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 to 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. 
     
     
         2 . The method of  claim 1 , wherein the angiogenic protein is one or more of VEGF, FGF, PGF, NRP-1, ANG, PDGF, TGF-β, MCP-1, ephrin, plasminogen activator or plasminogen activator inhibitor, eNOS, COX-2, CD133, MMP, and DLL44. 
     
     
         3 . The method of  claim 1 , wherein the angiogenic protein is VEGF. 
     
     
         4 . The method of  claim 1 , wherein the cardio-differentiating transcription factor is one or more of Hopx, Nkx2-5, Hrt2, Pitx2, Smyd1, Myocd, Baf60c, Tbx5, Srf, Gata4, Isl1, Mef2c, Hand2, or Mesp1. 
     
     
         5 . The method of  claim 4 , wherein the cardio-differentiating transcription factors are Gata4, Mef2c, and Tbx5 (GMT). 
     
     
         6 . The method of  claim 1 , wherein the first vector and the second vector are viral vectors. 
     
     
         7 . The method of  claim 6 , wherein the viral vectors are retroviral vectors, lentiviral vectors, HIV-based vectors, HSV-based vectors, adenovirus-based vectors, parvoviral-based vectors, AAV-based vectors, or AAV-adenoviral chimeric vectors. 
     
     
         8 . The method of  claim 1 , wherein the first vector is an adenoviral vector. 
     
     
         9 . The method of  claim 8 , wherein the adenoviral vector is of serotype 5 and has deletions in the E1 and E3 regions. 
     
     
         10 . The method of  claim 1 , wherein the second vector is a lentiviral vector. 
     
     
         11 . The method of  claim 1 , wherein the first vector and the second vector are administered to a myocardial scar or peri-infarcted region of the heart. 
     
     
         12 . The method of  claim 1 , wherein the coronary artery disease is myocardial infarction. 
     
     
         13 . The method of  claim 1 , whereby the ventricular function of the heart of the mammal is improved. 
     
     
         14 . The method of  claim 1 , wherein the iCM are derived from myocardial fibroblasts. 
     
     
         15 . The method of  claim 1 , wherein the first vector is administered before the second vector. 
     
     
         16 . The method of  claim 15 , wherein the first vector is administered about 3 weeks before the second vector. 
     
     
         17 . The method of  claim 1 , wherein the first vector is administered at the same time as the second vector. 
     
     
         18 . The method of  claim 1 , wherein the first vector is an adenoviral vector, the second vector is a lentiviral vector, and the angiogenic protein is VEGF.