Compounds of chemically modified oligonucleotides and methods of use thereof

Abstract

The present disclosure relates to isolated compounds including a nucleic acid sequence capable of hybridizing to an RNA sequence 10 to 270 nucleobases downstream of the transcription start site of a mammalian microRNA-379 transcript; method of treating diabetic nephropathy in a subject with the compounds; and method of inhibiting expression of a mammalian microRNA-379 megacluster with the compounds.

1 .- 10 . (canceled) 
     
     
         11 . A method of treating diabetic nephropathy in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound comprising a nucleic acid sequence capable of hybridizing to an RNA sequence 10 to 270 nucleobases downstream of the transcription start site of a mammalian microRNA-379 transcript, wherein said nucleic acid sequence comprises a nucleobase analog or internucleotide linkage. 
     
     
         12 . The method of  claim 11 , wherein said compound inhibits expression of a long non-coding RNA (lncMGC) comprising microRNA-376a, microRNA-299, microRNA-376c, microRNA-410, microRNA-494, microRNA-380-5p, microRNA-369-3p, microRNA-300, microRNA-541, microRNA-329, microRNA-381, microRNA-411, microRNA-134, microRNA-379, microRNA-154, microRNA-382, microRNA-376b, microRNA-496, microRNA-409-5p, microRNA-543, microRNA-377, microRNA-380-3p, or microRNA-495, in said subject. 
     
     
         13 . The method of  claim 11 , wherein said compound inhibits expression of a microRNA-379 gene cluster. 
     
     
         14 . The method of  claim 11 , wherein said treating diabetic nephropathy is at an early stage of the disease. 
     
     
         15 . The method of  claim 11 , wherein said nucleobase analog is at the 5′-end or the 3′-end of said nucleic acid sequence. 
     
     
         16 . The method of  claim 15 , wherein said nucleic acid sequence comprises three nucleobase analogs at the 5′-end or the 3′-end of said nucleic acid sequence. 
     
     
         17 . The method of  claim 16 , wherein said nucleobase analog is a Locked Nucleic Acid (LNA), 2′-O-alkyl nucleobase, 2′-Fluoro nucleobase, or 2′-OMe nucleobase. 
     
     
         18 . The method of  claim 11 , wherein said RNA sequence is 11 to 27, 61 to 93, 115 to 139, or 246 to 265 nucleobases downstream of said transcription start site. 
     
     
         19 . The method of  claim 11 , wherein said nucleic acid sequence comprises modified internucleotide linkage. 
     
     
         20 . The method of  claim 19 , wherein said modified internucleotide linkage is a phosphorothioate linkage. 
     
     
         21 . The method of  claim 11 , wherein the nucleic acid sequence has at least 90% sequence identity with a continuous 10 nucleobase sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24. 
     
     
         22 . The method of  claim 11 , wherein the compound inhibits renal glomerular podocyte death, glomerular mesangial expansion, glomerular hypertrophy, glomerular extracellular matrix accumulation. 
     
     
         23 . The method of  claim 11 , wherein:
 (a) said nucleic acid sequence (i) is perfectly complementary to at least 15 continuous nucleobases from nucleobases 11 to 27, or 115 to 139 of SEQ ID NO: 25, 118, 26 or 119, or (ii) is selected from SEQ ID NOs: 10-21;   (b) said nucleic acid sequence comprises at least one nucleobase analog or at least one modified internucleotide linkage; and   (c) said nucleic acid is 15 to 20 nucleobases in length.   
     
     
         24 . The method of  claim 11 , wherein said nucleic acid sequence comprises three nucleobase analogs at the 5′-end or the 3′-end of said nucleic acid sequence. 
     
     
         25 . The method of  claim 11 , wherein said nucleic acid sequence is perfectly complementary to at least 16 continuous nucleobases from nucleobases 11 to 27, or 115 to 139 of SEQ ID NO: 25, 118, 26 or 119. 
     
     
         26 . The method of  claim 11 , wherein said nucleic acid sequence is selected from SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21. 
     
     
         27 . The method of  claim 11 , wherein said nucleic acid sequence is perfectly complementary to at least 15 continuous nucleobases from nucleobases 11 to 27, or 115 to 139 of SEQ ID NO: 25, 118, 26 or 119. 
     
     
         28 . The method of  claim 11 , wherein said nucleic acid sequence is perfectly complementary to a sequence that is at least 90% identical to the entire length of at least 18 continuous nucleobases from nucleobases 11 to 27, or 115 to 139 of SEQ ID NO: 25, 118, 26 or 119.