Inhibition of gliadin peptides
Inventors
Alkan, Sefik • Tamiz, Amir • Kitchens, Kelly Marie • Durai, Malarvizhi • Poloso, Neil • Carrasco, Rosa A.
Assignees
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Publication Number
US-8957032-B2
Publication Date
2015-02-17
Expiration Date
Abstract
Novel compounds and methods for the inhibition of biological barrier permeability and for the inhibition of peptide translocation across biological barriers are identified. Assays for determining modulators of biological barrier permeability and for peptide translocation across biological barriers are provided. Methods for treating diseases relating to aberrant biological barrier permeability and peptide translocation across biological barriers are provided. Such diseases include celiac disease, necrotizing enterocolitis, diabetes, cancer, inflammatory bowel diseases, asthma, COPD, excessive or undesirable immune response, gluten sensitivity, gluten allergy, food allergy, rheumatoid arthritis, multiple sclerosis, immune-mediated or type 1 diabetes mellitus, systemic lupus erythematosus, psoriasis, scleroderma and autoimmune thyroid diseases.
Core Innovation
The invention describes peptide permeability inhibitors that inhibit gliadin-derived peptide translocation and are associated with tight-junction function. The peptide inhibitors include peptide sequences identified in the document, including SEQ ID NO:1 (AT-1001) and variants, and specific PTG-derived peptide translocation, including PYPQPQLPY and SEQ ID NO:163, is inhibited.
PBMCs secrete permeability-increasing signals upon stimulation with LPS or with pepsin/trypsin-treated gliadin (PTG). These signals increase CaCO2 paracellular permeability as reflected by lucifer yellow flux and changes in TEER, and the permeability-increasing effects are inhibited by specific peptide inhibitors.
The invention describes use in treating loss of intestinal epithelial barrier integrity associated with an acute intestinal inflammatory attack in a patient having Celiac Disease, including treatment where the patient is undergoing concurrent anti-inflammatory therapy. The peptide of SEQ ID NO:1 is administered to the intestine in a formulation with a delayed release coating that is substantially stable in gastric fluid and substantially unstable in intestinal fluid.
Claims Coverage
The partial content identifies one independent claim and dependent claims refining aspects of the anti-inflammatory agent and the peptide formulation and release behavior. The independent claim contains inventive features focused on timing and dosing of SEQ ID NO:1 delivery after an acute inflammatory attack, concurrent anti-inflammatory therapy, and a delayed-release, gastric-stable/intestinal-unstable formulation.
Treatment of loss of intestinal epithelial barrier integrity in celiac patients after acute inflammatory attack using SEQ ID NO:1
A method for treating loss of intestinal epithelial barrier integrity associated with an acute intestinal inflammatory attack in a patient having Celiac Disease by administering the peptide of SEQ ID NO:1 to the intestine of the patient a plurality of times per day for a plurality of days about 48 hours after the acute intestinal inflammatory attack, where the acute intestinal inflammatory attack involves factors that cause increased permeability of intestinal cells.
Concurrent anti-inflammatory therapy with peptide administration
The method of administering the peptide of SEQ ID NO:1 is carried out while the patient is undergoing therapy with an anti-inflammatory agent selected from an anti-inflammatory steroid or non-steroidal anti-inflammatory agent.
Delayed release coating substantially stable in gastric fluid and substantially unstable in intestinal fluid
The peptide is formulated with a delayed release coating that is substantially stable in gastric fluid and substantially unstable in intestinal fluid.
Delayed release composition delivery
The method includes administering the peptide using a delayed-release composition.
Quantitative delayed-release profile under intestinal pH
The composition releases at least 70% by weight of a peptide within 30 to 90 minutes when exposed to a pH greater than 5.
Anti-inflammatory agent selection: aspirin or aminosalicylate
The anti-inflammatory agent selected from an anti-inflammatory steroid or non-steroidal anti-inflammatory agent is aspirin or an aminosalicylate.
Anti-inflammatory agent selection: corticosteroid
The anti-inflammatory agent selected from an anti-inflammatory steroid or non-steroidal anti-inflammatory agent is a corticosteroid.
Across the independent claim and its dependents, the coverage centers on administering the peptide of SEQ ID NO:1 to the intestine about 48 hours after an acute intestinal inflammatory attack in Celiac Disease with increased permeability, while the patient receives anti-inflammatory therapy, and with a delayed-release coating characterized as gastric-stable and intestinal-unstable, including an explicit release threshold in intestinal pH conditions.
Stated Advantages
Inhibits gliadin-induced TJ disassembly.
Inhibits gliadin-derived peptide translocation.
Inhibits permeability-increasing signals that increase CaCO2 paracellular permeability (lucifer yellow flux and TEER changes).
Protects or maintains intestinal epithelial barrier integrity in the context of an acute intestinal inflammatory attack associated with increased permeability in celiac patients.
Documented Applications
Treatment of loss of intestinal epithelial barrier integrity associated with an acute intestinal inflammatory attack in a patient having Celiac Disease.
Treatment applications spanning celiac disease and other inflammation/autoimmune and barrier dysfunction-associated diseases, including necrotizing enterocolitis, inflammatory bowel disease (Crohn's, ulcerative colitis), asthma, COPD, food allergy, gluten sensitivity, gluten allergy, systemic lupus erythematosus, psoriasis, multiple sclerosis, and type 1 diabetes mellitus.
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