Therapeutic compositions

An iRNA duplex comprising:

• a first monomer in a first sequence and a second monomer in a second sequence within the first 3, 4, 5, or 6 positions from either the 3′ end or the 5′ end,
• wherein the first and second monomers are selected such that the stability of the pairing of the monomers contributing to forming a duplex between the first and second sequences differs from the stability of the pairing between the first sequence and a target sequence or between the second sequence and a target sequence,
• wherein the iRNA duplex is represented by
• S
• 5′ R1N1N2N3N4N5 [N] N-5 N-4 N-3 N-2 N-1 R2 3′
• AS
• 3′ R3N1N2N3N4N5 [N] N-5 N-4 N-3 N-2 N-1 R4 5′
• S:AS
• P1 P2 P3 P4 P5 [N] P-5P-4P-3P-2P-1 5′
• wherein:
• S represents a sense strand corresponding to the second sequence;
• AS represents an antisense strand corresponding to the first sequence;
• R1 is an optional overhang at the 5′-end of the sense strand;
• R2 is an optional overhang at the 3′-end of the sense strand;
• R3 is an optional overhang at the 3′-end of the antisense strand;
• R4 is an optional overhang at the 5′-end of the antisense strand;
• N is a monomeric subunit;
• [N] indicates the optional presence of additional subunit pairs;
• and
• Px is a pairing of sense Nx and antisense Nx where x is −5 to 5,
• wherein the subunit at P−1 of the 5′-end of the antisense strand is A or a modified base which pairs with T, or U or a modified base which pairs with A, and
• wherein the subunits at P−1 are the first monomer and second monomer, respectively.