Treatment of tendinopathy by inhibition of molecules that contribute to cartilage formation

A tendon and cartilage technology, applied in the field of tendinopathy treatment, can solve the problems of expensive surgery, deep infection, scarring and other problems

Inactive Publication Date: 2009-05-13
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, open or arthroscopic surgery has many potential complications, such as deep infection, damage to neurovascular structures, and scar formation
Surgery is also expensive and carries the added risk of accompanying local or general anesthesia

Method used

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  • Treatment of tendinopathy by inhibition of molecules that contribute to cartilage formation
  • Treatment of tendinopathy by inhibition of molecules that contribute to cartilage formation
  • Treatment of tendinopathy by inhibition of molecules that contribute to cartilage formation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Example 1: Rat supraspinatus tendon expresses cartilage markers due to overuse

[0164] The response of the rat supraspinatus tendon to overuse was investigated at the molecular level using transcriptional profiling. A rat model of tendon overuse has been described previously. Soslowsky et al., J Shoulder Elbow Surg 9:79-84 (2000). It has been shown that inflammatory and angiogenic markers are altered in this model (Perry et al., J Shoulder Elbow Surg 14:79S-83S (2005)), but a broader approach is taken to understand the events surrounding overuse injury.

[0165] Twenty-four male Sprague-Dawley rats (400-450 g) were subjected to a supraspinatus tendon (SST) overuse protocol for 1 week (n=8), 2 weeks (n=8) and 4 weeks (n=8). The protocol consisted of running downhill at 17 m / min (10% incline) for 1 hour per day, 5 days per week. An additional 6 rats were used as controls for cage activity (time 0). At each time point, two additional non-running rats were used as age-...

Embodiment 2

[0168] Embodiment 2: Preparation of siRNA inhibitor

[0169] The siRNA is selected by entering the nucleotide sequence of CS-GalNAcT-1, GalNT-1 or Hs3st1 into a commercial website (e.g. sirnawizard.com or Ambion siRNA TargetFinder) to design specific siRNA. Sequence selection guidance is included with these tools.

[0170] The efficacy of siRNA was measured by transfecting it into C-20 / A4 and / or C-28 / I2 chondrocytes and monitoring the expression of CS-GalNAcT-1 and / or GalNT-1 by real-time RT-PCR. Appropriate scrambled siRNAs with the same nucleotide composition were used as experimental controls.

Embodiment 3

[0171] Example 3: In vitro test system for inhibitors of proteoglycan synthesis

[0172] If siRNAs were able to reduce the expression of CS-GalNAcT-1, GalNT-1 or Hs3st1 in C-20 / A4 and / or C-28 / I2 chondrocytes, they were tested for their ability to reduce proteoglycan GAG side chain production. C-20 / A4 and / or C-28 / I2 chondrocytes were treated with BMP-2 protein or BMP-2-expressing adenovirus to stimulate extracellular matrix and GAG synthesis. siRNA or, alternatively, a small molecule, inhibitor of GAG synthesis, is added to the culture and the effect of the inhibitor is assessed by comparing the incorporation of 35S into proteoglycans in the presence or absence of the inhibitor. Alternatively, the effect of inhibitors is assessed by comparing the levels of GAGs in the presence or absence of inhibitors using the DMMB assay, as described in Arai et al., Osteoarthritis and Cartilage 12:599-613 (2004).

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Abstract

The invention provides methods for treating tendinopathy. The disorders treated or prevented include, for example tendinitis, tendonitis, tendinosis, paratendinitis, tenocynovitis, tendon overuse injury and trauma, peritendinitis, paratenonitis, or other tendon degenerative disorders. The disclosed therapeutic methods include administering to a patient an inhibitor of molecules involved in cartilage or fibrocartilage formation in tendinopathic tendon in an amount effective to treat or prevent a tendon degenerative disorder, slow tendon deterioration, restore tendon healthy structure, stimulate tendon regeneration, and/or maintain tendon mass and/or quality.

Description

[0001] Description of the invention [0002] previous application [0003] This application claims priority to US Provisional Patent Application Serial No. 60 / 779,165, filed March 3, 2006, the contents of which are hereby incorporated by reference. field of invention [0004] The technical field of the invention relates to the treatment of tendinopathy by reducing cartilage and / or fibrocartilage production in damaged tendons. The present invention further relates to the inhibition of molecules associated with cartilage and / or fibrocartilage production in damaged tendons. Background of the invention [0005] Tendinopathy is a general term used to describe various types of tendon disorders. The term "tendinitis" (meaning "inflammation of the tendon") is often used to describe tendon problems, but inflammation is rarely the cause of tendon pain. Most commonly, tendon pain is actually a symptom of a series of microtears in the connective tissue in or around the tendon, more p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00
CPCA61K48/005A61P19/02A61P43/00
Inventor J·M·阿查姆褒特S·叶林斯基
Owner WYETH LLC
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