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Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems

a technology for delivering compounds and mucous membranes, applied in drug compositions, blood/immune system cells, immunological disorders, etc., can solve the problems of alarmingly increasing incidence of diseases, challenging system and immunomodulatory properties, and challenging effective delivery of desired compounds or substances to mucous membranes, etc., to suppress immunity, reduce dendritic cell activation, and inhibit t cell proliferation

Inactive Publication Date: 2016-05-26
CALIFORNIA INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Effective delivery of a desired compound or substance to mucous membrane has been challenging in particular when referred to delivery to the digestive tract, and in particular to human gastrointestinal tract.
However, identification of the mechanism and / or molecular triggers by which B. fragilis (or any commensal bacteria) delivers beneficial microbial molecules to the immune system and performs the immunomodulatory properties has been challenging.
In addition to the medical and social burden of IBD, the incidences of disease are alarmingly increasing in ‘Western’ societies and current therapies are largely inadequate.

Method used

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  • Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
  • Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
  • Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems

Examples

Experimental program
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Effect test

example 1

Immunomodulatory Capsular Polysaccharide PSA is Actively Sorted into OMVs of B. fragilis

[0176]Ultrathin sections of EDL-enriched B. fragilis were prepared as described in materials and methods and imaged by transmission electron microscopy.

[0177]The results illustrated in FIG. 1a show that OMVs were abundantly produced by bacteria, and could be observed budding from the bacterial envelope (FIG. 1a, higher magnification). Applicants' previous studies have shown that deletion of PSA abrogates the immunomodulatory capacity of B. fragilis (Mazmanian, Liu, Tzianabos, and Kasper (2005) An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System. Cell 122:1 107-118) (Mazmanian, Round, and Kasper (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 453 (7195) 620-625. Electron micrographs of a PSA mutant strain (B. fragilis ΔPSA) illustrate no defect in OMV synthesis, and the size, shape and abundance of OMVs produced wer...

example 2

OMVs Protect Animals from Experimental Colitis and Intestinal Inflammation in a PSA-Dependent Manner

[0184]To investigate if OMVs can ameliorate clinical symptoms of disease, mice were treated by gavage with OMVs during the induction of TNBS (2,4,6-trinitrobenzene sulfonic acid) colitis.

[0185]The results illustrated in FIG. 2a indicate that control animals rapidly lost weight following rectal administration of TNBS (FIG. 2a; TNBS+PBS), which did not recover compared to vehicle treated mice (FIG. 2a; ETOH+PBS). Remarkably, OMVs given orally to TNBS animals significantly protected from weight loss (FIG. 2a; TNBS+WT-OMV). Most importantly, when OMVs from B. fragilis ΔPSA were administered, weight loss was indistinguishable from TNBS animals (FIG. 2a; TNBS+ΔPSA-OMV), demonstrating that PSA is responsible for preventing wasting disease.

[0186]Our efforts to detect intact vesicles in the colon after intra-gastric gavage were confounded by observations of host-derived vesicles, even in germ-...

example 3

PSA Containing OMVs Inhibits TNF-α / IL-17, Enhances IL-10 Expression

[0192]The production of canonical pro- and anti-inflammatory cytokines associated with colitis was measured in mice treated as exemplified in Example 2. In particular, cytokine transcript analysis was performed by qRT-PCR from RNA recovered from whole colons or purified CD4+ T cell from mesenteric lymph nodes.

[0193]The relevant results representative of 3 independent trials are reported in FIG. 2e (whole colons) and FIG. 2f (purified CD4+ T cell from mesenteric lymph nodes). Those results show that transcript levels of pro-inflammatory biomarkers / cytokines tumor necrosis factor (TNF-α) and IL-17A were elevated in TNBS− treated animals, but reduced by OMV administration in a PSA-dependent manner (FIG. 2e). Consistent with protection from pathology, OMVs elicited the production of increased anti-inflammatory biomarkers / cytokines IL-10 levels compared to animals orally given ΔPSA-OMV (FIG. 2f). Analysis of cytokine prod...

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Abstract

PSA is delivered to the host by outer membrane vesicles (OMVs), secretion structures that target bacterial molecules to host cells. Purified OMVs direct the in vitro differentiation of functional Tregs with potent suppressive activity in a PSA dependent manner. Treatment of animals with OMVs containing PSA prevents experimental colitis and suppresses pro-inflammatory cytokine responses in the gut, and indicate that compositions, medicaments, and methods useful for the treatment of inflammation, and more particularly, inflammatory bowel diseases.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of application Ser. No. 13 / 082,183, filed on Apr. 7, 2011, which claims the benefit of Provisional Patent Application No. 61 / 321,527, filed on Apr. 7, 2010, and Provisional Patent Application No. 61 / 345,039 filed on May 14, 2010, all of which are incorporated by reference herein.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The invention was made with government support under Grant No. DK078938 awarded by the National Institutes of Health. The government has certain rights in the inventionREFERENCE TO SEQUENCE LISTING[0003]A Sequence Listing is submitted electronically via EFS-Web as an ASCII formatted text file with the name “7920110N1ST25”; the file was created on Jul. 16, 2015, is 2.04 kilobytes in size, and is incorporated herein by reference in its entirety.BACKGROUND[0004]1. Field of the Invention[0005]The present disclosure relates to a vehicle for delivering a c...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/715C12N5/0783G01N33/50A61K9/10A61K39/00
CPCA61K31/715A61K9/10A23L1/30G01N33/505C12N5/0637A61K39/0216A61K2039/542A61K2039/55555A61K2039/55583A61K2039/57A61K2039/58C08B37/006G01N2333/5428A61K9/0065A23L33/10A61K47/6901A61P1/00A61P1/04A61P29/00A61P35/00A61P37/02A61P37/06A61P43/00
Inventor SHEN, YUEMAZMANIAN, SARKIS K.
Owner CALIFORNIA INST OF TECH
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