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US20090069247A1 - Use of tight junction antagonists to treat inflammatory bowel disease - Google Patents

Use of tight junction antagonists to treat inflammatory bowel disease Download PDF

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Publication number
US20090069247A1
US20090069247A1 US11/869,230 US86923007A US2009069247A1 US 20090069247 A1 US20090069247 A1 US 20090069247A1 US 86923007 A US86923007 A US 86923007A US 2009069247 A1 US2009069247 A1 US 2009069247A1
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seq
peptide
tight junction
composition
antagonist
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Blake Paterson
Amir Tamiz
Niranjan Pandey
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9 Meters Biopharma Inc
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Individual
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Priority to US11/869,230 priority Critical patent/US20090069247A1/en
Assigned to ALBA THERAPEUTICS CORPORATION reassignment ALBA THERAPEUTICS CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PANDEY, NIRANJAN, PATERSON, BLAKE, TAMIZ, AMIR
Publication of US20090069247A1 publication Critical patent/US20090069247A1/en
Priority to US12/789,081 priority patent/US8299017B2/en
Priority to US13/625,293 priority patent/US8796203B2/en
Priority to US14/305,409 priority patent/US20140296165A1/en
Priority to US15/014,731 priority patent/US20160151449A1/en
Abandoned legal-status Critical Current

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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • IBD Inflammatory bowel disease
  • CD Crohn's disease
  • UC ulcerative colitis
  • IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity (Heller, et al., Gastroenterology 129(2): 550-64, 2005).
  • TNF- ⁇ has been implicated in the pathology of CD and antibodies directed against TNF- ⁇ have been used to treat CD (see Nakamura, et al. World J Gastroenterol 2006 August 7; 12(29): 4628-4635).
  • the barrier function of the intestines is impaired in IBD.
  • Crohn's disease is associated with increased permeability of the intestinal barrier even in quiescent patients (Oshitani, et al., Int J Mol Med 15(3):407-10, 2005).
  • a TNF- ⁇ -induced increase in intestinal epithelial tight junction (TJ) permeability has been proposed to be an important proinflammatory mechanism contributing to intestinal inflammation in Crohn's disease and other inflammatory conditions (see Ye et al., American Journal of Physiology-Gastrointestinal and Liver Physiology, 290(3):496-504, 2006).
  • Increased intestinal permeability during episodes of active disease correlates with destruction or rearrangement of the tight junction protein complex (Willemsen, et al. Clin. Exp. Immunol. 142(2): 275-284, 2005).
  • ZOT Zonula occludens toxin
  • Peptide antagonists of tight junction opening were described in U.S. Pat. No. 6,458,925, which is incorporated by reference herein in its entirety, which corresponds to WO 00/07609.
  • Peptide antagonists of tight junction opening may bind to the receptor utilized by the zonnula occludens toxin expressed by Vibrio cholerae , yet not function to physiologically modulate the opening of mammalian tight junctions.
  • the peptide antagonists competitively inhibit the binding of ZOT and zonulin to the ZOT receptor, thereby inhibiting the ability of ZOT and zonulin to physiologically modulate the opening of mammalian tight junctions.
  • the main treatments available for IBD are steroids and immunosuppressive agents which non-specifically reduce immunity and inflammation. These therapies are prone to undesired side effects. There remains a need in the art for treatments of IBD. This need and others are met by the present invention.
  • the present invention provides methods and materials for treating inflammatory bowel disease.
  • the invention provides methods of treating inflammatory bowel disease comprising administering to a subject in need thereof a composition comprising a tight junction antagonist.
  • a “subject” may be any mammal, for example, a human, dog, cat, horse, cow, etc.
  • a subject may be a human.
  • a subject may be a dog.
  • Any tight junction antagonist may be used, for example, a tight junction antagonist of the invention may be a peptide.
  • the peptide may comprise one or more of SEQ ID NOs: 1-24, which may be on the same or different molecules.
  • a peptide tight junction antagonist may comprise the sequence GGVLVQPG (SEQ ID NO: 15). In some embodiments, the peptide tight junction antagonist may consist essentially of the sequence GGVLVQPG (SEQ ID NO: 15).
  • Compositions suitable for use in treating IBD may be formulated in any manner known to those skilled in the art.
