MX2008011138A

MX2008011138A - Treatment of tendinopathy by inhibition of molecules that contribute to cartilage formation.

Info

Publication number: MX2008011138A
Application number: MX2008011138A
Authority: MX
Inventors: Joanne M Archambault; Scott Jelinsky
Original assignee: Wyeth Corp
Priority date: 2006-03-03
Filing date: 2007-03-02
Publication date: 2008-09-08
Also published as: AU2007223383A1; BRPI0708527A2; CA2644708A1; CN101432026A; WO2007103787A2; EP1991276A2; WO2007103787A3; JP2009533321A

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

TENDINOPATHY TREATMENT FOR INHIBITION OF MOLECULES THAT CONTRIBUTE TO CARTILAGE FORMATION FIELD OF THE INVENTION The technical field of the invention refers to the treatment of tendinopathy by reducing the production of cartilage tissue and / or fibrocartilage in damaged tendons. The invention also relates to the inhibition of molecules involved in the production of cartilage and / or fibrocartilage in damaged tendons. BACKGROUND OF THE INVENTION Tendinopathy is a general term used to describe various types of tendon disorders. The term "tendinitis" - which means "tendon inflammation" - is often used to describe tendon problems, but inflammation is seldom the cause of tendon pain.Most commonly, tendon pain is presently a symptom of a series of micro-tears in the connective tissue in or around the tendon, more appropriately called tendinosis Other tendon disorders include tendon pain, due to collagen degeneration with fiber disorientation, increased mucoid ground substance in the tendon, calcification Excessive use of tendon, vascularization, aging, tendon friction against a body protrusion Tendinopathy is used by a number of expert tendon producers to describe these conditions, often characterized as tendonitis, tendinosis, paratendinitis, tenosynovitis , paratenonitis, injuries due to excessive tendon use, and trauma, collectively Khan et al., S ports Med 27: 393-408 (1999). Normal tendon tissue is composed of densely packed connective tissue, with regularly arranged beams of collagen fibers running in the same direction in primary, secondary and tertiary fiber bundles, which have high fracture resistance. Scattered between these fibers are tapering, flat tenocytes, which synthesize the viscous extracellular matrix (ECM) rich in type I collagen. Beams of type I collagen provide the tendon flexibility and structural support. In healthy tendons, there is a dynamic balance between the synthesis and degradation of the ECM. Tendinopathy, however, adversely affects this balance and results in rearrangement and structural disorganization of the collagen fibers. The disorganization of the collagen bundles provides the tendon with the appearance of cartilage. The fibroblasts, myofibroblasts, neovascularization and pathological accumulation of glycosaminoglycans (GAGs) in the ECM are clearly remarkable in tendinopathic tissue. Tallón et al., Med Sci Sports Exerc 33 (12): 1983-90 (2001); Khan et al., Sports Med 27 (6): 393-408 (1999). Metabolic and morphological changes in a damaged tendon result in pain and susceptibility to tearing and rupture. Currently, the degradation and remodeling of a damaged tendon NDE is believed to be caused by the release of metalloproteinases from resident connective tissue cells and invading inflammatory cells that are capable of degrading macromolecules of matrix, such as aggrecans, decorin and biblicans. These metalloproteinases include MMP (Matrix metalloproteinases), ADAMs (One disintegrin and metalloproteinase), and ADAMTs (One disintegrin and metalloproteinase with thrombospondin portions, such as aggrecanase). Riley G., Expert Rev Mol Med 7 (5) -l-23 (2005); Rees et al., Biochem J 350: 180-188 (2000). However, clinical trials of broad spectrum MMP inhibitors were not successful in the treatment of osteoarthritis, which has pathological similarities with tendinopathy. Clark et al., Expert Opin Ther Targets 7 (l): 19-34 (2003). Therefore, inhibition of metalloproteinases is not likely to be effective in the treatment of tendinopathy. However, in highly stressed tendons, such as the supraspinatus and achilles tendons, a minimum level of metalloproteinase activity may be necessary to provide the tendon with an optimal level of ECM. Riley G., Expert Rev Mol Med 7 (5): l-23 (2005). Currently, there are several standard operative and non-operative tendinopathy treatments. Non-operative measures include rest, cryotherapy, activity modification, physiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. The modification of activity and rest, helps to maintain patients with some of these conditions, but a significant clinical population remains who are not treatable with these therapies. Due to widespread use, oral anti-inflammatory medications have not proven useful in controlled studies, and may have undesirable side effects. Some studies also suggest that non-steroidal medication can currently have an adverse effect on the healing process because to relieve pain, the patient is allowed to ignore the early symptoms of tendinopathy. Corticosteroids are normally used to reduce inflammation in tissues, but the use of such drugs to treat tendinopathy is not recommended, particularly because corticosteroids inhibit collagen synthesis. Several studies have observed a

Claims

CLAIMS Having described the invention as above, property is claimed as contained in the following: 1. Use of a compound that reduces the formation of cartilage-specific proteoglycans, in the manufacture of a drug to treat tendinopathy.
2. Use according to claim 1, wherein the compound reduces the activity of an enzyme or other protein involved in the synthesis of cartilage.
3. Use according to claim 2, wherein the compound directly or indirectly inhibits the function of the enzyme or protein.
4. Use according to claim 2 or claim 3, wherein the compound inhibits the expression of the enzyme or protein.
5. Use according to any one of claims 2 to 4, wherein the enzyme is selected from the group consisting of UDP-D-xylose: core protein β-D-xylosyltransferases, transacerase Gal, transferase GlcA, transferase GlcNAc, sulfotransferases, chondroitin sulfate synthases and heparin sulfate sulfotransferases.
6. Use according to claim 5, wherein the enzyme is selected from the group consisting of chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CS-GalNAcT-1), chondroitin sulfate N-acetylgalactosaminyltransferase 2 (CS-GalNAcT-2) , polypeptide galactosamine N-acetylgalactosaminyltransferase 1 (GA1NT-1), and eparin sulphate (glucosamine) 3-0-sulfotransferase 1 (Hs3stl).
7. Use according to claim 1, wherein the compound reduces the expression of a specific structural protein of the cartilage.
8. Use according to claim 1, wherein the compound reduces the activity of transcription factors involved in the expression of the specific structural protein of the cartilage.
9. Use according to claim 8, wherein the transcription factor is Sox9.
10. Use according to any of claims 1 to 9, wherein the proteoglycan is selected from the group consisting of aggrecan, versican, syndecan-3, and type II collagen.
11. Use according to any of claims 1 to 10, wherein the tendinopathy is selected from the group consisting of tendinitis, tendonitis, tendonosis, paratendinitis, tenosynovitis, tendon injury, tendon trauma, perin- tenndinitis and paratenonitis.
12. Use according to any of claims 1 to 11, wherein the medicament is administered to a patient, selected from the group consisting of primates, monkeys, rodents, sheep, rabbits, dogs, guinea pigs, pigs, horses, cows and cats
13. Method for identifying a useful agent in the treatment of tendinopathy, characterized in that it comprises administering a test agent to a subject in need of treatment, and measuring the ability of the agent to inhibit the activity of an enzyme involved in the synthesis of glycosaminoglycans in the tendon tissue.
14. Method according to claim 13, characterized in that it further comprises the steps of (a) providing at least one test component selected from the group consisting of CS-GalNAcT-1, CS-GalNAct2, heparin sulfate (glucosamine) 3 -0-sulfotransferase 1, GalNT-1 and Sox9; (b) combining the sample with a test agent; (c) measuring the activity of the sample component in response to the test agent; and (d) determining whether the test agent inhibits the activity of the sample component.