Rna for treatment or prophylaxis of a liver disease

Abstract

The present invention relates to an RNA suitable for treatment or prophylaxis of liver diseases. In particular, the present invention provides an RNA encoding at least one peptide or protein selected from the group consisting of an extracellular matrix protease, CCAAT/enhancer-binding protein alpha (CEBPA), TNF-related apoptosis-inducing ligand (TRAIL), Hepatocyte Growth Factor (HGF), hepatocyte nuclear factor 4 alpha (HNF4A), fibroblast growth factor 21 (FGF21), opioid growth factor receptor-like 1 (OGFRL1), Relaxin 1 (RLN1), Relaxin 2 (RLN2) and Relaxin 3 (RLN3), or a fragment or a variant of any of these peptides or proteins. The present invention concerns said RNA as well as compositions and kits comprising the RNA. Furthermore, the present invention relates to the RNA, compositions or kits as disclosed herein for use as a medicament, in particular for treatment or prophylaxis of a liver disease. The present invention also provides the use of the RNA, compositions or kits as disclosed herein for increasing the expression of said encoded protein, in particular in gene therapy.

1 . A method for treatment or prophylaxis of a liver disease comprising administering to a patient in need thereof an effective amount of RNA comprising at least one coding sequence,
 wherein the coding sequence encodes at least one peptide or protein selected from the group consisting of   a human collagenase MMP1, Hepatocyte Growth Factor (HGF), CCAAT/enhancer-binding protein alpha (CEBPA), TNF-related apoptosis-inducing ligand (TRAIL), extracellular matrix protease, hepatocyte nuclear factor 4 alpha (HNF4A), fibroblast growth factor 21 (FGF21), opioid growth factor receptor-like 1 (OGFRL1), Relaxin 1 (RLN1), Relaxin 2 (RLN2) and Relaxin 3 (RLN3).   
     
     
         2 . The method of  claim 1 , wherein the RNA is an mRNA, a viral RNA or a replicon RNA. 
     
     
         3 . The method of  claim 1 , wherein the RNA does not comprise a chemically modified sugar, a chemically modified backbone or a chemically modified nucleobase. 
     
     
         4 . The method of  claim 1 , wherein the RNA does not comprise a chemically modified nucleoside or nucleotide. 
     
     
         5 . The method of  claim 1 , wherein the RNA is not chemically modified. 
     
     
         6 . The method of  claim 1 , wherein the liver disease is selected from the group consisting of liver fibrosis, liver cirrhosis and liver cancer. 
     
     
         7 . The method of  claim 1 , wherein the peptide or protein comprises an extracellular matrix protease. 
     
     
         8 . The method of  claim 7 , wherein the extracellular matrix protease is selected from the group consisting of bacterial collagenases and mammalian matrix metalloproteinases. 
     
     
         9 . The method of  claim 7 , wherein the extracellular matrix protease is selected from matrix metalloproteinase-1. 
     
     
         10 . The method of  claim 7 , wherein the peptide or protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 20 to 28. 
     
     
         11 . The method of  claim 1 , wherein the peptide or protein comprises CCAAT/enhancer-binding protein alpha (CEBPA), preferably human CEBPA. 
     
     
         12 . The method of  claim 1 , wherein the peptide or protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 8 to 13. 
     
     
         13 . The method of  claim 1 , wherein the peptide or protein comprises TNF-related apoptosis-inducing ligand (TRAIL). 
     
     
         14 . The method of  claim 1 , wherein the peptide or protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 4 to 7. 
     
     
         15 . The method of  claim 1 , wherein the peptide or protein is selected from the group consisting of hepatocyte nuclear factor 4 alpha (HNF4A), Hepatocyte Growth Factor (HGF), fibroblast growth factor 21 (FGF21), opioid growth factor receptor-like 1 (OGFRL1), Relaxin 1 (RLN1), Relaxin 2 (RLN2) and Relaxin 3 (RLN3). 
     
     
         16 . The method of  claim 1 , wherein the at least one coding sequence of the RNA comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 32 to 71. 
     
     
         17 . The method of  claim 1 , wherein the RNA is mono-, bi-, or multicistronic. 
     
     
         18 . The method of  claim 1 , wherein the RNA is an mRNA. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the
 the G/C content of the at least one coding sequence of the RNA is increased compared to   the G/C content of the corresponding coding sequence of the corresponding wild type RNA,   the C content of the at least one coding sequence of the RNA is increased compared to the C content of the corresponding coding sequence of the corresponding wild type RNA, and/or wherein   at least one codon in the at least one coding sequence of the RNA is adapted to human codon usage, wherein the codon adaptation index (CAI) is preferably increased or maximised in the at least one coding sequence of the RNA,   wherein the amino acid sequence encoded by the RNA is preferably not modified compared to the amino acid sequence encoded by the corresponding wild type RNA.   
     
     
         21 . The method of  claim 20 , wherein the at least one coding sequence comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406 and 407. 
     
     
         22 - 66 . (canceled)