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 —NR1,
• 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-piperazinyl, 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 the antisense oligonucleotide is covalently attached to a cell-penetrating peptide and linker moiety of the formula -G-CPP, wherein G is the linker moiety selected from glycine, cysteine, proline, 6-aminohexanoic acid (Ahx), β-alanine (B), and Ahx-B, and CPP is the cell-penetrating peptide and is selected from SEQ ID NOS:
• 39-54.