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Motile Sperm Domain Containing Protein 2 and Inflammation

a technology of sperm domain and protein, applied in the field of antiinflammatory processes, can solve the problems of phase ii clinical trial failure of chemokine and chemokine receptor antagonists, and achieve the effects of treating, preventing, inhibiting or preventing one or more activities, and preventing or reducing the incidence of an inflammatory disease or disorder

Inactive Publication Date: 2018-08-02
VASCULAR BIOGENICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to methods of treating, preventing, or reducing the incidence of inflammatory diseases or disorders by inhibiting the activity of a protein called MOSPD2. The invention also includes methods of inhibiting MOSPD2 in a cell, as well as various polypeptides that can achieve this. The technical effect of the invention is to provide new methods for treating inflammatory diseases or disorders by targeting MOSPD2.

Problems solved by technology

Nevertheless, there have been several phase II clinical trial failures with chemokine and chemokine receptor antagonists, possibly due to redundancy of the target receptor and the complexity of heterogeneous diseases such as multiple sclerosis and rheumatoid arthritis.

Method used

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  • Motile Sperm Domain Containing Protein 2 and Inflammation
  • Motile Sperm Domain Containing Protein 2 and Inflammation
  • Motile Sperm Domain Containing Protein 2 and Inflammation

Examples

Experimental program
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Effect test

example 1

MOSPD2 and Chemokine-Induced Monocyte Migration

[0322]To assess the role of MOSPD2 in monocyte migration, MOSPD2 expression was silenced in U937 cells as described in the Materials and Methods section using Lenti-virus particles containing sh-RNA directed against three different regions of MOSPD2 mRNA (sh-MOSPD2). MOSPD2 mRNA expression in the cells was assessed using quantitative PCR (Q-PCR) and normalized to β-actin expression as control. FIG. 1 shows that all tested sh-MOSPD2 profoundly reduced mRNA expression levels of human MOSPD2. U937 cells transduced with control Lenti-virus particles or with sh-MOSPD2 Lenti-virus particles were then tested for migration towards the chemokine, RANTES, using a trans-well migration assay. FIGS. 2 and 3 show that cell migration induced by RANTES was significantly inhibited in sh-MOSPD2 transduced cells compared to cells in which MOSPD2 was not silenced.

example 2

MOSPD2,ERK Phosphorylation and AKT Phosphorylation

[0323]The effect of MOSPD2 inhibition on the activation of chemokine-induced signaling pathways was determined by testing the effects of MOSPD2 inhibition on phosphorylation of ERK and AKT. U937 cells transduced with control Lenti-virus particles or sh-MOSPD2 Lenti-virus particles were treated with RANTES for 2 or 5 minutes and then analyzed by western blot for phosphorylated ERK and AKT. Heat shock protein 90 (HSP90) was used as a loading control. FIG. 4 shows that inhibition of MOSPD2 almost completely abolished RANTES-induced phosphorylation of ERK and AKT.

example 3

MOSPD2 and Chemokine Receptor-Driven Signaling

[0324]The effect of MOSPD2 inhibition on other chemokines was also tested. U937 cells transduced with control Lenti-virus particles or sh-MOSPD2 Lenti-virus particles were tested for migration towards MCP-3, MCP-1, RANTES and SDF-1 in a trans-well assay and for levels of phosphorylated ERK and AKT by western blot. FIG. 5 shows that MOSPD2 inhibition significantly inhibited cell migration induced by all the tested chemokines. Furthermore, FIG. 6 shows that inhibition of MOSPD2 almost completely abolished phosphorylation of ERK and AKT induced by all the tested chemokines. As such, the effects of MOSPD2 inhibition on migration and signaling are not limited to a single chemokine or chemokine receptor pathway.

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Abstract

Disclosed herein are methods of treating, preventing, or reducing the incidence of an inflammatory disease or disorder and methods of inhibiting, preventing, or reducing the incidence of one or more activities in a cell with an inhibitor of a Motile Sperm Domain containing Protein 2 (MOSPD2). Also disclosed are inhibitors of MOSPD2 and pharmaceutical compositions containing MOSPD2 inhibitors.

Description

FIELD OF THE INVENTION[0001]This invention relates to anti-inflammatory processes, for example, methods of treating, preventing, or reducing the incidence of one or more activities in a cell, or one or more inflammatory diseases or disorders with an inhibitor of Motile Sperm Domain containing Protein 2 (MOSPD2). The invention also relates to pharmaceutical compositions comprising one or more inhibitors of MOSPD2.BACKGROUND OF THE INVENTION[0002]Leukocytes are the cells of the immune system that are involved in defending the body against infectious disease and foreign materials. Monocytes are a type of leukocytes and have critical roles in innate and adaptive immunity, immune surveillance, and particle scavenging. While a subset of monocytes is “resident” and recruited to tissues independently of inflammatory stimuli to assist in steady-state surveillance, wound-healing and resolution of inflammation, the majority (80-90%) of human circulating monocytes are classified as “inflammator...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P29/00A61P37/06A61K39/00
CPCA61K39/3955A61P29/00A61P37/06A61K39/0008A61K2039/505C07K16/28C12N15/113A61K39/001102Y02A50/30C12N2310/14C12N2310/531A61K48/00A61K48/0016A61K31/7105
Inventor MENDEL, ITZHAKPROPHETA-MEIRAN, OSHRATSALEM, YANIVSHOHAM, ANATBREITBART, EYAL
Owner VASCULAR BIOGENICS
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