Compositions and methods for treating disease associated with permeability of intestinal epithelium
Inventors
MADAN, Jay P. • BLIKSLAGER, ANTHONY • Laumas, Sandeep
Assignees
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Publication Number
US-11058902-B2
Publication Date
2021-07-13
Expiration Date
Abstract
The present invention provides methods for treating disorders associated with intestinal barrier dysfunction and increased intestinal permeability. The invention involves administering an effective amount larazotide or a larazotide derivative to a subject or a patient in need thereof.
Core Innovation
The disclosed invention relates to treating a subject having intestinal barrier dysfunction and increased intestinal permeability by administering larazotide or a larazotide derivative, including derivatives with one or two amino acid modifications relative to SEQ ID NO: 1 and/or one or more (d)-amino acids. The approach links intestinal barrier restoration to reduced passage of toxins such as lipopolysaccharide (LPS) through the intestinal barrier and is associated with clinical and disease contexts involving increased permeability, including necrotizing enterocolitis (NEC), ischemic colitis, intestinal volvulus, and sepsis.
For ischemic intestinal conditions, the invention specifies treating ischemic colitis and intestinal volvulus by administering an effective amount of larazotide or a derivative using a sustained release or controlled release formulation. The formulation releases larazotide or derivative to the small and/or large intestine while maintaining functional peptide release over a sustained period during exposure to simulated intestinal fluid.
The disclosed formulation concepts also include enteric and gastric-resistant coatings and colon-targeted delivery concepts. The document ties these release strategies to preserving functional activity and maintaining therapeutic effect while controlling release kinetics, and reports dose-dependent recovery of transepithelial resistance with changes in tight junction proteins, including increased occludin and reduced claudin-2, and reduced LPS permeability.
Claims Coverage
The partial content provides two independent claims. Across these claims, the inventive coverage is directed to administering larazotide or specified larazotide derivatives to subjects with ischemic colitis or intestinal volvulus, with one claim further requiring sustained or controlled release delivery to the small and/or large intestine and maintained peptide release during exposure to simulated intestinal fluid.
Sustained or controlled release treatment for ischemic intestinal condition
A method for treating a subject having an ischemic intestinal condition selected from ischemic colitis and intestinal volvulus, comprising administering an effective amount of larazotide, or a larazotide derivative having one or two amino acid modifications with respect to SEQ ID NO: 1 and/or having one or more (d)-amino acids, wherein the larazotide or derivative is administered in a sustained release or controlled release formulation that releases from about 0.5 to about 5 mg of larazotide or derivative to the small and/or large intestine, and wherein the formulation releases peptide for at least about 2 hours during exposure to simulated intestinal fluid.
Direct larazotide or modified derivative for ischemic colitis or intestinal volvulus
A method for treating a subject having an ischemic intestinal condition selected from ischemic colitis and intestinal volvulus, comprising administering an effective amount of larazotide, or a larazotide derivative having one or two amino acid modifications with respect to SEQ ID NO: 1 and/or having one or more (d)-amino acids, to the subject.
The claim set centers on larazotide or specified larazotide derivatives for ischemic colitis or intestinal volvulus, with one independent claim adding sustained/controlled release delivery and maintained peptide release during simulated intestinal-fluid exposure.
Stated Advantages
Restores intestinal barrier function associated with reduced toxin translocation, including reduced LPS permeability.
Provides sustained peptide functional activity by releasing peptide for at least about 2 hours during exposure to simulated intestinal fluid.
Avoids accumulation of inactive peptide fragments that act as competitive inhibitors.
Increases occludin and reduces claudin-2 in the jejunum in an ischemia/reperfusion context described in the disclosure.
Produces dose-dependent recovery of transepithelial resistance in the described porcine ischemia/reperfusion jejunum study.
Documented Applications
Treating a subject with an ischemic intestinal condition selected from ischemic colitis and intestinal volvulus.
Treating intestinal barrier dysfunction/increased intestinal permeability associated with necrotizing enterocolitis (NEC) using larazotide or modified larazotide derivatives.
Treating ischemic colitis using larazotide or modified larazotide derivatives, with described mild-to-moderate and severe contexts.
Treating intestinal volvulus and sepsis contexts via reduced toxin translocation through the intestinal barrier.
Treating liver diseases including NAFLD, NASH, cirrhosis, and hepatitis described through reduced toxin (e.g., LPS) translocation.
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