de colitis (después de tratamiento con DSS). Este incremento en las citoquinas Th2 en respuesta al Lb. casei recombinante para elafina, podría explicar al menos en parte, los efectos anti-inflamatorios de esta bacteria recombinante. Los niveles de IL-2, IL-4, IL-5, IL-10 y IL-13 no se modificaron por ninguno de los otros tratamientos en cualquiera de los ratones inflamados (DSS) o no inflamados (Fig. 6A a E).
Lactococcus lactis recombinante para la expresión de elafina en el descenso del comportamiento al dolor visceral
La administración intracolónica de aceite de mostaza causó un aumento significativo en el número de comportamientos al dolor: tanto el número de retracciones abdominales como en el número de comportamientos de dolor integrados tales como lamidos, estiramientos y aplastamiento contra el suelo (Fig. 7A y B). Considerando todos los comportamientos en conjunto, el tratamiento con L. lactis de tipo salvaje, que secreta IL-10 recombinante o elafina, no tuvo efecto (Fig. 7A). Cuando se consideran sólo los comportamientos de dolor integrados, L. lactiselafina, pero no IL-10 recombinante o de tipo salvaje, redujo significativamente el número de comportamientos al dolor (Fig. 7B). Por otra parte, sólo L. lactis recombinante que expresa elafina indujo un notable descenso en el número de comportamientos al dolor comparado con el tratamiento PBS o con el tratamiento L. lactis de tipo salvaje (Fig. 7B).
Resultados con la cepa htrA
L. lactis expresa sólo un proteasa extracelular constitutiva llamada htrA que degrada todas las proteínas desdobladas exportadas (Poquet et al, 2000 y solicitudes de patente de E.E.U.U. 6.994.997 y FR2787810). Se preparó una cepa inactivada de L. lactis en un gen htrA mutante y se permitió aumentar la razón de producción de varias proteínas heterólogas secretadas en L. lactis (Poquet et al, 2000 y Miyoshi et al, 2002). Según la invención, se clonó el casete de expresión de elafina en el htrA mutante. Se compararon los niveles de producción de elafina en el htrA mutante y en la cepa de tipo salvaje (wt) mediante experimentos Western blot (Fig. 8). Se observó un incremento significativo de la elafina secretada en el sobrenadante de la htrA mutante comparado al de la cepa wt. Por tanto, la cepa htrA permitirá mayor producción y secreción de los niveles de elafina.
Estas dos cepas se ensayaron después en un modelo de colitis inducida por DSS y confirmamos in vivo que el htrA mutante protege a los ratones contra los daños de la colitis mejor que la cepa wt (Fig. 9A, B y C).
Comparación de resultados
Evaluamos en paralelo los efectos protectores de las cepas L. casei que producen IL-10, superóxido dismutasa (SOD) y elafina en un modelo de colitis inducida por DSS 5%. Debe recordarse que L. casei posee dos diferencias importantes comparado con L. lactis: i) mayor persistencia en el TGI y ii) propiedades anti-inflamatorias intrínsecas (Rochat et al, 2007; Watterlot et al, 2010). Como se muestra en la Fig. 10A/B/C, los mejores efectos protectores sobre los tres criterios (macroscópico, histológico y actividad MPO) se obtuvieron con la cepa L. casei que produce Elafina seguido por la cepa de L. casei que produce SOD. La cepa L. casei que produce IL-10 proporcionó sólo efectos pobres.
Por otra parte, la cepa L. casei que produce elafina permitió una mejor protección que las dos cepas de L. lactis (cepa L. lactis wt y htrA) (Fig. 11).
Estos resultados son muy sorprendentes considerando el hecho de que elafina posee actividades antibacterianas in vitro e in vivo [Simpson AJ et al, 1999]. Por consiguiente, el experto en la técnica habría esperado una pobre o ninguna producción por la bacteria hospedadora. Por el contrario, los resultados obtenidos por los inventores muestran una producción muy buena de elafina por el probiótico y una mejora del efecto terapéutico.
Por otra parte, ambos estudios in vitro e in vivo (incluyendo los estudios clínicos) mostraron que la falta de protección del hospedador antimicrobiano es potencialmente perjudicial en enfermedades colónicas [Salzman NH et al, 2003 y Bevins CL et al, 2009].
Por tanto, la actividad anti-microbiana pleiotrópica/anti-inflamatoria de la elafina la hace una muy buena molécula terapéutica candidata en comparación a IL-10.
Inducción por EDTA de la expresión del Promotor Zinc (PZn) controlada por zitR en L. lactis. La producción de elafina en L. lactis dirigida por PZn zitR [Llull D y Poquet I. 2004] se ensayó mediante análisis Western blot después de 1 hora de inducción con 1 mM de EDTA. Muestras de cultivos no inducidos, de gránulo celular (C) y
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Vergnolle, N., L.Cellars, A.Mencarelli ,G.Rizzo, S.Swaminathan, P.Beck, M.Steinhoff, P.Andrade-Gordon, N.W.Bunnet, M.D.Hollenberg, J.L.Wallace, G.Cirino, y S.Fiorucci. 2004. Un papel para el receptor-1 activado por la proteinasa en enfermedades inflamatorias intestinales. J Clin Invest 114:1444-1456.
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Claims (1)

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ES11700274.1T 2010-01-14 2011-01-14 Bacteria probiótica recombinante para la prevención y tratamiento de la Enfermedad Inflamatoria Intestinal (EII) y del Síndrome del Intestino Irritable (SII) Active ES2613755T3 (es)

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EP10305045 2010-01-14
EP10305045 2010-01-14
PCT/EP2011/050489 WO2011086172A1 (en) 2010-01-14 2011-01-14 Recombinant probiotic bacteria for the prevention and treatment of inflammatory bowel disease (ibd) and irritable bowel syndrome (ibs)

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ES2613755T3 true ES2613755T3 (es) 2017-05-25

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US (3) US20120195859A1 (es)
EP (1) EP2451467B1 (es)
JP (1) JP6007106B2 (es)
KR (1) KR101667982B1 (es)
CN (1) CN102740867A (es)
AU (1) AU2011206532B8 (es)
BR (1) BR112012016982B8 (es)
CA (1) CA2786847C (es)
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WO (1) WO2011086172A1 (es)

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CN110331148B (zh) * 2019-08-20 2021-05-04 华中农业大学 一种编码IFNα蛋白的基因、重组载体pELSH-IFNα、重组干酪乳杆菌及应用
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CN111617099B (zh) * 2020-06-16 2022-12-20 青岛农业大学 一种无抗高细胞亲和性结肠炎修复剂与应用方法
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EP1560935A2 (en) * 2002-11-15 2005-08-10 VIB vzw Self-containing lactobacillus strain
KR20110027823A (ko) * 2004-03-24 2011-03-16 트리패스 이미징, 인코포레이티드 자궁경부 질환의 검사 방법 및 조성물
WO2005111194A1 (en) * 2004-05-18 2005-11-24 Vib Vzw Self-containing lactobacillus strain

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US9688742B2 (en) 2017-06-27
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