Methods for heart regeneration

Abstract

Methods for heart regeneration are provided. The invention provided herein includes methods of modulating proliferation of cardiomyocytes using small molecules and micro RNAs. In embodiments, the methods provided may be used to increase proliferation or cardiomyocytes. Further provided are methods to be used for the treatment of myocardial infarction.

What is claimed is: 
     
         1 . A method of treating a subject with heart damage, comprising:
 administering to the subject a therapeutically effective amount of a nucleic acid encoding an antagonist of a micro RNA (miR) 99 micro RNA, a nucleic acid encoding an antagonist of a miR 100 micro RNA, a nucleic acid encoding an antagonist of a let-7a micro RNA, and a nucleic acid encoding an antagonist of a let-7c micro RNA,   thereby inducing proliferation of cardiomyocytes and treating the heart damage in the subject.   
     
     
         2 . The method of  claim 1 , comprising administering to the subject a therapeutically effective amount of
 a) a lentiviral vector or an adeno-associated viral (AAV) vector comprising the nucleic acid encoding the antagonist of the miR 99 micro RNA and the nucleic acid encoding the antagonist of the miR 100 micro RNA, and   b) a lentiviral vector or an AAV vector encoding the nucleic acid encoding the antagonist of the let-7a micro RNA and the antagonist of the let-7c micro RNA.   
     
     
         3 . The method of  claim 2 , wherein a) the lentiviral vector or the AAV vector comprising the nucleic acid encoding the antagonist of the miR 99 micro RNA and the antagonist of the miR 100 micro RNA, and b) the lentiviral vector or the AAV vector encoding the nucleic acid encoding the antagonist of the let-7a micro RNA and the antagonist of the let-7c micro RNA, are the same vector. 
     
     
         4 . The method of  claim 2 , wherein a) the lentiviral vector or the AAV vector comprising the nucleic acid encoding the antagonist of the miR 99 micro RNA and the antagonist of the miR 100 micro RNA, and b) the lentiviral vector or the AAV vector encoding the nucleic acid encoding the antagonist of the let-7a, are different vectors. 
     
     
         5 . The method of  claim 1 , comprising administering to the subject a therapeutically effective amount of a nucleic acid molecule comprising the nucleic acid sequence as set forth in SEQ ID NO:1124 or SEQ ID NO:1125. 
     
     
         6 . The method of  claim 5 , comprising administering to the subject the therapeutically effective amount of the nucleic acid molecule comprising the nucleic acid sequence set forth as SEQ ID NO: 1124. 
     
     
         7 . The method of  claim 5 , comprising administering to the subject the therapeutically effective amount of the nucleic acid molecule comprising the nucleic acid sequence set forth as SEQ ID NO: 1125. 
     
     
         8 . The method of  claim 1 , further comprising measuring the proliferation of cardiomyocytes in the subject. 
     
     
         9 . The method of  claim 1 , wherein the method regenerates cardiac tissue in the subject. 
     
     
         10 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         11 . The method of  claim 10 , wherein the mammal is a human. 
     
     
         12 . The method of  claim 10 , wherein the method improves ejection fraction in the subject. 
     
     
         13 . The method of  claim 1 , wherein the heart damage is a myocardial infarction. 
     
     
         14 . The method of  claim 13 , wherein the method reduces fibrotic scarring and/or infarct size in the subject. 
     
     
         15 . A method of regenerating heart muscle in a subject, comprising
 administering to the subject a therapeutically effective amount of a small molecule that modulates expression or activity of a miR 99 micro RNA-regulated protein, a small molecule that modulates expression or activity of a miR 100 micro RNA-regulated protein, a small molecule that modulates expression or activity of a let-7a micro RNA -regulated protein, and small molecule that modulates expression or activity of a let-7c micro RNA regulated protein, thereby forming a treated cardiomyocyte,   thereby inducing proliferation of cardiomyocytes and regenerating heart muscle in the subject.   
     
     
         16 . The method of  claim 15 , wherein the small molecule that modulates expression or activity of the miR 99 micro RNA-regulated protein, the small molecule that modulates expression or activity of the miR 100 micro RNA-regulated protein, the small molecule that modulates expression or activity of the let-7a micro RNA -regulated protein, and/or the small molecule that modulates expression or activity of the let-7c micro RNA regulated protein is a synthetic micro RNA molecule. 
     
     
         17 . The method of  claim 15 , further comprising measuring the proliferation of cardiomyocytes in the subject. 
     
     
         18 . The method of  claim 15 , wherein the subject is human. 
     
     
         19 . The method of  claim 15 , wherein the subject is a mammal. 
     
     
         20 . The method of  claim 15 , wherein the mammal is a human. 
     
     
         21 . The method of  claim 15 , wherein the method improves ejection fraction in the subject. 
     
     
         22 . The method of  claim 15 , wherein the subject has a myocardial infarction. 
     
     
         23 . The method of  claim 22 , wherein the method reduces fibrotic scarring and/or infarct size in the subject.