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Definitions

• Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5 -methyl cytosine ( m C) and guanine (G).
• Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated.
• double-stranded antisense compound means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex, and wherein one of the two said oligomeric compounds comprises an antisense oligonucleotide.
• effective amount means the amount of compound sufficient to effectuate a desired physiological outcome in an individual in need of the compound.
• the effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual's medical condition, and other relevant factors.
• efficacy means the ability to produce a desired effect.
• inhibiting the expression or activity refers to a reduction or blockade of the expression or activity relative to the expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.
• MOE means methoxyethyl.
• 2'-MOE or “2'-0-methoxyethyl” means a 2'- OCH2CH2OCH3 group in place of the 2'-OH group of a ribosyl ring.
• prodrug means a therapeutic agent in a form outside the body that is converted to a differentform within the body or cells thereof. Typically conversion of a prodrug within the body is facilitated by the action of an enzymes (e.g., endogenous or viral enzyme) or chemicals present in cells or tissues and/or by physiologic conditions.
• an enzymes e.g., endogenous or viral enzyme
• chemicals present in cells or tissues and/or by physiologic conditions.
• Certain embodiments provide compounds comprising or consisting of oligonucleotides complementary to an ⁇ -ENaC or SCN IA nucleic acid.
• the ⁇ -ENaC or SCNNIA nucleic acid has the sequence set forth in RefSeq or GenBank Accession No. NM_001038.5 (disclosed herein as SEQ ID NO: 1), the complement of NC_000012.12 truncated from nucleosides 6343001 to 6380000 (disclosed herein as SEQ ID NO: 2), or NG_011945.1 (disclosed herein as SEQ ID NO: 1957).
• the compound is an antisense compound or oligomeric compound.
• the compound is single-stranded.
• the compound is double-stranded.
• Certain embodiments provide a compound comprising a modified oligonucleotide 11 to 50 linked nucleosides in length and having a nucleobase sequence comprising at least 11 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-1954.
• the compound is an antisense compound or oligomeric compound.
• the compound is single -stranded.
• the compound is double-stranded.
• the modified oligonucleotide is 11 to 30 linked nucleosides in length.
• a compound comprises a modified oligonucleotide described herein and a conjugate group.
• the conjugate group is linked to the modified oligonucleotide at the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate group is linked to the modified oligonucleotide at the 3 ' end of the modified oligonucleotide.
• the oligonucleotide is complementary to a sequence within nucleotides 4,497-5, 163; 5,634-16,290; 16,559-17,759; 17,951-24,120; 24,225-24,565; 24,730-25,152; 25,252-25,445; 25,564-30,595; 30,675-30,779; 30,838-30,995; 31,052-31,198; or 31,275-31,747 of SEQ ID NO: 2.
• the modified oligonucleotide is complementary to intron 1, intron 2, intron 3, intron 4, intron 5, intron 6, intron 7, intron 8, intron 9, intron 10, intron 11, or intron 12 of an ⁇ -ENaC nucleic acid transcript.
• Certain embodiments are drawn to a compound comprising an ⁇ -ENaC inhibitor for use in increasing or improving spirometry or mucociliary clearance of an individual having or at risk of having cystic fibrosis, COPD, asthma, or chronic bronchitis.
• the compound comprises an antisense compound targeted to ⁇ -ENaC.
• the compound comprises an oligonucleotide complementary to an ⁇ -ENaC nucleic acid transcript.
• the oligonucleotide is a modified oligonucleotide.
• the compound comprise a modified oligonucleotide complementary to an intron of an ⁇ -ENaC nucleic acid transcript.
• the modified oligonucleotide comprises agap segment consisting of linked 2'-deoxynucleosides; a 5' wing segment consisting of linked nucleosides; and a 3' wing segment consisting of linked nucleosides, wherein the gap segment is positioned immediately adjacent to and between the 5' wing segment and the 3' wing segment and wherein each terminal wing nucleoside comprises a modified sugar.
• a 3' wing segment consisting of linked nucleosides
• a 3' wing segment consisting of 3 linked nucleosides
• a secondary agent is selected from: hypertonic saline, dornase alfa, ivacaftor, tezacaftor, and lumacaftor.
• Certain embodiments are directed to the use of a compound comprising a modified oligonucleotide complementary to an ⁇ -ENaC nucleic acid transcript as described herein in combination with two or more secondary agents. In particular embodiments such use is in a method of treating a patient suffering from cystic fibrosis, COPD, asthma, or chronic bronchitis or in the preparation or manufacture of a medicament for treating cystic fibrosis, COPD, asthma, or chronic bronchitis.
• Certain embodiments are drawn to a combination of a compound comprising a modified oligonucleotide complemetary to an ⁇ -ENaC nucleic acid transcript as described herein and two or more secondary agents, such as secondary agents selected from: hypertonic saline, dornase alfa, ivacaftor, tezacaftor, and lumacaftor.
• secondary agents selected from: hypertonic saline, dornase alfa, ivacaftor, tezacaftor, and lumacaftor.
• a compound or antisense compound is single-stranded.
• Such a single- stranded compound or antisense compound comprises or consists of an oligomeric compound.
• such an oligomeric compound comprises or consists of an oligonucleotide and optionally a conjugate group.
• the oligonucleotide is an antisense oligonucleotide.
• the oligonucleotide is modified.