  • a composition suitable for treating IBD may comprise a tight junction antagonist and may be a delayed release composition.
  • Compositions for use in treating IBD, delayed release or otherwise may comprise one or more tight junction antagonists and one or more therapeutic agents. Suitable therapeutic agents include, but are not limited to, aminosalicylates, corticosteroids, immunomodulators, antibiotics, and biologic therapeutics.
  • a composition suitable for treating IBD may comprise a peptide tight junction antagonist (e.g., a peptide comprising SEQ ID NO: 15) and a therapeutic agent, e.g., a steroid.
  • the present invention provides methods and materials for treating Crohn's disease.
  • the invention provides methods of treating Crohn's disease comprising administering to a subject in need thereof a composition comprising a tight junction antagonist.
  • Any tight junction antagonist may be used, for example, a tight junction antagonist of the invention may be a peptide.
  • the peptide may comprise one or more of SEQ ID NOs: 1-24, which may be on the same or different molecules.
  • a peptide tight junction antagonist may comprise the sequence GGVLVQPG (SEQ ID NO:15).
  • the peptide tight junction antagonist may consist essentially of the sequence GGVLVQPG (SEQ ID NO:15).
  • compositions suitable for use in treating Crohn's disease may be formulated in any manner known to those skilled in the art.
  • a composition suitable for treating Crohn's disease may comprise a tight junction antagonist and may be a delayed release composition.
  • Compositions for use in treating Crohn's disease, delayed release or otherwise may comprise one or more tight junction antagonists and one or more therapeutic agents.
  • Suitable therapeutic agents include, but are not limited to, aminosalicylates, corticosteroids, immunomodulators, antibiotics, and biologic therapeutics.
  • a composition suitable for treating Crohn's disease may comprise a peptide tight junction antagonist (e.g., a peptide comprising SEQ ID NO: 15) and a therapeutic agent, e.g., a steroid.
  • a peptide tight junction antagonist e.g., a peptide comprising SEQ ID NO: 15
  • a therapeutic agent e.g., a steroid.
  • the present invention provides methods and materials for treating ulcerative colitis.
  • the invention provides methods of treating ulcerative colitis comprising administering to a subject in need thereof a composition comprising a tight junction antagonist.
  • a tight junction antagonist of the invention may be a peptide.
  • the peptide may comprise one or more of SEQ ID NOs: 1-24, which may be on the same or different molecules.
  • a peptide tight junction antagonist may comprise the sequence GGVLVQPG (SEQ ID NO:15).
  • the peptide tight junction antagonist may consist essentially of the sequence GGVLVQPG (SEQ ID NO:15).
  • compositions suitable for use in treating ulcerative colitis may be formulated in any manner known to those skilled in the art.
  • a composition suitable for treating ulcerative colitis may comprise a tight junction antagonist and may be a delayed release composition.
  • Compositions for use in treating ulcerative colitis, delayed release or otherwise may comprise one or more tight junction antagonists and one or more therapeutic agents.
  • Suitable therapeutic agents include, but are not limited to, aminosalicylates, corticosteroids, immunomodulators, antibiotics, and biologic therapeutics.
  • a composition suitable for treating ulcerative colitis may comprise a peptide tight junction antagonist (e.g., a peptide comprising SEQ ID NO: 15) and a therapeutic agent, e.g., a steroid.
  • FIG. 1 shows Body Weight area under the curve from 4-17 weeks of age.
  • FIG. 2 shows a measurement of Gastric Permeability measured as sucrose excretion.
  • FIG. 3 shows Small Intestinal Permeability measured by lactulose mannitol test.
  • FIG. 4 shows Small Intestinal Permeability measured by lactulose mannitol test.
  • FIG. 5 shows in vitro measurement of colonic permeability at 8 weeks of age.
  • FIG. 6 shows in vitro colonic electrical resistance at 8 weeks of age.
  • FIG. 7 shows colonic inflammation (neutrophil infiltration) at 17 weeks.
  • FIG. 8 shows colonic inflammation at 17 weeks (TNF secretion over 24 hours).
  • FIG. 9 shows colonic inflammation at 17 weeks (IFN secretion over 24 hours).
  • FIG. 10 shows Colonic Permeability as measured by sucralose excretion.
