Inhibition of histone methyltransferase for cardiac reprogramming

Abstract

A method for promoting the reprogramming of a non-cardiomyocytic cell or tissue into cardiomyocytic cell or tissue comprising is carried out by contacting a non-cardiomyocytic cell or tissue with a modulator of histone methyltransferase activity or expression.

What is claimed is: 
     
         1 . A method for promoting the reprogramming of a non-cardiomyocytic cell or tissue into cardiomyocytic cell or tissue comprising contacting said non-cardiomyocytic cell or tissue with a composition comprising a modulator of histone methyltransferase activity or expression. 
     
     
         2 . The method of  claim 1 , wherein said modulator comprises a small molecule, a polynucleotide, or a polypeptide. 
     
     
         3 . The method of  claim 1 , wherein said modulator comprises an inhibitor of histone methyltransferase activity. 
     
     
         4 . The method of  claim 1 , wherein said modulator inhibits or reduces the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aurkb. 
     
     
         5 . The method of  claim 1 , wherein said modulator inhibits or reduces methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H3 (H3K27), or arginine at position 3 on histone H4 (H4R3). 
     
     
         6 . The method of  claim 3 , wherein the inhibitor of histone methyltransferase activity is 2-(Hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine trihydrochloride hydrate (BIX-01294) or 3-Deazaneplanocin A hydrochloride (DZNep). 
     
     
         7 . The method of  claim 1 , wherein said modulator comprises an enhancer of histone methyltransferase activity. 
     
     
         8 . The method of  claim 1 , wherein said modulator enhances or increases methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H3 (H3K27), or arginine at position 3 on histone H4 (H4R3). 
     
     
         9 . The method of  claim 1 , wherein said modulator enhances or increases the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aurkb. 
     
     
         10 . The method of  claim 1 , further comprising the administration of a JAK inhibitor or a histone deacetylase inhibitor. 
     
     
         11 . The method of  claim 10 , wherein said JAK inhibitor inhibits or reduces the activity or expression of JAK-1, JAK-2, or JAK-3. 
     
     
         12 . The method of  claim 10 , wherein the JAK inhibitor is JAK inhibitor-I. 
     
     
         13 . The method of  claim 1 , wherein said non-cardiomyocytic cell or tissue comprises cardiac fibrotic tissue. 
     
     
         14 . The method of  claim 1 , wherein said non-cardiomyocytice cell comprises a fibroblast, adipocyte, or a hematopoietic cell. 
     
     
         15 . The method of  claim 14 , wherein said hematopoietic cell is a CD34 +  umbilical cord blood cell. 
     
     
         16 . The method of  claim 1 , wherein said non-cardiomyocytic cell is directly reprogrammed into cardiomyocytic tissue without a stem cell intermediary state. 
     
     
         17 . The method of  claim 1 , wherein said cardiomyocytic tissue is characterized by an increased expression of a cardiomyocyte marker protein after said contacting step compared to the level of said marker protein before said contacting step. 
     
     
         18 . The method of  claim 17 , wherein said marker protein is selected from the group consisting of sarcomeric actinin, L-type calcium channel, brachyury, Flk1, Islet1, Mesp1, Gata4, Mef2c, Hand2, TroponinT2, and Tbx-5. 
     
     
         19 . The method of  claim 13 , wherein said fibrotic tissue is present in a heart diagnosed as comprising myocardial infarction, ischemic heart disease, hypertrophic cardiomyopathy, valvular heart disease, congenital cardiomyopathy, hypertension, or other cardiac disease or condition associated with fibrosis. 
     
     
         20 . The method of  claim 1 , wherein contacting comprises intravenous administration or direct injection into cardiac tissue. 
     
     
         21 . The method of  claim 1 , wherein said contacting occurs ex vivo. 
     
     
         22 . The method of  claim 21 , further comprising delivering the reprogrammed cardiomyocyte cell or tissue to the heart of a subject in need thereof. 
     
     
         23 . The method of  claim 22 , wherein said delivering comprises intravenous administration or direct injection into cardiac tissue. 
     
