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Matrix bound vesicles (MBVS) containing il-33 and their use

A technology of extracellular matrix and nanovesicles, which is applied in the directions of medical preparations containing active ingredients, medical preparations without active ingredients, and drug combinations.

Pending Publication Date: 2021-05-14
联邦高等教育系统匹兹堡大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it was previously unknown which components of the ECM have this function

Method used

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  • Matrix bound vesicles (MBVS) containing il-33 and their use
  • Matrix bound vesicles (MBVS) containing il-33 and their use
  • Matrix bound vesicles (MBVS) containing il-33 and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0321] Matrix-bound nanovesicles isolated from ECM bioscaffolds contain full-length IL-33

[0322] Isolation of MBV from ECM bioscaffolds and characterization of miRNA content have been previously described (Huleihelet al., Sci Adv 2, e1600502 (2016); Huleihel et al., Tissue Eng Part A 23, 1283-1294 (2017)) . In order to identify protein signaling molecules associated with MBV, R&D system's mouse XL cytokine array kit was used to detect cells from decellularized wild-type (wt) mouse small intestine or decellularized IL33 - / - MBV isolated from mouse small intestine was screened for preliminary cytokines, chemokines and growth factors ( Figure 1A ). Quantification of the protein with the highest expression level in MBV showed that, compared with that from il33 - / - MBV isolated from mouse (IL33 - MBV) compared to MBV isolated from wt mice (IL33 + IL-33 was highly expressed in MBV), while the expression of other proteins present in isolated MBV was minimally different ( ...

Embodiment 2

[0324] IL-33 is stored in the MBV lumen and protected from proteolytic degradation

[0325] To verify that the detected IL-33 was not a contaminant of the MBV isolation process, use CL-2B resin was used to further purify MBV by size exclusion chromatography (SEC), and the eluted fractions were continuously monitored by UV absorbance at 280 nm ( Figure 2A ). Western blot analysis confirmed the presence of IL-33 in heavy MBV fractions ( Figure 2B , above). In another experiment, first use 1% MBV was lysed by X-100 and the extracts were analyzed by SEC. The results showed that the molecular components of the cleaved MBV were mainly eluted in the lighter fractions, by UV chromatogram ( Figure 2A ) and Western blot analysis ( Figure 2B , the figure below) OK. Additionally, transmission electron microscopy of pooled fractions 6-8 revealed the presence of vesicles in these fractions ( Figure 2C ). These results confirm that IL-33 is associated with MBV and not a solub...

Embodiment 3

[0327] IL33 + Activation of MBV promotes remodeling of macrophage phenotype through a non-canonical ST2-independent pathway

[0328]IL-33 + or IL-33 - Extensive mechanistic studies of MBV effects on myeloid cells. Given the location of IL-33 in the lumen of MBV, it can be hypothesized that encapsulation of IL-33 would prevent binding to its cognate ST2 receptor, suggesting a non-ST2 transduction mechanism. To investigate this situation, cells from B6 wt ( Figure 3A ) or st2 - / - mice ( Figure 3B ) isolated bone marrow macrophages (BMDM) induced M1-like macrophage phenotype, interleukin 4 (IL-4) induced M2-like phenotype, recombinant IL-33, from decellularized wild-type (IL33 + MBV) or il33 - / - (IL33-MBV) MBV isolated from mouse intestine, or MBV isolated from porcine small intestinal submucosa (SIS MBV). The results showed that macrophages respond to SIS MBV and IL33 + MBV expresses arginase 1 (Arg-1), similar to the expression pattern of IL-4-stimulated (M2) cel...

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Abstract

Methods are disclosed for treating a subject with a disorder, such as, but not limited to, a) fibrosis of an organ or tissue; b) solid organ transplant rejection; or c) a cardiac disease that is not myocardial infarction or myocardial ischemia. These methods include selecting a subject having or at risk of having the disorder, and administering to the subject a therapeutically effective amount of isolated nanovesicles derived from an extracellular matrix, wherein the nanovesicles contain interleukin (IL)-33 and comprise lysyl oxidase, and wherein the nanovesicles a) do not express CD63 or CD81, or b) are CD63loCD81lo. In additional embodiments, methods are disclosed for increasing myoblast differentiation.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application 62 / 666,624, filed May 3, 2018, the entire contents of which are incorporated herein by reference. [0003] Statement of Government Support [0004] This invention was made with government support under grant numbers AR073527 and HL122489 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The present invention relates to the use of membrane-bound nanovesicles (MBVs) comprising interleukin (IL)-33 in the treatment of a) organ or tissue fibrosis, b) solid organ transplant rejection and c) heart disease. Background technique [0006] Heart disease or injury leads to fibrosis, which leads to stiffness of the heart muscle, loss of function, and heart failure (HF). Alternative fibrosis occurs after myocardial ischemia (MI) as damaged cardiomyocytes are replaced by fibroblasts and asso...

Claims

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Application Information

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IPC IPC(8): A61K35/12A61K9/127A61K9/72A61K38/20A61K45/06A61P9/10A61P9/04A61P9/00A61P9/06A61P11/00A61P9/12A61P37/06
CPCA61K38/20A61K35/12A61P9/10A61K45/06A61K31/7105C12N5/0658C12Y104/03013A61K38/44A61K31/436A61K38/13A61K31/365A61K31/573A61K9/5184A61K9/0019A61K2300/00A61K9/127A61K47/46A61K9/5063A61P9/04A61P43/00C12N5/0679C07K14/54C12N9/0014C12N2501/999C12N2509/00A61L27/3633
Inventor S·F·贝狄拉克G·S·赫西H·特恩奎斯特J·L·迪兹凯刘全张忠强
Owner 联邦高等教育系统匹兹堡大学
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