  • tight junction antagonists prevent, inhibit or reduce the opening of tight junctions.
  • a tight junction antagonist may bind to the zonulin receptor and prevent, inhibit, reduce or reverse the tight junction opening triggered by zonulin.
  • antagonists of the invention may comprise peptide antagonists. Examples of peptide antagonists include, but are not limited to, peptides that comprise an amino acid sequence selected from the group consisting of
  • any length of peptide may be used.
  • the size of the peptide antagonist will range from about 6 to about 100, from about 6 to about 90, from about 6 to about 80, from about 6 to about 70, from about 6 to about 60, from about 6 to about 50, from about 6 to about 40, from about 6 to about 30, from about 6 to about 25, from about 6 to about 20, from about 6 to about 15, from about 6 to about 14, from about 6 to about 13, from about 6 to about 12, from about 6 to about 11, from about 6 to about 10, from about 6 to about 9, or from about 6 to about 8 amino acids in length.
  • Peptide antagonists of the invention may be from about 8 to about 100, from about 8 to about 90, from about 8 to about 80, from about 8 to about 70, from about 8 to about 60, from about 8 to about 50, from about 8 to about 40, from about 8 to about 30, from about 8 to about 25, from about 8 to about 20, from about 8 to about 15, from about 8 to about 14, from about 8 to about 13, from about 8 to about 12, from about 8 to about 11, or from about 8 to about 10 amino acids in length.
  • Peptide antagonists of the invention may be from about 10 to about 100, from about 10 to about 90, from about 10 to about 80, from about 10 to about 70, from about 10 to about 60, from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, from about 10 to about 25, from about 10 to about 20, from about 10 to about 15, from about 10 to about 14, from about 10 to about 13, or from about 10 to about 12 amino acids in length.
  • Peptide antagonists of the invention may be from about 12 to about 100, from about 12 to about 90, from about 12 to about 80, from about 12 to about 70, from about 12 to about 60, from about 12 to about 50, from about 12 to about 40, from about 12 to about 30, from about 12 to about 25, from about 12 to about 20, from about 12 to about 15, or from about 12 to about 14 amino acids in length.
  • Peptide antagonists of the invention may be from about 15 to about 100, from about 15 to about 90, from about 15 to about 80, from about 15 to about 70, from about 15 to about 60, from about 15 to about 50, from about 15 to about 40, from about 15 to about 30, from about 15 to about 25, from about 15 to about 20, from about 19 to about 15, from about 15 to about 18, or from about 17 to about 15 amino acids in length.
  • the peptide antagonists can be chemically synthesized and purified using well-known techniques, such as described in High Performance Liquid Chromatography of Peptides and Proteins: Separation Analysis and Conformation , Eds. Mant et al., C.R.C. Press (1991), and a peptide synthesizer, such as Symphony (Protein Technologies, Inc); or by using recombinant DNA techniques, i.e., where the nucleotide sequence encoding the peptide is inserted in an appropriate expression vector, e.g., an E. coli or yeast expression vector, expressed in the respective host cell, and purified therefrom using well-known techniques.
  • an appropriate expression vector e.g., an E. coli or yeast expression vector
  • compositions of the invention may be formulated for enteric delivery, for example, may comprise one or more coatings, for example, delayed release coating containing one or more enteric agents.
  • a delayed release coating is typically substantially stable in gastric fluid and substantially unstable (e.g., dissolves rapidly or is physically unstable) in intestinal fluid, thus providing for substantial release of the tight junction antagonist from the composition in the duodenum or the jejunum.
  • compositions comprising a tight junction antagonist comprise a pharmaceutically effective amount of the antagonist.
  • the pharmaceutically effective amount of antagonist (e.g., peptide antagonist) employed may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Compositions of the invention may comprise one or more tight junction antagonists at a level of from about 0.1 wt % to about 20 wt %, from about 0.1 wt % to about 18 wt %, from about 0.1 wt % to about 16 wt %, from about 0.1 wt % to about 14 wt %, from about 0.1 wt % to about 12 wt %, from about 0.1 wt % to about 10 wt %, from about 0.1 wt % to about 8 wt %, from about 0.1 wt % to about 6 wt %, from about 0.1 wt % to about 4 wt %, from about 0.1 wt % to about 2 wt %, from about 0.1 wt % to about 1 wt %, from about 0.1 wt % to about 0.9 wt %, from about 0.1 wt % to about 0.8 wt
  • Compositions of the invention may comprise one or more tight junction antagonists at a level of about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, or about 0.9 wt % based on the total weight of the composition.
