Aav vectors for vascular gene therapy in coronary heart disease and peripheral ischaemia

Abstract

The invention relates to the provision of a gene therapy for coronary heart disease and peripheral ischemia in mammals. One embodiment is an adeno-associated viral vector (AAV vector) comprising a first gene encoding a myocardin-related transcription factor A (MRTF-A). The invention further also relates to a pharmaceutical composition comprising an AAV vector of the invention and a pharmaceutically acceptable carrier. Methods for preparing the vector of the invention are also disclosed.

1 . An adeno-associated viral vector (AAV vector) comprising a gene encoding a neovasoactive growth factor, wherein the neovasoactive growth factor is a myocardin-related transcription factor A (MRTF-A) or thymosin β4 (Tβ4), or a combination thereof. 
     
     
         2 . The AAV vector according to  claim 1 , wherein the AAV vector is an AAV9 vector or an AAV vector pseudotyped with AAV9 envelope proteins selected from AAV2.9, AAV1.9 and AAV6.9. 
     
     
         3 . The AAV vector according to  claim 1 , further comprising a gene encoding an MRTF-B. 
     
     
         4 . The AAV vector according to  claim 1 , wherein the MRTF-A gene is under the control of a cardio-specific promoter. 
     
     
         5 . The AAV vector according to  claim 4 , wherein the cardio-specific promoter is a CMV promoter, an MRC2 promoter, a MyoD promoter, or a troponin promoter. 
     
     
         6 . A pharmaceutical composition comprising an AAV vector of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         7 . The AAV vector according to  claim 1  formulated for treating coronary heart disease or chronic ischemic diseases in a mammal, wherein the AAV vector is present in an amount effective to enhance MRTF-A activation. 
     
     
         8 . A method of treating coronary heart disease or peripheral ischemia in a mammal by administering the pharmaceutical composition of  claim 6 . 
     
     
         9 . The method according to  claim 8 , wherein the coronary heart disease is acute heart attack, myocardial ischemia, stable angina pectoris and/or hibernating myocardium. 
     
     
         10 . (canceled) 
     
     
         11 . The method according to  claim 8 , wherein the mammal is suffering from diabetes mellitus or hypercholesterolemia. 
     
     
         12 . The method of  claim 8 , wherein the mammal is a human, a mouse, a rabbit, or a pig. 
     
     
         13 . The method according to  claim 12 , wherein the human is a human no option patient. 
     
     
         14 . The AAV vector according to  claim 7 , wherein the coronary heart disease is acute heart attack, myocardial ischemia, stable angina pectoris and/or hibernating myocardium. 
     
     
         15 . The AAV vector according to  claim 7 , wherein the mammal is a human, a mouse, a rabbit, or a pig. 
     
     
         16 . The method according to  claim 15 , wherein the human is a human no option patient. 
     
     
         17 . The AAV vector according to  claim 7 , wherein the mammal is suffering from diabetes mellitus or hypercholesterolemia. 
     
     
         18 . A method for therapeutic vessel reformation and increasing vessel profusion comprising administering the AAV vector of  claim 1  to a mammal in an amount sufficient to enhance MRTF-A activation. 
     
     
         19 . The method according to  claim 18 , wherein the mammal is a human, a mouse, a rabbit, or a pig. 
     
     
         20 . The method according to  claim 18 , wherein the mammal suffers from coronary heart disease, chronic ischemic diseases, diabetes or hypercholesterolemia.