Methods for treating conditions associated with the accumulation of excess extracellular matrix

Abstract

The present invention is methods and compositions for reducing and preventing the excess accumulation of extracellular matrix in a tissue and/or organ or at a wound site using a combination of agents that inhibit TGFβ, or using agents that inhibit TGFβ in combination with agents that degrade excess accumulated extracellular matrix, or at least one agent that degrades excess accumulated extracellular matrix. The compositions and methods of the invention are used to treat conditions such as fibrotic diseases and scarring that result from excess accumulation of extracellular matrix, impairing tissue or organ function or skin appearance in a subject.

1 . A method for reducing excess accumulation of extracellular matrix associated with TGFβ overproduction and/or activity, in a tissue and/or organ, or at a dermal wound site, by administering a combination of agents that inhibit TGFβ, in an amount sufficient to inhibit TGFβ overproduction and/or activity, the administration of said combination of agents resulting in greater reduction in extracellular matrix, than when each agent is administered separately, whereby the accumulation of extracellular matrix in said tissue and/or organ or wound site is reduced from the level existing at the time of administration of the agents. 
     
     
         2 . The method of  claim 1 , wherein said agents that inhibit TGFβ are selected from the group consisting of inhibitors of aldosterone, inhibitors of angiotensin II, anti-TGFβ antibodies, renin, ACE inhibitors, AII receptor antagonists, proteoglycans and ligands for the TGFβ receptor. 
     
     
         3 . The method of  claim 2 , wherein said agent is a proteoglycan selected from the group consisting of decorin, biglycan, fibromodulin, lumican, betaglycan and endoglin. 
     
     
         4 . The method of  claim 2 , wherein said ACE inhibitor is Enalapril™. 
     
     
         5 . The method of  claim 2 , wherein said All receptor antagonist is Losartan™. 
     
     
         6 . The method of  claim 2 , wherein said anti-TGFβ antibody is 1D11. 
     
     
         7 . The method of  claim 2 , wherein one agent of the combination is an anti-TGFβ antibody and another agent is an inhibitor of angiotensin II. 
     
     
         8 . The method of  claim 7 , wherein the anti-TGFβ antibody is 1D11. 
     
     
         9 . The method of  claim 8 , wherein the inhibitor of angiotensin II is enalapril. 
     
     
         10 . The method of  claim 7 , wherein the inhibitor of angiotensin II is enalapril. 
     
     
         11 . The method of  claim 1  wherein said reducing the accumulation of extracellular matrix associated with TGFβ activity, comprises contacting renin with an anti-renin agent. 
     
     
         12 . The method of  claim 1 , further comprising the step of degrading excess accumulated extracellular matrix in said tissue and/or organ or wound site. 
     
     
         13 . A method for reducing excess accumulation of extracellular matrix associated with TGFβ overproduction and/or activity, in a tissue and/or organ, or at a dermal wound site, by degrading excess accumulated extracellular matrix, whereby the accumulation of extracellular matrix in said tissue and/or organ or wound site is reduced from the level existing at the time of administration of the agent. 
     
     
         14 . The method of  claim 13 , wherein said degrading is achieved by administering a protease in an amount sufficient to degrade excess accumulated extracellular matrix to a level that does not impair the normal function of said tissue and/or organ or result in scarring. 
     
     
         15 . The method of  claim 14 , wherein said protease is selected from the group consisting of serine proteases, metalloproteinases and protease combinations. 
     
     
         16 . The method of  claim 13 , wherein said degrading accumulated extracellular matrix comprises administering an agent which increases the amount of active protease sufficient to degrade excess accumulated matrix to a level that does not impair the normal function of said tissue and/or organ or result in scarring. 
     
     
         17 . The method of  claim 16 , wherein said protease is selected from the group consisting of serine proteases, metalloproteinases and protease combinations. 
     
     
         18 . The method of  claim 17 , wherein said protease is plasmin, and said agent which increases the amount of active plasmin is tPA. 
     
     
         19 . The method of  claim 1  or  13 , wherein said excess accumulation of extracellular matrix is associated with a fibrotic condition. 
     
     
         20 - 28 . (canceled)