Methods for treating tissue damage associated with ischemia with apolipoprotein d

Abstract

The invention provides methods for treating tissue damage associated with impaired blood flow using ApoD, or an active variant thereof, or an agent that increases the expression of ApoD. The invention also encompasses active variants of ApoD for use in the methods.

1 . A method of treating ischemic injury in a tissue of a subject or treating a subject at risk of tissue damage associated with ischemia, comprising administering to a subject a composition comprising an effective amount an agent that increases the expression of ApoD, thereby treating ischemic injury in the tissue or treating the subject at risk of tissue damage. 
     
     
         2 . (canceled) 
     
     
         3 . A method of increasing the amount of circulating ApoD in a subject in need thereof, comprising administering a composition comprising an agent that increases the expression of ApoD, into the subject, wherein an increase in the amount of circulating ApoD reduces tissue damage in the subject. 
     
     
         4 . A method of treating tissue damage associated with coronary artery disease in a subject or treating a subject at risk of tissue damage associated with coronary artery disease, comprising administering to the subject a composition comprising an effective amount of an agent that increases the expression of ApoD, thereby treating tissue damage in the subject or treating the subject at risk of the tissue damage. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the tissue is selected from the group consisting of heart, brain, kidney, bowel, liver, skeletal muscle, and skin. 
     
     
         8 . The method of  claim 1 , wherein the ischemic injury is associated with a disease or disorder selected from the group consisting of: coronary artery disease, myocardial infarction, stroke, peripheral arterial disease, peripheral vascular disease, and surgery involving temporary disruption of blood flow. 
     
     
         9 . The method of  claim 1 , wherein the subject has one or more clinical indicators of coronary artery disease selected from the group consisting of frequency and intensity of anginal symptoms, myocardial perfusion, electrocardiogram tracings, scores on quantitative angina scales, and angiography. 
     
     
         10 . The method of  claim 1 , wherein the area of tissue damage relative to the area at risk of damage is reduced up to about 90%, up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 30%, up to about 20%, up to about 10%, or up to about 5%. 
     
     
         11 . The method of  claim 1 , wherein the composition is administered directly to damaged tissue or tissue at risk of damage by ischemia. 
     
     
         12 . The method of  claim 1 , wherein the composition is administered to a tissue other than damaged tissue or tissue at risk of damage by ischemia. 
     
     
         13 . The method of  claim 1 , wherein the agent that increases the expression of ApoD is a replication-deficient viral vector or complementary DNA. 
     
     
         14 . The method of  claim 13 , wherein the agent is a replication deficient viral vector. 
     
     
         15 . The method of  claim 14 , wherein the viral vector is an adenovirus, adeno-associated virus, or lentivirus. 
     
     
         16 . The method of  claim 1 , wherein the agent is a complementary DNA (cDNA). 
     
     
         17 . The method of  claim 1 , wherein the agent increases ApoD expression in a tissue-specific manner. 
     
     
         18 . The method of  claim 17 , wherein the agent is administered directly to the damaged tissue, or tissue at risk of damage. 
     
     
         19 . The method of  claim 18 , wherein the agent is administered directly to the heart. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , further comprising administering one or more additional therapeutic agents or treatments. 
     
     
         22 . The method of  claim 21 , wherein the one or more therapeutic agents is selected from the group consisting of: angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril, lisinopril, and captopril), angiotensin II (A-II) receptor blockers (e.g., losartan and valsartan), diuretics (e.g., bumetanide, furosemide, and spironolactone), digoxin, beta blockers, nesiritide, cholestyramine, colestipol, nicotinic acid, gemfibrozil, probucol, atorvastatin, lovastatin, aspirin, ticlopidine, clopidogrel, anti-coagulants, inhibitors of smooth muscle proliferation, inhibitors of DP1 and/or DP2 receptor, inhibitors of MAP kinase, fibroblast growth factors (e.g., FGF1, FGF2, and FGF5), vascular endothelial growth factors (VEGF) and active fragments thereof (e.g., VEGF 165 ), hypoxia inducible factor (HIF-1), platelet-derived growth factors (PDGF1, PDGF2), developmental embryonic locus (DEL) 1, angiopoietins, hepatocyte growth factor (HGF), monocyte chemoattractant protein (MCP-1), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) 
     
     
         23 . The method of  claim 21 , wherein the one or more therapeutic treatments is selected from the group consisting of: angioplasty, single coronary artery bypass grafting (CABG), or multiple CABG. 
     
     
         24 . The method of  claim 1 , wherein the composition is administered by a route selected from the group consisting of oral, intravenous injection, subcutaneous injection, intramuscular injection, myocardial injection, intrapericardial injection, endomyocardial injection, or intracoronary infusion. 
     
     
         25 .- 30 . (canceled)