Treatment of thymic stromal lymphopoietin (tslp) related diseases by inhibition of long-form tslp transcripts

Abstract

Provided are compositions comprising an oligonucleotide that targets Thymic stromal lymphopoietin (TSLP). The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating an airway disorder by providing an oligonucleotide that targets TSLP to a subject in need thereof. In some embodiments, the oligonucleotide targeting is specific for a long isoform of TSLP (lfTSLP).

1 - 20 . (canceled) 
     
     
         21 . A composition comprising a double-stranded RNA comprising a sense strand and an antisense strand, wherein the sense strand or antisense strand comprises any of the following modification patterns: modification pattern 1S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′, modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, modification pattern 3S: 5′ nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′, modification pattern 1AS: 5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′, modification pattern 2AS: 5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′, modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′, or modification pattern 4AS: 5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3′; wherein “Nf” comprises a 2′-fluoro-modified nucleoside, “n” comprises a 2′-O-methyl modified nucleoside, and “s” comprises a phosphorothioate linkage. 
     
     
         22 . The composition of  claim 21 , wherein the antisense strand comprises modification pattern 1AS: 5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′. 
     
     
         23 . The composition of  claim 21 , wherein the sense strand comprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′. 
     
     
         24 . The composition of  claim 21 , wherein the antisense strand comprises modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′. 
     
     
         25 . The composition of  claim 21 , wherein the sense strand comprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, and the antisense pattern comprises modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′. 
     
     
         26 . The composition of  claim 21 , further comprising a targeting ligand. 
     
     
         27 . The composition of  claim 26 , wherein the targeting ligand comprises N-acetylgalactosamine (GalNAc). 
     
     
         28 . The composition of  claim 21 , further comprising a lipid attached at a 3′ or 5′ terminus of the oligonucleotide. 
     
     
         29 . The composition of  claim 28 , wherein the lipid comprises a lipid selected from the group consisting of cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, and α-tocopherol, or a combination thereof. 
     
     
         30 . The compositions of  claim 21 , wherein the double-stranded RNA comprises a siRNA 
     
     
         31 . The composition of  claim 21 , wherein the modified double-stranded RNA has improved stability compared to the corresponding unmodified double-stranded RNA. 
     
     
         32 . A method of treating a subject in need thereof, the method compositing administering to the subject a double-stranded RNA comprising a sense strand and an antisense strand, wherein the sense strand or antisense strand comprises any of the following modification patterns: modification pattern 1S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′, modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, modification pattern 3S: 5′ nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′, modification pattern 1AS: 5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′, modification pattern 2AS: 5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′, modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′, or modification pattern 4AS: 5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3′; wherein “Nf” comprises a 2′-fluoro-modified nucleoside, “n” comprises a 2′-O-methyl modified nucleoside, and “s” comprises a phosphorothioate linkage. 
     
     
         33 . The method of  claim 32 , wherein the antisense strand comprises modification pattern 1AS: 5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′. 
     
     
         34 . The method of  claim 32 , wherein the sense strand comprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′. 
     
     
         35 . The method of  claim 32 , wherein the antisense strand comprises modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′. 
     
     
         36 . The method of  claim 32 , wherein the sense strand comprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, and the antisense pattern comprises modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′. 
     
     
         37 . The method of  claim 32  wherein the double-stranded RNA is formulated for administration to a patient intravenously, subcutaneously, topically, rectally, anally, vaginally, nasally, endotracheally, by inhalation, ocularly or transdermally. 
     
     
         38 . A pharmaceutical composition comprising: a double-stranded RNA comprising a sense strand and an antisense strand, wherein the sense strand or antisense strand comprises any of the following modification patterns: modification pattern 1S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′, modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, modification pattern 3S: 5′ nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′, modification pattern 1AS: 5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′, modification pattern 2AS: 5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′, modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′, or modification pattern 4AS: 5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3′; wherein “Nf” comprises a 2′-fluoro-modified nucleoside, “n” comprises a 2′-O-methyl modified nucleoside, and “s” comprises a phosphorothioate linkage. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the double-stranded RNA is encapsulated in a liposome. 
     
     
         40 . The pharmaceutical composition of  claim 38 , wherein the double-stranded RNA is attached to a carrier molecule.