Double Stranded Oligonucleotide Compounds Comprising Positional Modifications

A double stranded nucleic acid molecule having structure A1 set forth below:

• (A1) 5′ (N)x-Z 3′ (antisense strand)
• 3′ Z′-(N′)y-z″ 5′ (sense strand)
• wherein said double stranded nucleic acid molecule is an siRNA, siNA, or miRNA, and wherein each of N and N′ is a ribonucleotide that may be unmodified or modified, or an unconventional moiety;
• wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;
• wherein each of Z and Z′ is independently present or absent, but if present independently includes 1-5 consecutive nucleotides or non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present;
• wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of (N′)y;
• wherein each of x and y is independently an integer between 18 and 25;
• wherein the sequence of (N′)y has complementarity to the sequence of (N)x, and (N)x comprises an antisense sequence complementary to a consecutive sequence in a target RNA;
• and
• wherein the molecule comprises the following modification b and at least one of the following modifications a and c:
• a. a 2′5′ nucleotide or a mirror nucleotide is present in (N)x in at least one of positions 5, 6, 7, 8, or 9 from the 5′ terminus;
• b. a threose nucleic acid moiety is present in the sense strand at positions 14 and 16-19, positions 13-14 and 16-19, or positions 12-14 and 16-19, and a 2′5′ nucleotide is present in the same sense strand;
• and
• c. from 1 to 10 2′5′ nucleotides are present in (N′)y at the 3′ terminal or penultimate positions,
• wherein the threose nucleic acid is an L-alpha-threofuranosyl nucleotide.