Dual activity super toxic RNAi active dsRNAs

An shRNA polynucleotide comprising a dsRNA sequence having a first strand, otherwise referred to as an “A” strand, and a second strand, otherwise referred to as a “B” strand, the dsRNA defined as follows:

• 5′-A01 A02 A03 A04 A05 A06 A07 A08 A09 A10 A11 A12
• | | | | | | | | | | | |
• 3′-B21 B20 B19 B18 B17 B16 B15 B14 B13 B12 B11 B10
• A13 A14 A15 A16 A17 A18 A19 A20 A21-3′
• | | | | | | | | |
• B09 B08 B07 B06 B05 B04 B03 B02 B01-5′
• wherein:
• A01 through A21 and B01 through B21 are any ribonucleotide selected from A, U, G, and C, provided that:
• (i) A01-A21 are complementary to B01-B21, respectively;
• (ii) A01 and B01 are A or U;
• (iii) one of the A strand from A02-A07 and the B strand from B02-B07 comprises the sequence GGGGGC;
• and
• (iv) the other of the A strand and the B strand comprises a trinucleotide repeat sequence (CAG)n, wherein n is an integer from 3-10;
• wherein the 3′ end of the A strand is linked via polynucleotides to the 5′ end of the B strand;
• and
• wherein both of the A strand and the B strand are toxic after the shRNA is introduced into a cell and the shRNA is processed for RNA interference, wherein the dsRNA sequence comprises:
• (SEQ ID NOs:
• 47 and 48)
• 5′-CAGCAGCAGCAGCCCCC-3′
• |||||||||||||||||
• 3′-GUCGUCGUCGUCGGGGG-5′.