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Sox9 inhibitors

A technology of inhibitors and pharmaceuticals, applied in the direction of non-active ingredient medical preparations, active ingredient-containing medical preparations, cyclic peptide ingredients, etc., can solve problems such as therapies that do not promote CNS damage or disease regeneration

Inactive Publication Date: 2013-02-27
UNIV OF WESTERN ONTARIO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Currently, there are no therapies or approved strategies to promote regeneration after CNS injury or disease

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Astrocyte Culture System

[0066] It has been established that the transcription factor SOX9 is able to upregulate the transcription of XT-I, XT-II and C4ST and downregulate the expression of the pro-regenerative extracellular matrix (ECM) molecules laminin and fibronectin in primary astrocyte cultures . Consistent with the assumption that CSPG genes are jointly regulated, Genomatix software analysis identified 5 transcription factors with putative binding sites in all 9 of their respective promoters. The relative positioning and characteristics of these units are shown in figure 1 middle.

[0067] To determine whether SOX9 upregulated the expression of XT-I, XT-II, and C4ST was direct or indirect, chromatin immunoprecipitation (ChIP) analysis was performed. Chromatin immunoprecipitation (ChIP) using anti-SOX9 antibodies on cells from the germline ridges of female (non-SOX9 expressing) or male (SOX9 expressing) mice confirmed that SOX9 binds to the promote...

Embodiment 2-S

[0070] Example 2-Sox9 is associated with various CNS disorders

[0071] To evaluate the potential role of SOX9 in human CNS injury and disease, the expression of SOX9 in human hemorrhagic stroke (n=3), ischemic stroke (n=3), traumatic brain injury (n=2) cases was investigated . Briefly, human tissues were formalin-fixed and either frozen-sectioned or paraffin-embedded and sectioned for histological examination. Sections were stained with a combination of commonly commercially available differentially fluorescent antibodies, including GFAP, CS56, and Sox9, followed by counterstaining with the fluorescent nuclear dye DAPI. SOX9 expression was clearly observed in GFAP-positive astrocytes and in CSPG-enriched regions in samples from human tissues following ischemic stroke, TBI, and spinal cord injury. Uninjured human CNS samples were devoid of Sox9, GFAP and CSPG staining. Similarly, immunohistochemical staining of mouse tissues after MCAO and SCI showed a pattern similar to th...

Embodiment 3

[0081] Example 3 - Calmodulin antagonists affect SOX9 expression in astrocytes and SCI

[0082] The efficacy of calmodulin antagonists (inhibitors) to reduce the expression of SOX9 target genes was evaluated in cultured rat astrocytes transfected with pGL4.1 4x48 Col2a1 as described in Example Prepared as described in 1. This plasmid contains a 4-48bp SOX9 binding site from the Col2A1 enhancer, which promotes expression of the luciferase reporter gene in cells where SOX9 is active in the nucleus. The next day after transfection, the cells were used as follows and in Figure 5 Inhibitors were treated for 24 h at the concentrations indicated in the luciferase assay. In the case of chlorpromazine, there was a clear dose-dependent response limiting luciferase expression in mature astrocyte cultures, optimized to be most pronounced at 20 μM ( Figure 5 A, B, D). In addition, the calmodulin inhibitors W7 and W5 also showed a dose-dependent decrease in reporter activity, showing ...

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Abstract

Methods for treating a condition associated with proteoglycan production in a mammal are provided. The methods comprise the administration of at least one of a calmodulin antagonist, a transient receptor potential (TRP) channel inhibitor and a calmodulin-binding peptide to the mammal.

Description

field of invention [0001] The present invention relates to inhibiting SOX9 to treat some undesirable pathological conditions, in particular, the present invention relates to the use of known and novel compounds for inhibiting SOX9. Background of the invention [0002] Spinal cord injury (SCI) is a catastrophic event of major healthcare concern that can lead to lifelong disability. In the United States and Canada, more than 12,000 spinal cord injuries occur each year, and approximately 275,000 people live with permanent and severe disabilities due to SCI (Univ. of Alabama Nat. SCI Stat. Cntr. and the Cdn. Paraplegic Assoc.). The impact of neurotrauma is estimated to be one of the single most costly emergencies in the Ontario healthcare system. Currently, there is no effective treatment for SCI. Loss of axon regeneration after SCI has been attributed to axon-resisting molecules in damaged myelin and scar. Among the inhibitory molecules of scarring, the major molecule is cho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/10A61K31/00A61K33/00A61P25/00A61K33/24
CPCC07K7/08C07K14/4702A61K47/48315A61K31/00A61K31/138A61K31/18A61K38/13A61K31/5415A61K31/69A61K38/00A61K33/24A61K38/10A61K31/4745A61P25/00
Inventor 亚瑟·布朗桑迪·吉安·万斯克托
Owner UNIV OF WESTERN ONTARIO
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