  • Compositions of the invention may comprise one or more tight junction antagonists at a level of from about 1 wt % to about 20 wt %, from about 1 wt % to about 18 wt %, from about 1 wt % to about 16 wt %, from about 1 wt % to about 14 wt %, from about 1 wt % to about 12 wt %, from about 1 wt % to about 10 wt %, from about 1 wt % to about 9 wt %, from about 1 wt % to about 8 wt %, from about 1 wt % to about 7 wt %, from about 1 wt % to about 6 wt %, from about 1 wt % to about 5 wt %, from about 1 wt % to about 4 wt %, from about 1 wt % to about 3 wt %, or from about 1 wt % to about 2
  • Compositions of the invention may comprise one or more tight junction effectors at a level of about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, or about 9 wt % based on the total weight of the composition.
  • stable in gastric fluid or “stable in acidic environments” refers to a composition that releases 30% or less by weight of the total tight junction antagonist in the composition in gastric fluid with a pH of 5 or less, or simulated gastric fluid with a pH of 5 or less, in approximately sixty minutes.
  • compositions of the of the invention may release from about 0% to about 30%, from about 0% to about 25%, from about 0% to about 20%, from about 0% to about 15%, from about 0% to about 10%, 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 5% to about 10% by weight of the total tight junction antagonist in the composition in gastric fluid with a pH of 5, or less or simulated gastric fluid with a pH of or less, in approximately sixty minutes.
  • “about” used to modify a numerical value means within 10% of the value.
  • compositions of the invention may release about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of the total tight junction antagonist in the composition in gastric fluid with a pH of 5 or less, or simulated gastric fluid with a pH of 5 or less, in approximately sixty minutes.
  • unstable in intestinal fluid refers to a composition that releases 70% or more by weight of the total tight junction antagonist in the composition in intestinal fluid or simulated intestinal fluid in approximately sixty minutes.
  • stable in near neutral to alkaline environments refers to a composition that releases 70% or more by weight of the total amount of tight junction antagonist in the composition in intestinal fluid with a pH of 5 or greater, or simulated intestinal fluid with a pH of 5 or greater, in approximately ninety minutes.
  • a composition that is unstable in near neutral or alkaline environments may release 70% or more by weight of a tight junction antagonist peptide in a fluid having a pH greater than about 5 (e.g., a fluid having a pH of from about 5 to about 14, from about 6 to about 14, from about 7 to about 14, from about 8 to about 14, from about 9 to about 14, from about 10 to about 14, or from about 11 to about 14) in from about 5 minutes to about 90 minutes, or from about 10 minutes to about 90 minutes, or from about 15 minutes to about 90 minutes, or from about 20 minutes to about 90 minutes, or from about 25 minutes to about 90 minutes, or from about 30 minutes to about 90 minutes, or from about 5 minutes to about 60 minutes, or from about 10 minutes to about 60 minutes, or from about 15 minutes to about 60 minutes, or from about 20 minutes to about 60 minutes, or from about 25 minutes to about 90 minutes, or from about 30 minutes to about 60 minutes.
  • compositions of the invention may further comprise one or more therapeutic agents.
  • therapeutic agents include, but are not limited to, steroids and other anti-inflammatory compounds.
  • Suitable therapeutic agents may include one or more of aminosalicylates, corticosteroids, immunomodulators, antibiotics, and biologic therapies.
  • suitable therapeutic agents that may be included in the compositions of the invention to treat IBD (e.g., Crohn's disease and/or ulcerative colitis) include, but are not limited to:
  • 5-ASA agents e.g., Sulfasalazine
  • Azulfidine®l Asacol
  • ® Dipentum ® Pentasa,® and Rowasa®
  • Pentasa ® and Rowasa®
  • Antibiotics for example, metronidazole (Flagyl®) and ciprofloxacin (Cipro®), although there are many others that may be effective in certain individuals;
  • Steroids e.g., corticosteroids.
