Use of Insulin for the Treatment of Cartilaginous Disorders

Abstract

The present invention relates to methods for the treatment and repair of cartilage, including cartilage damaged by injury or cartilaginous disorders, including arthritis, comprising the administration of insulin and/or insulin variants. Optionally, the administration may be in combination with a cartilage agent (e.g., peptide growth factor, catabolism antagonist, osteo-, synovial, anti-inflammatory factor), in an extended- or sustained-release form. Alternatively, the method provides for the treatment and repair of cartilage damaged by injury or cartilaginous disorders comprising the administration of insulin and/or insulin in combination with standard surgical techniques. Alternatively, the method provides for the treatment and repair of cartilage damaged by injury or cartilaginous disorders comprising the administration of chondrocytes previously treated with an effective amount of insulin and/or insulin variant.

1 . A method of treating cartilage damaged from a cartilaginous disorder comprising contacting the cartilage with an effective amount of insulin or insulin variant.  
     
     
         2 . The method of  claim 1 , wherein the cartilage is articular cartilage.  
     
     
         3 . The method of  claim 1 , wherein the cartilage is contained in a mammal and the amount administered is a therapeutically effective amount.  
     
     
         4 . The method of  claim 1 , wherein the cartilaginous disorder is a degenerative cartilaginous disorder.  
     
     
         5 . The method of  claim 4 , wherein the degenerative cartilaginous disorder is rheumatoid arthritis.  
     
     
         6 . The method of  claim 4 , wherein the degenerative cartilaginous disorder is osteoarthritis.  
     
     
         7 . The method of  claim 1 , wherein the cartilaginous disorder results from an injury.  
     
     
         8 . The method of  claim 7 , wherein the type of injury is a microdamage or blunt trauma, a chondral fracture, an osteochondral fracture or damage to meniscus, tendon or ligament.  
     
     
         9 . The method of  claim 7 , wherein the injury is the result of excessive mechanical stress or other biomechanical instability resulting from a sports injury or obesity.  
     
     
         10 . The method of  claim 1 , wherein the insulin or insulin variant is present in the form of a composition further comprising a carrier, excipient or stabilizer.  
     
     
         11 . The method of  claim 10 , wherein the cartilage is present in a mammal, and the amount administered is a therapeutically effective amount.  
     
     
         12 . The method of  claim 11 , wherein the composition is administered by direct injection into the afflicted cartilaginous region or joint.  
     
     
         13 . The method of  claim 11 , wherein the composition is an extended- or sustained-release formulation.  
     
     
         14 . The method of  claim 13 , wherein the composition further comprises PLGA.  
     
     
         15 . The method of  claim 13 , wherein the composition further comprises a polyvalent metal salt.  
     
     
         16 . The method of  claim 15 , wherein the polyvalent metal salt is zinc acetate.  
     
     
         17 . The method of  claim 1 , wherein the treatment further comprises contacting the cartilage with an effective amount of a cartilage agent.  
     
     
         18 . The method of  claim 17 , wherein the cartilage is present in a mammal and the amount administered of insulin or insulin variant and cartilage agent is a therapeutically effective amount.  
     
     
         19 . The method of  claim 18 , wherein the cartilage agent selected from the group consisting of peptide growth factor, catabolism antagonist, osteo-factor, synovial-factor and anti-inflammatory factor.  
     
     
         20 . The method of  claim 19 , wherein the peptide growth factor is selected from a family member from the group consisting of: IGF (1,2), PDGF (AA, AB, BB), BMPs, FGF (1-20), TGF-β (1-3) and EGF.  
     
     
         21 . The method of  claim 19 , wherein the catabolism antagonist is selected from the group consisting of IL-1ra, NO inhibitors, ICE inhibitor, agents which inhibit activity of IL-6, IL-8, LIF, IFN-γ, TNFα activity, tetracyclines and variants thereof, inhibitors of apoptosis, MMP inhibitors, aggrecanase inhibitors and inhibitors of serine and cysteine proteinases (such as cathepsins and urokinase or tissue plasminogen activator (uPA or tPA)).  
     
     
         22 . The method of  claim 19 , wherein the osteo-factor is selected from the group consisting of bisphosphonates, osteoprotegerin.  
     