• the oligonucleotide of a single-stranded antisense compound or oligomeric compound comprises a self-complementary nucleobase sequence.
• the compound contains a capped strand, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000.
• the compound consists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides.
• the compound can comprise a conjugate group.
• compounds described herein comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid.
• the target nucleic acid is an endogenous RNA molecule.
• the target nucleic acid encodes a protein.
• the target nucleic acid is selected from: an mRNA and a pre-mRNA, including intronic, exonic and untranslated regions.
• the target RNA is an mRNA.
• the target nucleic acid is a pre-mRNA.
• a pre-mRNA and corresponding mRNA are both target nucleic acids of a single compound.
• the mismatch is at position 1, 2, 3, or 4 from the 5 '-end of the wing segment. In certain such embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3 '-end of the wing segment. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide not having a gapmer motif. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, or 12 from the 5'-end of the oligonucleotide. In certain such embodiments, the mismatch is at position , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, or 12 from the 3 '-end of the oligonucleotide.
• modified sugar moieties are sugar surrogates.
• the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom.
• such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein.
• certain sugar surrogates comprise a 4'-sulfur atom and a substitution at the 2'- position (see, e.g., Bhat et al., U.S. 7,875,733 and Bhat et al., U.S. 7,939,677) and/or the 5' position.
• modified THP nucleosides are provided wherein qi, q2, q3, q4, qs, qe and q7 are each H. In certain embodiments, at least one of qi, q2, q3, q4, qs, qe and q7 is other than H. In certain embodiments, at least one of qi, q2, q3, q4, qs, qe and q7 is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of Ri and R2 is F. In certain embodiments, Ri is F and R2 is H, in certain embodiments, Ri is methoxy and R2 is H, and in certain embodiments, Ri is methoxyethoxy and R2 is H.
• morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure.
• sugar surrogates are refered to herein as "modifed morpholinos.”
• modified nucleobases are selected from: 5-substituted pyrimidines, 6- azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines.
• modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration.
• populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate intemucleoside linkages in a particular, independently selected stereochemical configuration.
• the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population.
• compounds described herein comprise or consist of oligonucleotides.
• Oligonucleotides can have a motif, e.g. a pattern of unmodified and/or modified sugar moieties, nucleobases, and/or intemucleoside linkages.
• modified oligonucleotides comprise one or more modified nucleoside comprising a modified sugar.
• modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase.
• modified oligonucleotides comprise one or more modified intemucleoside linkage.
• each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage .
• each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate, a ( ⁇ Sp) phosphorothioate, and a (Rp) phosphorothioate.
• the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified.
• the internucleoside linkages in the wings are unmodified phosphate linkages.
• the terminal internucleoside linkages are modified.
• the sugar motif of a modified oligonucleotide is a gapmer, and the intemucleoside linkage motif comprises at least one phosphodiester intemucleoside linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal intemucleoside linkage, and the remaining intemucleoside linkages are phosphorothioate intemucleoside linkages.
• all of the phosphorothioate linkages are stereorandom.
• compounds described herein comprise or consist of modified oligonucleotides.
• the above modifications are incorporated into a modified oligonucleotide.
• modified oligonucleotides are characterized by their modifications, motifs, and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each intemucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications.
• Such embodiments do not include modified oligonucleotides where A and C each consist of 6 linked nucleosides and B consists of 10 linked nucleosides (even though those numbers of nucleosides are permitted within the requirements for A, B, and C) because the overall length of such oligonucleotide is 22, which exceeds the upper limit of 20 for the overall length of the modified oligonucleotide.
• all modifications are independent of nucleobase sequence except that the modified nucleobase 5- methylcytosine is necessarily a "C" in an oligonucleotide sequence.
• oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid.
• a region of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid.
• the nucleobase sequence of a region or entire length of an oligonucleotide is at least 70%, at least 80%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.
• a conjugate moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, ( ⁇ S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.
• an active drug substance for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, ( ⁇ S)-(+)-pranoprofen
• n is from 1 to about 3, m is 0 when n is 1, m is 1 when n is 2 or greater, j is 1 or 0, and k is 1 or 0.
• each tether of a cell-targeting moiety comprises one or more groups selected from alkyl, substituted alkyl, ether, thioether, disulfide, amino, oxo, amide, phosphodiester, and polyethylene glycol, in any combination.
• each tether is a linear aliphatic group comprising one or more groups selected from alkyl, ether, thioether, disulfide, amino, oxo, amide, and polyethylene glycol, in any combination.
• each tether is a linear aliphatic group comprising one or more groups selected from alkyl, phosphodiester, ether, amino, oxo, and amide, in any combination.
• each ligand of a cell-targeting moiety has an affinity for at least one type of receptor on a target cell. In certain embodiments, each ligand has an affinity for at least one type of receptor on the surface of a mammalian lung cell.
• a pharmaceutical composition consists of one compound and sterile water.
• the sterile water is pharmaceutical grade water.
• a pharmaceutical composition comprises or consists of one or more compound and phosphate-buffered saline (PBS).
• PBS phosphate-buffered saline
• a pharmaceutical composition consists of one or more compound and sterile PBS.
• the sterile PBS is pharmaceutical grade PBS.
• the compounds or compositions further comprise a pharmaceutically acceptable carrier or diluent.

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