  • Suitable steroids include, but are not limited to, prednisone, hydrocortisone, Medrol®, and budesonide multiple-release capsule MRC (EntocortREC®).
  • 6-mercaptopurine (6-MP, Purinethol®) and azathioprine (Imuran®);
  • Infliximab antibodies against inflammatory cytokines, e.g., Infliximab (RemicadeTM).
  • compositions of the invention may also comprise one or more pharmaceutically acceptable excipients.
  • suitable excipients include, but are not limited to, buffers, buffer salts, bulking agents, salts, surface active agents, acids, bases, and binders.
  • compositions of the invention can be used for preventing, slowing the onset of, ameliorating and/or treating IBD (e.g., Crohn's disease and/or ulcerative colitis).
  • IBD e.g., Crohn's disease and/or ulcerative colitis
  • the present invention provides a method of treating Crohn's disease by administering a composition comprising one or more tight junction antagonists.
  • the present invention provides a method of treating ulcerative colitis by administering a composition comprising one or more tight junction antagonists.
  • compositions of the invention may be given repeatedly over a protracted period, i.e., may be chronically administered.
  • compositions may be administered one or more times each day in an amount suitable to prevent or reduce the likelihood of an attack of IBD (e.g., Crohn's disease and/or ulcerative colitis).
  • IBD e.g., Crohn's disease and/or ulcerative colitis
  • Such compositions may be administered chronically, for example, one or more times daily over a plurality of days.
  • compositions of the invention may be use to treat acute IBD (e.g., Crohn's disease and/or ulcerative colitis) attacks.
  • acute IBD e.g., Crohn's disease and/or ulcerative colitis
  • embodiments of this type will require administration of the compositions of the invention to a subject undergoing an attack in an amount suitable to reduce the severity of the attack.
  • One or more administration may be used.
  • the purpose of this study is to determine the ability of AT-1001, administered daily in drinking water to alter intestinal permeability (measured by absorption/excretion of lactulose and mannitol) and to inhibit the development of colitis in the 129/Svev/IL-10 KO mouse.
  • Suc/lac/man/sucralose (Groups 1-4) Timepoints 1. Weeks 1-2 Suc/lac/man/suralose solution on days 3, 6, and 9 2. Weeks 3-15 Suc/lac/man/suralose solution first day of every week Probiotic conditioned media: (Group 2) Daily in the mornings (Start Day 1 of study) AT-1001 Neat Chemical 0.1 mg/ml: (Group 3) Ad libidum (Start Day 1 of study) AT-1001 Neat Chemical 1 mg/ml: (Group 4) Ad libidum (Start Day 1 of study) Duration Eighty days Frequency AT-1001: continuously. Suc/lac/man/sucralose: Days 3, 6, 9, 14, 21, 28, 35, 41, 49, 56, 63, 70, 77, 84 Volume Suc/lac/man/sucralose 0.2 mL gavage per animal
  • AT-1001 neat chemical will be administered ad libidum every day starting at day 1 to Group 3 at 0.1 mg/ml and Group 4 at 1 mg/ml in sterile water via the drinking water supply. Dosing of AT-1001 will be continued when the animals are in the metabolic cages for 22 hours. Probiotic conditioned medium will be given every morning to Group 2. The solution is prepared by dissolving 0.01 g in 10 ml of MRS medium and incubating it at 37° C. for 24 h. After incubation, the tube will be centrifuged 10 minutes at 10,000 rpm. The supernatant will be filtered through a 0.22 micron filter and diluted 1:10 with MRS medium. Animals will receive 30 ⁇ l of this dilution every morning.
  • Sucrose/lactulose/mannitol/sucralose solution is prepared by dissolving Sucrose (50 mg), lactulose (6 mg), mannitol (4 mg), and sucralose (3 mg) in water (100 mL).
  • Test Article Suc/lac/man/suralose AT1001 AT1001 solution (neat chemical) (neat chemical) (Groups 1, 2, 3, and 4) (Group 3) (Group 4) Type of Solution in water Oral solution in Oral solution in Formulation drinking water drinking water
  • Animals to be used on this study will be selected on the basis of acceptable findings from physical examination and body weights. The animals will then be assigned to treatment groups prior to dosing.
