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Use of hedgehog agonists in the treatment of musculoskeletal-related disorders

An agonist, skeletal technology in the field of use of HEDGEHOG agonists in the treatment of musculoskeletal-related disorders

Inactive Publication Date: 2010-12-29
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since there are currently no compounds capable of activating endogenous muscle satellite cells, the identification of Shh agonistic compounds capable of acting in a similar manner to recombinant Shh proteins is needed for the treatment of myopathies and musculoskeletal disorders

Method used

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  • Use of hedgehog agonists in the treatment of musculoskeletal-related disorders
  • Use of hedgehog agonists in the treatment of musculoskeletal-related disorders
  • Use of hedgehog agonists in the treatment of musculoskeletal-related disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Example 1: Determination of the effect of Shh-Ag on Shh signal transduction in vitro

[0204] To determine whether Shh-Ag can activate Shh signaling in myocytes, the well-established Shh-sensitive cell line TM3 and three other murine myocyte lines: primary myoblasts (PM), commercially available C2C12 myoblasts Expression of the target gene and a downstream functional gene (Gli1) in cells and isolated SCs was measured by quantitative PCR analysis. Gli1 gene expression was compared in vehicle (DMSO) and Shh-Ag treated (10 μM) cells, measured by real-time taqman analysis and normalized to GAPDH levels, according to the methods and protocols described above.

[0205] As shown in Figure 1, 24 hours of Shh-Ag treatment (10 μM) significantly increased Gli1 mRNA levels in all cell lines examined (i.e. over 40-fold in TM3 cells and over 40-fold in myoblasts and myotubes, respectively). 20 times). Figure 1A showed 41.79±3.09 in TM3 cells; 23.09±3.21 in PM cells; 7.80±1.24 in C2C1...

Embodiment 2

[0209] Example 2: Intramuscular injection of Shh-Ag induces satellite cell proliferation in vivo

[0210] Shh-Ag in vivo assays were performed by direct intramuscular (IM) injection of Shh-Ag into mouse skeletal muscle. wild-type (WT) or DMD MDX The tibialis anterior muscle (TA) or gastrocnemius muscle (GA) of mice (muscular dystrophy model) was injected with 20 μL (TA) or 40 μL (GA) of medium (10% DMSO / PBS) or Shh-Ag (500 μM), once a day, Inject for two consecutive days. Immediately after the second IM injection, mice were injected intraperitoneally (IP) with 100 μL of BrdU. 24 hours after BrdU injection, mice were sacrificed and their muscles were harvested and prepared for FACS analysis (GA) or immunostaining (TA). For immunostaining, muscle sections were probed with anti-laminin to label the basal layer, anti-BrdU to identify proliferating cells, and treated with hematoxylin dye to stain all nuclei.

[0211] For BrdU staining, Shh-Ag-injected muscles showed BrdU+ precu...

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Abstract

The invention provides methods for the diagnosis and treatment of musculoskeletal disorders relating to the Hedgehog pathway, including but not limited to muscular dystrophy (e.g., Duchenne Muscular Dystrophy) using agents that agonize Sonic Hedgehog (shh), and thereby, the Hedgehog signaling pathway. Said agonizing agents include, e.g., the compounds of the invention (e.g., a compound of Formula I). The invention also provides methods of screening for agents that are capable of increases the proliferation of muscle and / or muscle precursor cells.

Description

Background of the invention [0001] Hedgehog (Hh) signaling was first identified in Drosophila as an important regulatory mechanism for embryonic patterning, or as a process by which embryonic cells form ordered spatial arrangements of differentiated tissues (Nusslein - Volhard et al. (1980) Nature 287, 795-801). In mammalian cells, three Hedgehog genes have been identified, Sonic Hedgehog (Shh), India Hedgehog (Ihh) and Desert Hedgehog (Dhh). The Hedgehog gene encodes a secreted protein that undergoes post-translational modifications including autocatalytic cleavage and lipid modification (palmitoylation) at the N-terminus and cholesterol modification at the C-terminus. [0002] The lipid-modified N-terminal Hedgehog protein triggers the signaling activity of the protein pathway and causes cell-to-cell communication through the sending of soluble Hedgehog protein from signaling cells and receipt by responding cells. In responding cells, the 12-channel transmembrane receptor ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/4436A61P21/00G01N33/15
CPCA61K31/00A61K31/4436A61P5/30A61P9/10A61P19/00A61P19/02A61P19/04A61P19/08A61P19/10A61P21/00A61P21/04A61P43/00
Inventor D·D·阿姆斯特朗S·卡达姆
Owner NOVARTIS AG
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