Modulation of nuclear-retained rna

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of a nrRNA in an animal. Also provided herein are methods, compounds, and compositions for treating, ameliorating, delaying or reducing a symptom of a disease or disorder associated with a nuclear-retained RNA in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate a disease or condition associated with a nuclear-retained RNA, or a symptom thereof.

1 .- 69 . (canceled) 
     
     
         70 . A method of achieving a pharmacologically relevant reduction of a nuclear-retained RNA in a cell or tissue having low antisense oligonucleotide uptake, comprising administering to an animal suspected of having said nuclear-retained RNA a chemically-modified antisense oligonucleotide complementary to said nuclear-retained RNA in an amount effective to activate a nuclear ribonuclease capable of cleaving the nuclear-retained RNA to achieve said pharmacologically relevant reduction. 
     
     
         71 . The method of  claim 70 , wherein said nuclear-retained RNA is associated with a disease or condition in said tissue and wherein said animal is selected as having said disease or condition. 
     
     
         72 . The method of  claim 70 , wherein said nuclear-retained RNA is a non-coding RNA. 
     
     
         73 . The method of  claim 72 , wherein said non-coding RNA is a long non-coding RNA, short non-coding RNA, large intervening non-coding RNA, repeat element containing RNA, expanded nucleotide repeat-containing RNA, snoRNA, scaRNA, or enrRNA. 
     
     
         74 . The method of  claim 72  wherein said non-coding RNA is any of Xlsirt, Satellite III, Hox C5 transcript variant 2 (non-coding), Menβ, Neat1, Neat2, hsr-omega, hothead, Kit, Xist, Air, Tsix, Mirg, Kcnq1ot1, AK045070, P-rex1, ZNF127AS, NESPAS, SRG1, Hotair, Gomafu, Sox2ot, Rian, CAT2, Xite, Jpx, Ftx, RoX1, RoX2, H19, Igf2, IPW, UBE3A, ATP10C, pgc, 7SK, RNA Pol II transcription elongation factor P-TEFb, B2, HSR-1, BC1, BC200, NRSE, NRON, NFAT transcription factor, Makorin-p1, HAR1F, HAR1R, OCC1, DD3/PCA3, PCGEM1, NCRMS, HIS-1, BCMS, CMPD, NC612, SRA, DISC2, PSZA11q14, RAY1/ST7, UBE3A-AS, SCA8, 22k48, C6orf37OS, COPG2IT1, DGCR5, KCNQ1 overlapping transcript 1 (non-protein coding), MESTIT 1, and PRINS. 
     
     
         75 . The method of  claim 73  wherein said expanded nucleotide repeat-containing RNA is any of SCA8/ataxin 8, ATN1/DRPLA, FMR1, AFF2/FMR2, frataxin/FXN, Htt, junctophilin-3 (JPH3), DMPK, zinc finger protein-9, Androgen receptor (AR) (X-linked), ataxin-1 (ATXN1), ATXN10, protein phosphatase PP2A (PPP2R2B), TATA box-binding protein (TBP), ATXN2, ATXN3, CACNA1A, ATXN7, and SCA8. 
     
     
         76 . The method of  claim 72  wherein said non-coding RNA is any of NEAT2, DMPK, U16, and U 50. 
     
     
         77 . The method of  claim 70 , wherein the oligonucleotide is a gapmer 
     
     
         78 . The method of  claim 77 , wherein the nucleobase sequence of the oligonucleotide is at least 95% complementary to the nuclear-retained RNA as measured over the entirety of said oligonucleotide. 
     
     
         79 . The method of  claim 77 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the nuclear-retained RNA as measured over the entirety of said modified oligonucleotide. 
     
     
         80 . The method of  claim 77 , wherein at least one internucleoside linkage of said oligonucleotide is a modified internucleoside linkage. 
     
     
         81 . The method of  claim 80 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         82 . The method of  claim 70 , wherein at least one nucleoside of said oligonucleotide comprises a modified sugar. 
     
     
         83 . The method of  claim 82 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         84 . The method of  claim 83 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a 4′-CH(CH 3 )—O-2′ bridge, or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2. 
     
     
         85 . The method of  claim 70 , wherein at least one nucleoside of said oligonucleotide comprises a modified nucleobase. 
     
     
         86 . The method of  claim 85 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         87 . The method of  claim 70 , wherein the oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides;   a 3′ wing segment consisting of linked nucleosides;   
       wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     
     
         88 . The method of  claim 87 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         89 . The method of  claim 87 , wherein each modified sugar comprises a 2′-O-methoxyethyl modification. 
     
     
         90 . The compound of  claim 89 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.