  • Moribund/unscheduled animals that are sacrificed during normal working hours will be taken immediately to necropsy. A terminal body weight will be taken and the animal will be necropsied. Protocol defined tissues for histology will be taken. Moribund/unscheduled sacrifice animals that are sacrificed outside of normal working hours will be refrigerated after a terminal body weight and necropsied at the earliest possible time (within working hours). Organ weights will not be collected unless the entire study is sacrificed early and control organ weights can be collected at the same time or the study is taken down at the scheduled sacrifice.
  • stomachs, small intestines, and colons will be collected and weighed. Each tissue will be scored for macroscopic lesions to assess intestinal damage by the Study Pathologist. ELISAs will be performed on each tissue to measure the levels of MPO, IL-8, TNF ⁇ , and IFN ⁇ . A section of the tissues will be fixed in formalin for HE histology. The day after the final intestinal permeability measures on day 77, all surviving animals will be euthanized and intestinal tissues collected and processed.
  • Sucrose, lactulose, mannitol, and sucralose and lactulose:mannitol ratios will be determined according to the published procedures.
  • Week 8 Day 57 of study permeability with Sacrifice 4 animals from each group to dissect out stomachs, small Ussing chambers intestines and colons and measure intestinal permeability 2.
  • Week 11 termination of study at day 77 Sacrifice the remaining 8 animals from each group to dissect out stomachs, small intestines and colons and measure intestinal permeability Scoring lesions 1.
  • Day 1 histologically Dissect out stomachs, small intestines and colons of 4 animals in Group 5 for scoring macroscopic lesions as control, fix sections for histology.
  • Week 11 - Day 77 of study Dissect out stomachs, small intestines and colons of remaining 8 animals from Groups 1-4 for scoring macroscopic lesions, fix sections for histology Zonulin levels 1. Sacrifice all 4 animals from Group 5 to measure zonulin levels day 1 2. Week 8 - Day 57 of study Measure zonulin levels in the animals from Groups 1-4 sacrificed on this day 2. Week 11- Day 77 of study Measure zonulin levels in the animals from Groups 1-4 sacrificed on this day Levels of MPO, 1. Measure levels of these proteins in animals from Group 5 IL-8, TNF- ⁇ , IFN ⁇ 2. Measure levels of these proteins in animals from Groups 1-4 at the beginning of Week 8 - Day 57 of study 3. Measure levels of these proteins in animals from Groups 1-4 when study is terminated at Week 11 - Day 77 of study Water 1. Measure water consumption daily for dose measurement consumption
  • FIGS. 1-4 show that development of disease is associated with an increase in small intestinal permeability. This increase can be abrogated by high dose AT-1001.
  • FIG. 5-10 show the results of analysis of disease in the colon.
  • Disease in the colon was evaluated at both 8 and 17 week time points.
  • the former with Ussing chamber measurements and the latter with histology, mucosal cytokine secretion, MPO and sucralose permeability.
  • AT-1001 reduced colonic permeability to mannitol and prevented the reduction in electrical resistance observed in the untreated animals.
  • AT-1001 reduced all tissue markers of colonic inflammation that were measured

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Priority Applications (5)

Application Number Priority Date Filing Date Title
US11/869,230 US20090069247A1 (en) 2006-10-06 2007-10-09 Use of tight junction antagonists to treat inflammatory bowel disease
US12/789,081 US8299017B2 (en) 2006-10-06 2010-05-27 Use of tight junction antagonists to treat inflammatory bowl disease
US13/625,293 US8796203B2 (en) 2006-10-06 2012-09-24 Use of tight junction antagonists to treat inflammatory bowel disease
US14/305,409 US20140296165A1 (en) 2006-10-06 2014-06-16 Use of tight junction antagonists to treat inflammatory bowel disease
US15/014,731 US20160151449A1 (en) 2006-10-06 2016-02-03 Use of tight junction antagonists to treat inflammatory bowel disease

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WO2008043107A2 (fr) 2008-04-10
US20160151449A1 (en) 2016-06-02
US8299017B2 (en) 2012-10-30
US20110136747A1 (en) 2011-06-09
US8796203B2 (en) 2014-08-05
US20130102547A1 (en) 2013-04-25
WO2008043107A3 (fr) 2009-04-09

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