Organic compositions to treat beta-ENaC-related diseases
The present disclosure relates to RNAi agents useful in methods of treating Beta-ENaC-related diseases such as cystic fibrosis, pseudohypoaldosteronism type 1 (PHA1), Liddle's syndrome, hypertension, alkalosis, hypokalemia, and obesity-associated hypertension, using a therapeutically effective amount of a RNAi agent to Beta-ENaC.
1. A composition comprising a RNAi agent comprising a first strand and a second strand, wherein: the sequence of the first strand comprises the base sequence of nucleotides 1-19 of any sequence of SEQ ID NOs: 111-119 or 150; wherein the length of the first and the second strand are each no more than about 30 nucleotides; and
wherein the first or the second strand comprises at least one modified nucleotide.
2. The composition of claim 1 , wherein the composition further comprises a second RNAi agent to Beta-ENaC.
3. The composition of claim 1 , wherein the RNAi agent comprises a phosphorothioate and/or at least one 2′-modified nucleotide.
4. The composition of claim 1 , wherein the RNAi agent is ligated to one or more agents, wherein the one or more agents are selected from: diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecogenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.
5. A method of reducing the level and/or expression of Beta-ENaC in an individual, the method comprising the step of administering to the individual a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and a composition of claim 1 .
6. The method of claim 5 , wherein the composition further comprises a second RNAi agent to Beta-ENaC.
7. The method of claim 5 , wherein the RNAi agent comprises a phosphorothioate and/or a 2′-modified nucleotide.
8. The method of claim 5 , wherein the RNAi agent is ligated to one or more agents, wherein the one or more agents are selected from: diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecogenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.
9. The composition of claim 1 , wherein the first and the second strand both comprise at least one modified nucleotide.
10. The composition of claim 9 , wherein the modified nucleotide is selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2 ′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O- dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).
11. The composition of claim 9 , wherein the RNAi agent is ligated to one or more agents, wherein the one or more agents are selected from: diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecogenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.
12. The composition of claim 9 , wherein the composition comprises a second RNAi agent targeted to Beta-ENaC.
13. The composition of claim 9 , wherein the RNAi agent comprises a phosphorothioate and/or a 2′-modified nucleotide.
14. A composition comprising a therapeutically effective amount of a composition of claim 1 and a pharmaceutically acceptable carrier.
15. A composition comprising a therapeutically effective amount of a composition of claim 9 and a pharmaceutically acceptable carrier.