dsRNA MOLECULES COMPRISING OLIGONUCLEOTIDE ANALOGS HAVING MODIFIED INTERSUBUNIT LINKAGES AND/OR TERMINAL GROUPS

A double-stranded ribonucleic acid (dsRNA) molecule for inhibiting the expression of a target gene in a cell, wherein said dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a target gene mRNA, wherein said region of complementarity is less than about 30 nucleotides in length, wherein one or both of the sense and antisense strands comprise an oligomer backbone having at least one morpholino subunit joined by intersubunit linkages, wherein each morpholino subunit supports a base-pairing moiety, and wherein the intersubunit linkages comprise a structure selected from the group consisting of (A) and (B) below:

• (A). an intersubunit linkage comprising the following structure (A-I):
• where
• W is S or O,
• X═NR1R2 or OR6,
• Y═O or NR7,
• and each said linkage is selected from:
• (a) uncharged linkage (a), where each of R1, R2, R6 and R7 is independently selected from hydrogen and lower alkyl;
• (b1) cationic linkage (b1), where X═NR1R2 and Y═O, and NR1R2 represents an optionally substituted piperazino group, such that R1R2═—CHRCHRN(R3)(R4)CHRCHR—, where
• each R is independently H or CH3,
• R4 is H, CH3 or an electron pair, and
• R3 is selected from H, lower alkyl, C(═NH)NH2, Z-L-NHC(═NH)NH2, and [C(O)CHR′NH]mH, where Z is carbonyl (C(O)) or a direct bond, L is an optional linker up to 18 atoms in length having bonds selected from alkyl, alkoxy, and alkylamino, 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;
• (b2) cationic linkage (b2), where X═NR1R2 and Y═O, R1═H or CH3, and R2=LNR3R4R5, where L, R3, and R4 are as defined above, and R5 is H, lower alkyl, or lower (alkoxy)alkyl;
• and
• (b3) cationic linkage (b3), where Y═NR7 and X═OR6, and R7=LNR3R4R5, where L, R3, R4 and R5 are as defined above, and R6 is H or lower alkyl;
• and at least one said linkage is selected from cationic linkages (b1), (b2), and (b3);
• and
• (B). an intersubunit linkage comprising the following structure (B-I):
• where each of the intersubunit linkages (I) are selected from:
• (a) linkage (a) wherein:
• W is S or O;
• X is —N(CH3)2;
• and
• Y is O, and
• (b) linkage (b) wherein:
• W is S or O;
• X is NR1R2 or OR3;
• and
• Y is O or NR4,
• wherein R1 is hydrogen or optionally substituted C2-C12 alkyl, each of R2, R3 and R4 is independently hydrogen or optionally C1-C12 alkyl, and wherein each of R1, R2, R3 and R4 may join with another of R1, R2, R3 or R4 to form an optionally substituted 5, 6 or 7-membered heterocycle comprising one or more N, O or S atoms or combinations thereof, and wherein at least one of the intersubunit linkages comprises linkage (b).