Angiogenic conditioning to enhance cardiac cellular reprogramming of fibroblasts of the infarcted myocardium

Abstract

Provided is a method of treating coronary artery disease in a mammal, comprising administering to a region of the heart of the mammal (a) a first vector encoding one or more angiogenic proteins which induce vascularization in the heart of the mammal, and (b) a second vector encoding one or more cardio-differentiating transcription factors which induce the production of induced cardiomyocytes (iCM) in the heart of the mammal, whereby the coronary artery disease in the mammal is treated. In a preferred embodiment, the first vector is an adenoviral vector encoding VEGF and the second vector is a lentiviral vector encoding Gata4, Mef2c, and Tbx5 (GMT).

1 . A method of treating coronary artery disease in a mammal, comprising administering directly to a region of the heart of the mammal
 (a) a first expression vector encoding a promoter operably linked to a nucleic acid sequence encoding VEGF, and   (b) a second expression vector encoding a promoter operably linked to a nucleic acid sequence encoding one or more cardio-differentiating transcription factors which induce the production of induced cardiomyocytes (iCM) in the heart of the mammal,   
       whereby the coronary artery disease in the mammal is treated. 
     
     
         2 . The method of  claim 1 , wherein the one or more cardio-differentiating transcription factors is selected from the group consisting of Hopx, Nkx2-5, Hrt2, Pitx2, Smyd1, Myocd, Baf60c, Tbx5, Srf, Gata4, Isl1, Mef2c, Hand2, and Mesp1. 
     
     
         3 . The method of  claim 2 , wherein the one or more cardio-differentiating transcription factors are Gata4, Mef2c, and Tbx5 (GMT). 
     
     
         4 . The method of  claim 1 , wherein the first expression vector and the second expression vector are viral vectors. 
     
     
         5 . The method of  claim 4 , wherein the viral vectors are retroviral vectors, lentiviral vectors, HIV vectors, HSV vectors, adenovirus vectors, parvovirus vectors, AAV vectors, or AAV-adenoviral chimeric vectors. 
     
     
         6 . The method of  claim 1 , wherein the first expression vector is an adenoviral vector. 
     
     
         7 . The method of  claim 6 , wherein the adenoviral vector is of serotype 5 and has deletions in the E1 and E3 regions. 
     
     
         8 . The method of  claim 1 , wherein the second expression vector is a lentiviral vector. 
     
     
         9 . The method of  claim 1 , wherein the region of the heart is a myocardial scar or peri-infarcted region of the heart. 
     
     
         10 . The method of  claim 1 , wherein the coronary artery disease is myocardial infarction. 
     
     
         11 . The method of  claim 1 , whereby the ventricular function of the heart of the mammal is improved. 
     
     
         12 . The method of  claim 1 , wherein the first and second expression vectors are expressed in myocardial fibroblasts and the iCMs are produced from the myocardial fibroblasts. 
     
     
         13 . The method of  claim 1 , wherein the first expression vector is administered before the second expression vector. 
     
     
         14 . The method of  claim 13 , wherein the first expression vector is administered about 3 weeks before the second expression vector. 
     
     
         15 . The method of  claim 1 , wherein the first expression vector is administered at the same time as the second expression vector. 
     
     
         16 . The method of  claim 1 , wherein the first expression vector is an adenoviral vector, the second expression vector is a lentiviral vector. 
     
     
         17 . The method of  claim 1 , wherein the mammal is a human patient. 
     
     
         18 . The method of  claim 17 , wherein the patient has coronary artery disease. 
     
     
         19 . The method of  claim 18 , wherein the coronary artery disease is selected from the group consisting of angina, ischemia, myocardial infarction, cardiomyopathy, congestive heart failure, arrhythmias, and aneurysm formation.