     
         24 . A method for treating or reducing cardiac fibrosis comprising identifying a subject having or at risk of cardiac fibrosis and administering a modulator of histone methyltransferase activity or expression. 
     
     
         25 . The method of  claim 24 , wherein said administering a modulator of histone methyltransferase activity or expression causes reprogramming of cardiac fibrotic tissue into cardiomyocytic cells or tissue. 
     
     
         26 . The method of  claim 24 , wherein said modulator comprises a small molecule, a polynucleotide, or a polypeptide. 
     
     
         27 . The method of  claim 24 , wherein said modulator comprises an inhibitor of histone methyltransferase activity. 
     
     
         28 . The method of  claim 24 , wherein said modulator inhibits or reduces methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H3 (H3K27), or arginine at position 3 on histone H4 (H4R3). 
     
     
         29 . The method of  claim 24 , wherein said modulator inhibits or reduces the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aurkb. 
     
     
         30 . The method of  claim 24 , wherein said modulator comprises an enhancer of histone methyltransferase activity. 
     
     
         31 . The method of  claim 24 , wherein said modulator enhances or increases methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H3 (H3K27), or arginine at position 3 on histone H4 
     
     
         32 . The method of  claim 24 , wherein said modulator enhances or increases the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aurkb. 
     
     
         33 . The method of  claim 24 , further comprising the administration of a JAK inhibitor, or a histone deacetylase inhibitor. 
     
     
         34 . The method of  claim 24 , wherein said non-cardiomyocytic cell or tissue comprises cardiac fibrotic tissue. 
     
     
         35 . The method of  claim 24 , wherein said non-cardiomyocytice cell comprises a fibroblast, adipocyte, or a hematopoietic cell. 
     
     
         36 . The method of  claim 33 , wherein said hematopoietic cell is a CD34 +  umbilical cord blood cell. 
     
     
         37 . The method of  claim 25 , wherein said direct reprogramming occurs without a stem cell intermediary state. 
     
     
         38 . The method of  claim 24 , wherein said cardiomyocytic tissue is characterized by an increased expression of a cardiomyocyte marker protein after said contacting step compared to the level of said marker protein before said contacting step. 
     
     
         39 . The method of  claim 38 , wherein said marker protein is selected from the group consisting of sarcomeric actinin, L-type calcium channel, brachyury, Flk1, Islet1, Mesp1, Gata4, Mef2c, Hand2, TroponinT2, and Tbx-5. 
     
     
         40 . The method of  claim 24 , wherein said subject has been diagnosed with or is at risk of developing a cardiac disease or condition comprising myocardial infarction, ischemic heart disease, hypertrophic cardiomyopathy, valvular heart disease, congenital cardiomyopathy, hypertension, or other cardiac disease or condition associated with fibrosis. 
     
     
         41 . The method of  claim 24 , wherein said administering comprises intravenous administration or direct injection into cardiac tissue. 
     
     
         42 . The method of  claim 24 , wherein said treating or reducing cardiac fibrosis comprises at least one selected from increasing exercise capacity, increasing cardiac ejection volume, decreasing left ventricular end diastolic pressure, decreasing pulmonary capillary wedge pressure, increasing cardiac output, increasing cardiac index, lowering pulmonary artery pressures, decreasing left ventricular end systolic and diastolic dimensions, decreasing collagen deposition in cardiac muscle or tissue, decreasing left and right ventricular wall stress, decreasing heart wall tension, increasing quality of life, decreasing disease related morbidity or mortality, or combinations thereof. 
     
     
         43 . A method for regenerating cardiomyocytic cell or tissue comprising reprogramming of a non-cardiomyocytic cell or tissue into cardiomyocytic cell or tissue, wherein said reprogramming comprises contacting said non-cardiomyocytic cell or tissue with a modulator of histone methyltransferase activity or expression. 
     
     
         44 . The method of  claim 43 , wherein said modulator comprises a small molecule, a polynucleotide, or a polypeptide. 
     
     
         45 . The method of  claim 43 , wherein said modulator comprises an inhibitor of histone methyltransferase activity. 
     
