Compositions and methods for treating or preventing intestinal paracellular permeability
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Publication Number
US-12016889-B2
Publication Date
2024-06-25
Expiration Date
Abstract
The present invention provides methods and compositions for maintaining and improving the integrity of gastrointestinal epithelial tight junctions, thereby helping to maintain healthy paracellular permeability of the GI epithelium. The present invention provides methods and compositions for the treatment or prevention of various conditions that are associated with gastrointestinal paracellular permeability, including various autoimmune conditions, inflammatory liver diseases, as well as inflammatory conditions of the large or small intestines.
Core Innovation
The invention relates to engineered commensal/probiotic microorganisms and engineered bacteriophages for heterologous expression of a peptide that consists of the amino acid sequence of larazotide (SEQ ID NO: 1) or a larazotide derivative. The engineered microorganism or bacteriophage includes a polynucleotide encoding the larazotide peptide and a promoter controlling expression of the peptide in a host context. The system is configured to target the duodenum and/or jejunum by using microorganisms that are naturally present in the duodenum and/or jejunum and by using bacteriophages that infect host bacteria naturally present in the duodenum and/or jejunum.
The encoded larazotide peptide can be expressed under a promoter and can also include an N-terminus secretory signal for secretion, including cleavage associated with the secretory signal. The described genetic implementations include promoter-driven expression, and the polynucleotide may be provided on plasmids with chromosomal integration and transposon integration. For bacteriophages, different phage types are described, including lytic phage and lysogenic phage, and phage classification can be provided using viral taxonomy such as Caudovirales, Siphoviridae, Myoviridae, and Podoviridae.
The invention further defines the larazotide peptide scope as including larazotide variants described as peptide derivatives with substitutions and deletions, and optionally peptide fusions of multiple peptide copies with protease cleavage to form monomer or dimer. The described approach is aimed at improving intestinal epithelial tight-junction integrity while maintaining GI paracellular permeability, and it is carried out by administering the engineered microorganism and/or engineered bacteriophage to subjects.
The disclosed use contexts include prevention or treatment of paracellular permeability-associated conditions, with specific examples including celiac disease, inflammatory bowel disease, and irritable bowel syndrome. Additional described conditions include environmental enteropathy/environmental enteric dysfunction, necrotizing enterocolitis, and inflammatory liver diseases including NAFLD, NASH, and various hepatitis types, as well as other autoimmune/inflammatory diseases and ischemic injury to intestines such as ischemic colitis.
Claims Coverage
The document provides two independent claims: one directed to an engineered microorganism and one directed to an engineered bacteriophage. The independent claims share the common inventive concept of encoding a larazotide peptide (SEQ ID NO: 1) under promoter control and situating expression through duodenum/jejunum-relevant host presence or infection.
Duodenum/jejunum-resident microorganism expressing larazotide
A microorganism comprising a polynucleotide encoding a peptide that consists of the amino acid sequence of larazotide (SEQ ID NO: 1), the polynucleotide further comprising a promoter controlling expression of the peptide, wherein the microorganism is a species or strain naturally present in the duodenum and/or jejunum.
Duodenum/jejunum-infecting bacteriophage expressing larazotide
A bacteriophage comprising a polynucleotide encoding a peptide that consists of the amino acid sequence of larazotide (SEQ ID NO: 1), the polynucleotide further comprising a promoter controlling expression of the peptide in a host bacteria, wherein the bacteriophage infects a host bacteria naturally present in the duodenum and/or jejunum.
Across both independent claims, the inventive core is a larazotide (SEQ ID NO: 1) encoding polynucleotide controlled by a promoter, positioned in the duodenum/jejunum via either a microorganism naturally present there or via a bacteriophage that infects bacteria naturally present there. The dependent claims further refine these constructs by adding features such as an N-terminal secretory signal, restricting microorganism/host to commensal or probiotic categories and enumerated genera/species, and specifying bacteriophage lifecycle and phage taxonomy.
Stated Advantages
Improves intestinal epithelial tight-junction integrity.
Maintains GI paracellular permeability.
Prevents or treats paracellular permeability-associated conditions.
Supports delivery to the duodenum and/or jejunum using microorganisms naturally present there and bacteriophages infecting naturally present host bacteria.
Documented Applications
Prevention or treatment of celiac disease, including refractory/non-responsive celiac disease.
Prevention or treatment of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis.
Prevention or treatment of irritable bowel syndrome, including IBS-D/IBS-C/IBS-A.
Prevention or treatment of environmental enteropathy/environmental enteric dysfunction.
Prevention or treatment of necrotizing enterocolitis, including pediatric/premature infant cases.
Prevention or treatment of inflammatory liver diseases, including NAFLD and NASH, and hepatitis types (A/B/C/D/E), as well as alcoholic hepatitis and autoimmune hepatitis.
Prevention or treatment of autoimmune/inflammatory diseases, including diabetes mellitus, rheumatoid arthritis, multiple sclerosis, Sjögren’s, SLE, and ankylosing spondylitis.
Prevention or treatment of ischemic injury to intestines, including ischemic colitis.
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