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 . An in vitro combination comprising (I) damaged cartilage and (II) a composition comprising an effective amount of insulin or insulin variant, wherein the amount is effective to (i) retain proteoglycans in the matrix, (ii) inhibit proteoglycan release from the matrix, or (iii) stimulate proteoglycan synthesis. 
     
     
         2 . The combination of  claim 1 , wherein the cartilage is articular cartilage. 
     
     
         3 . The combination of  claim 1 , wherein the cartilage is contained in a mammal and the amount administered is a therapeutically effective amount. 
     
     
         4 . The combination of  claim 1 , wherein the cartilaginous disorder is a degenerative cartilaginous disorder. 
     
     
         5 . The combination of  claim 4 , wherein the degenerative cartilaginous disorder is rheumatoid arthritis. 
     
     
         6 . The combination of  claim 4 , wherein the degenerative cartilaginous disorder is osteoarthritis. 
     
     
         7 . The combination of  claim 1 , wherein the cartilaginous disorder results from an injury. 
     
     
         8 . The combination 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 combination 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 combination 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 combination of  claim 10 , wherein the cartilage is present in a mammal, and the amount administered is a therapeutically effective amount. 
     
     
         12 . The combination of  claim 11 , wherein the composition is an extended- or sustained-release formulation. 
     
     
         13 . The combination of  claim 12 , wherein the composition further comprises PLGA. 
     
     
         14 . The combination of  claim 12 , wherein the composition further comprises a polyvalent metal salt. 
     
     
         15 . The combination of  claim 14 , wherein the polyvalent metal salt is zinc acetate. 
     
     
         16 . The combination of  claim 11 , wherein the combination further comprises a therapeutically effective amount of a peptide growth factor 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. 
     
     
         17 . The combination of  claim 11 , wherein the composition further comprises a therapeutically effective amount of a 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)). 
     
     
         18 . The combination of  claim 11 , wherein the composition further comprises a therapeutically effective amount of an osteo-factor is selected from the group consisting of bisphosphonates, osteoprotegerin. 
     
     
         19 . The combination of  claim 11 , wherein the composition further comprises a therapeutically effective amount of an 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. 
     
     
         20 . The combination of  claim 25 , wherein the formulation is selected from the group consisting of: microencapsulation, semi-permeable membrane of solid hydrophobic polymers, biodegradable polymer and dispersion. 
     
     
         21 . The combination of  claim 20 , wherein the microencapsulation is a microsphere. 
     
     
         22 . The combination of  claim 20 , wherein the semi-permeable membrane is polylactic-co-glycolic acid. 
     
     
         23 . The combination of  claim 20 , wherein the biodegradable polymer is cross-linked hyaluronic acid (HA). 
     
     
         24 . The combination of  claim 20 , wherein the dispersion is selected from the group consisting of a suspension and emulsion. 
     
     
         25 . The combination of  claim 1  wherein the composition of insulin is an extended- or sustained release formulation.