     
         23 . The method of  claim 19 , wherein the anti-inflammatory factor is selected from the group consisting of anti-TNFα, soluble TNF receptors, IL1ra, soluble IL1 receptors, IL4, IL-10 and IL-13.  
     
     
         24 . The method of  claim 1 , wherein the treatment further comprises a standard surgical technique.  
     
     
         25 . A method of preventing initial or continued damage to cartilage by a cartilaginous disorder comprising contacting the cartilage with an effective amount of insulin or insulin variant.  
     
     
         26 . The method of  claim 25 , wherein the cartilage is articular cartilage.  
     
     
         27 . The method of  claim 25 , wherein the cartilage is contained in a mammal and the amount administered is a therapeutically effective amount.  
     
     
         28 . The method of  claim 25 , wherein the cartilaginous disorder is a degenerative cartilaginous disorder.  
     
     
         29 . The method of  claim 28 , wherein the degenerative cartilaginous disorder is rheumatoid arthritis.  
     
     
         30 . The method of  claim 28 , wherein the degenerative cartilaginous disorder is osteoarthritis.  
     
     
         31 . The method of  claim 27 , wherein the cartilaginous disorder results from an injury.  
     
     
         32 . The method of  claim 31 , wherein the type of injury is a microdamage or blunt trauma, a chondral fracture, an osteochondral fracture or damage to meniscus, tendon or ligament.  
     
     
         33 . The method of  claim 31 , wherein the injury is the result of excessive mechanical stress or other biomechanical instability resulting from a sports injury or obesity.  
     
     
         34 . The method of  claim 25 , wherein the insulin or insulin variant is present in the form of a a composition further comprising a carrier, excipient or stabilizer.  
     
     
         35 . The method of  claim 34 , wherein the cartilage is present in a mammal, and the amount administered is a therapeutically effective amount.  
     
     
         36 . The method of  claim 35 , wherein the composition is administered by direct injection into the afflicted cartilaginous region or joint.  
     
     
         37 . The method of  claim 36 , wherein the composition is an extended- or sustained-release formulation.  
     
     
         38 . The method of  claim 37 , wherein the composition further comprises PLGA.  
     
     
         39 . The method of  claim 38 , wherein the composition further comprises a polyvalent metal salt.  
     
     
         40 . The method of  claim 39 , wherein the polyvalent metal salt is zinc acetate.  
     
     
         41 . The method of  claim 25 , wherein the treatment further comprises contacting the cartilage with an effective amount of a cartilage agent.  
     
     
         42 . The method of  claim 41 , wherein the cartilage is present in a mammal and the amount administered of insulin or insulin variant and cartilage agent is a therapeutically effective amount.  
     
     
         43 . The method of  claim 41 , wherein the cartilage agent selected from the group consisting of peptide growth factor, catabolism antagonist, osteo-factor, synovial-factor and anti-inflammatory factor.  
     
     
         44 . The method of  claim 43 , wherein the peptide growth factor is selected from a family member from the group consisting of: IGF (1,2), PDGF (AA, AB, BB), BMPs, FGF (1-20), TGF-β (1-3) and EGF.  
     
     
         45 . The method of  claim 43 , wherein the catabolism antagonist is selected from the group consisting of IL-1ra, NO inhibitors, ICE inhibitor, agents which inhibit activity of IL-6, IL-8, LIF, IFN-γ, TNFα activity, tetracyclines and variants thereof, inhibitors of apoptosis, MMP inhibitors, aggrecanase inhibitors and inhibitors of serine and cysteine proteinases (such as cathepsins and urokinase or tissue plasminogen activator (uPA or tPA)).  
     
     
         46 . The method of  claim 43 , wherein the osteo-factor is selected from the group consisting of bisphosphonates, osteoprotegerin.  
     
     
         47 . The method of  claim 43 , wherein the anti-inflammatory factor is selected from the group consisting of anti-TNFα, soluble TNF receptors, IL1ra, soluble IL1 receptors, IL4, IL-10 and IL-13.  
     
     
         48 . The method of  claim 25 , wherein the treatment further comprises contacting the cartilage with an effective amount of a cartilage agent.