Promotion of Cardiomyocyte Proliferation and Regenerative Treatment of the Heart by Inhibition of microRNA-128

Abstract

Inhibitors of miRNA-128 capable of promoting cardiomyocyte mitotic cell proliferation and methods effective for regeneration of heart tissue.

1 - 16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising:
 at least one miRNA-128 inhibitor; and   a pharmaceutically acceptable vehicle designed for targeted delivery to a myocardium.   
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the pharmaceutically acceptable vehicle is selected from liposomes, microparticles and nanoparticles formulated for targeted delivery to the myocardium. 
     
     
         19 . A method for promoting proliferation of cardiomyocytes, the method comprising adding an effective amount of an miRNA-128 inhibitor to a culture medium comprising cardiomyocytes in vitro, thereby providing proliferating regenerative cardiomyocytes. 
     
     
         20 . The method according to  claim 19 , wherein the regenerative cardiomyocytes are comprised of mitotic cells. 
     
     
         21 . A pharmaceutical composition comprising regenerative cardiomyocytes according to  claim 19 , and a pharmaceutically acceptable vehicle. 
     
     
         22 . A method of treating a subject suffering from a cardiac disorder, the method comprising administration of a therapeutically effective amount of the pharmaceutical composition according to  claim 21 . 
     
     
         23 . The method of treating according to  claim 22 , wherein administering comprises direct injection of the pharmaceutical composition via catheter-based direct intramyocardial injection to a damaged myocardial region of the subject. 
     
     
         24 . An isolated nucleic acid molecule comprising (a) a nucleotide sequence as set forth in SEQ ID NO: 1, or a precursor of SEQ ID NO: 1 and/or (b) a nucleotide sequence which is the complement of (a), and/or (c) a nucleotide sequence which has an identity of at least 80% to a sequence of (a) or (b), and/or (d) a nucleotide sequence which hybridizes under stringent conditions to a sequence of (a), (b) and/or (c) wherein said isolated nucleic acid molecule comprises at least one modified building block selected from the group consisting of nucleobase-modified building blocks, sugar-modified building blocks, backbone-modified building blocks and combinations thereof. 
     
     
         25 . The isolated nucleic acid molecule according to  claim 24 , wherein the identity of sequence (c) is at least 90%. 
     
     
         26 . The isolated nucleic acid molecule according to  claim 24  comprising a single-stranded or double-stranded nucleic acid molecule. 
     
     
         27 . The isolated nucleic acid molecule according to  claim 24 , wherein said isolated nucleic acid molecule is a miRNA molecule or an analog thereof having a length of from 18-25 nucleotides, or a miRNA precursor molecule having a length of 50-120 nucleotides, or a DNA molecule coding therefor. 
     
     
         28 . The length of the miRNA molecule or analog according to  claim 27  consisting of 21 or 22 nucleotides. 
     
     
         29 . The isolated nucleic acid molecule according to  claim 24  comprising an RNA molecule. 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The isolated nucleic acid molecule according to  claim 25 , wherein the identity of sequence (c) is at least 95%. 
     
     
         33 . A pharmaceutical composition comprising an inhibitor of miRNA-128, wherein the inhibitor is an isolated nucleic acid molecule comprising at least one modified building block selected from the group consisting of nucleobase-modified building blocks, sugar modified building blocks, backbone-modified building blocks and combinations thereof. 
     
     
         34 . The composition according to  claim 33 , wherein the inhibitor has sufficient complementarity to miRNA-128 to form a hybrid under physiological conditions. 
     
     
         35 . The composition according to  claim 33 , wherein the inhibitor is a single-stranded or double-stranded nucleic acid molecule. 
     
     
         36 . The composition according to  claim 33 , wherein the inhibitor is an RN A molecule comprising at least one modified building block. 
     
     
         37 . (canceled) 
     
     
         38 . The composition according to  claim 33 , wherein the inhibitor is a siRNA molecule or an antagomir.