     
         46 . The method of  claim 43 , wherein said modulator inhibits or reduces methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H3 (H3K27), or arginine at position 3 on histone H4 (H4R3). 
     
     
         47 . The method of  claim 43 , wherein said modulator inhibits or reduces the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aurkb. 
     
     
         48 . The method of  claim 43 , wherein said modulator comprises an enhancer of histone methyltransferase activity. 
     
     
         49 . The method of  claim 43 , wherein said modulator enhances or increases methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H3 (H3K27), or arginine at position 3 on histone H4 
     
     
         50 . The method of  claim 43 , wherein said modulator enhances or increases the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aurkb. 
     
     
         51 . The method of  claim 43 , further comprising administering a JAK inhibitor or a histone deacetylase inhibitor. 
     
     
         52 . The method of  claim 43 , wherein said non-cardiomyocytice cell comprises a fibroblast, adipocyte, or a hematopoietic cell. 
     
     
         53 . The method of  claim 52 , wherein said hematopoietic cell is a CD34 +  umbilical cord blood cell. 
     
     
         54 . The method of  claim 43 , wherein said non-cardiomyocytic cell is directly reprogrammed into cardiomyocytic cell or tissue without a stem cell intermediary state. 
     
     
         55 . The method of  claim 43 , wherein said cardiomyocytic cell or tissue is characterized by an increased expression of a cardiomyocyte marker protein after said contacting step compared to the level of said marker protein before said contacting step. 
     
     
         56 . The method of  claim 55 , wherein said marker protein is selected from the group consisting of sarcomeric actinin, L-type calcium channel, brachyury, Flk1, Islet1, Mesp1, Gata4, Mef2c, Hand2, TroponinT2, and Tbx-5. 
     
     
         57 . The method of  claim 43 , wherein said contacting comprising intravenous administration or direct injection into damaged or injured cardiac tissue of a subject. 
     
     
         58 . The method of  claim 43 , wherein said regenerating occurs in vitro or ex vivo. 
     
     
         59 . The method of  claim 58 , further comprising transplanting said regenerated cardiomyocytic cell or tissue into damaged or injured cardiac tissue of a subject. 
     
     
         60 . The method of  claim 57  or  59 , wherein said subject is suffering from a heart disease or condition comprising myocardial infarction, ischemic heart disease, hypertrophic cardiomyopathy, valvular heart disease, congenital cardiomyopathy, hypertension, physical trauma or injury to the heart, or complications from cardiac surgery. 
     
     
         61 . The method of  claim 58 , wherein said non-cardiomyocytic cell or tissue is from the subject. 
     
     
         62 . A composition promoting the reprogramming of a non-cardiomyocytic cell or tissue into cardiomyocytic cell or tissue comprising contacting said non-cardiomyocytic cell or tissue with a composition comprising a modulator of histone methyltransferase activity or expression. 
     
     
         63 . The composition of  claim 62 , wherein said modulator comprises a small molecule, a polynucleotide, or a polypeptide. 
     
     
         64 . The composition of  claim 62 , wherein said modulator comprises an inhibitor of histone methyltransferase activity. 
     
     
         65 . The composition of  claim 62 , wherein said modulator inhibits or reduces the expression or activity of Setdb2, Prmt7, Setd7, Setd8, Ezh1, Ezh2, or Aufkb. 
     
     
         66 . The composition of  claim 62 , wherein said modulator inhibits or reduces methylation of lysine at position 9 on histone H3 (H3K9), lysine at position 27 on histone H13 (H3K27), or arginine at position 3 on histone H4 (H4R3). 
     
     
         67 . The composition of  claim 64 , wherein the inhibitor of histone methyltransferase activity is 2-(Hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine trihydrochloride hydrate (BIX-01294) or 3-Deazaneplanocin A hydrochloride (DZNep). 
     
     
         68 . A pharmaceutical composition comprising the composition of  claim 62  and a pharmaceutically acceptable excipient. 
     
     
         69 . The pharmaceutical composition of  claim 68 , suitable for intravenous injection or direct injection to the site of injured or damaged cardiac tissue.