Oligonucleotide analogues targeting human LMNA

An antisense oligonucleotide, wherein the oligonucleotide modulates aberrant splicing of a human LMNA pre-mRNA, the oligonucleotide comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′-end of one morpholino ring structure to a 5′-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligonucleotide can bind in a sequence-specific manner to a target nucleic acid, comprising a targeting sequence comprising any one of SEQ ID NOS:

• 3-8, 10-18 and 20-34, wherein the intersubunit linkages have the following general structure (I):
• or a salt or isomer thereof, and wherein each of the intersubunit linkages (I) are independently linkage (A) or linkage (B):
• wherein for linkage (A):
• W is, at each occurrence, independently S or O;
• X is, at each occurrence, independently —N(CH3)2, —NR1R2, —OR3 or;
• Y is, at each occurrence, independently O or —NR2,
• R1 is, at each occurrence, independently hydrogen or methyl;
• R2 is, at each occurrence, independently hydrogen or -LNR4R5R7;
• R3 is, at each occurrence, independently hydrogen or C1-C6 alkyl;
• R4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH2, —Z-L-NHC(═NH)NH2 or —[C(O)CHR′NH]mH, where Z is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;
• R5 is, at each occurrence, independently hydrogen, methyl or an electron pair;
• R6 is, at each occurrence, independently hydrogen or methyl;
• R7 is, at each occurrence, independently hydrogen C1-C6 alkyl or C1-C6 alkoxyalkyl;
• L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof;
• and
• wherein for linkage (B):
• W is, at each occurrence, independently S or O;
• X is, at each occurrence, independently —NR8R9 or —OR3;
• and
• Y is, at each occurrence, independently O or —NR10,
• R8 is, at each occurrence, independently hydrogen or C2-C12 alkyl;
• R9 is, at each occurrence, independently hydrogen, C1-C12 alkyl, C1-C12 aralkyl or aryl;
• R10 is, at each occurrence, independently hydrogen, C1-C12 alkyl or -LNR4R5R7;
• wherein R8 and R9 may join to form a 5-18 membered mono or bicyclic heterocycle or R8, R9 or R3 may join with R10 to form a 5-7 membered heterocycle, and wherein when X is 4-piparazino, X has the following structure (III):
• wherein:
• R11 is, at each occurrence, independently C2-C12 alkyl, C1-C12 aminoalkyl, C1-C12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl;
• and
• R is, at each occurrence, independently an electron pair, hydrogen or C1-C12 alkyl;
• and
• R12 is, at each occurrence, independently, hydrogen, C1-C12 alkyl, C1-C12 aminoalkyl, —NH2, —NR13R14, NR13R14R15, C1-C12 alkylcarbonyl, oxo, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR13 or C1-C12 alkoxy, wherein R13, R14 and R15 are, at each occurrence, independently C1-C12 alkyl;
• and
• wherein at least one of the intersubunit linkages is linkage (B).

A compound, or pharmaceutically acceptable salt thereof, of formula:

• wherein:
• R is H or —C(O)CH3, and
• each Pj is a purine or pyrimidine base-pairing moiety, which taken together form a targeting sequence, wherein the targeting sequence is selected from:
• a) SEQ ID NO:
• 3 (CCGCTGGCAGATGCCTTGTCGGCAG), wherein X is 23,
• b) SEQ ID NO:
• 4 (CTGAGCCGCTGGCAGATGCCTTGTC), wherein X is 23,
• c) SEQ ID NO:
• 5 (GCTCCTGAGCCGCTGGCAGATGCCT), wherein X is 23,
• d) SEQ ID NO:
• 6 (TGGGCTCCTGAGCCGCTGGCAGATG), wherein X is 23,
• e) SEQ ID NO:
• 7 (CACCTGGGCTCCTGAGCCGCTGGCA), wherein X is 23,
• f) SEQ ID NO:
• 8 (CCACCCACCTGGGCTCCTGAGCCGC), wherein X is 23
• g) SEQ ID NO:
• 10 (AGATGGGTCCACCCACCTGGGCTCC), wherein X is 23,
• h) SEQ ID NO:
• 11 (GAGGAGATGGGTCCACCCACCTGGG), wherein X is 23,
• i) SEQ ID NO:
• 12 (GCCAGAGGAGATGGGTCCACCCCACC), wherein X is 23,
• j) SEQ ID NO:
• 13 (AAGAGCCAGAGGAGATGGGTCCACC), wherein X is 23,
• k) SEQ ID NO:
• 14 (CAGAAGAGCCAGAGGAGATGGGGTCC), wherein X is 23,
• l) SEQ ID NO:
• 15 (GAGGCAGAAGAGCCAGAGGAGATGG), wherein X is 23,
• m) SEQ ID NO:
• 16 (ACTGGAGGCAGAAGAGCCAGAGGAG), wherein X is 23,
• n) SEQ ID NO:
• 17 (ACGTGGTGGTGATGGAGCAGGTCAT), wherein X is 23,
• o) SEQ ID NO:
• 18 (ACTCACGTGGTGGTGATGGAGCAGG), wherein X is 23,
• p) SEQ ID NO:
• 20 (CGGCGGCTACCACTCACGTGGTGGT), wherein X is 23,
• q) SEQ ID NO:
• 21 (AGATGGGTCCACCCACCTGGGCTCC), wherein X is 23,
• r) SEQ ID NO:
• 22 (CCTCAGCGGCGGCTACCACTCACGT), wherein X is 23,
• s) SEQ ID NO:
• 23 (GGCCTCAGCGGCGGCTACCACTCAC), wherein X is 23,
• t) SEQ ID NO:
• 24 (GCTCGGCCTCAGCGGCGGCTACCAC), wherein X is 23,
• u) SEQ ID NO:
• 25 (CGAGTCTGGGACTGACCACTCAGGC), wherein X is 23,
• v) SEQ ID NO:
• 26 (AGGCTCAGGCGGGACGGCGAGTCTG), wherein X is 23,
• w) SEQ ID NO:
• 27 (AGACAAGGCTCAGGCGGGACGGCGA), wherein X is 23,
• x) SEQ ID NO:
• 28 (AGGGAGACAAGGCTCAGGCGGGACG), wherein X is 23,
• y) SEQ ID NO:
• 29 (GGGAAGGGAGACAAGGCTCAGGCGG), wherein X is 23,
• z) SEQ ID NO:
• 30 (GCCCTGGGAAGGGAGACAAGGCTCA), wherein X is 23,
• aa) SEQ ID NO:
• 31 (GTGGGAGCCCTGGGAAGGGAGACAA), wherein X is 23,
• bb) SEQ ID NO:
• 32 (CTGCTGCAGTGGGAGCCCTGGGAAG), wherein X is 23,
• cc) SEQ ID NO:
• 33 (AGCTGCTGCAGTGGGAGCCCTGGGA), wherein X is 23, and
• dd) SEQ ID NO:
• 34 (CCCCCGAGCTGCTGCAGTGGGAGCC), wherein X is 23.