| 摘要 |
RNAi constructs directed to MAP4K4 that demonstrate unexpectedly high gene silencing activities, and uses thereof are disclosed. The blunt-ended constructs have a double-stranded region of 19-49 nucleotides. The constructs have selective minimal modifications to confer an optimal balance of biological activity, toxicity, stability, and target gene specificity. For example, the strands may be modified (e.g., one or both ends of the sense strand is modified by 2′-O-methyl groups), such that the construct is not cleaved by Dicer or other RNAse III, the antisense strand may also be modified by a 2′-O-methyl group at the penultimate 5′-end nucleotide to greatly reduce off-target silencing. |
| 主权项 |
1. A blunt-ended double-stranded RNA (dsRNA) for inhibiting expression of a MAP4K4 gene, comprising:
(1) a sense strand of 25, 26, 27, 28, 29 or 30 nucleotides in length, having a 5′-end and a 3′-end, wherein the sense strand is highly modified with 2′-modified ribose sugars, comprising a continuous stretch of 2′-modified ribose sugars on the 5′-end, a continuous stretch of 2′-modified ribose sugars on the 3′-end and a central region that is unmodified, and, (2) an antisense strand of 25, 26, 27, 28, 29 or 30 nucleotides in length, having a 5′-end and a 3′-end, which hybridizes to the sense strand, wherein the sense strand comprises a sequence selected from the group consisting of: SEQ ID NO: 1, 3, 5, 7, 11, 12, 13, 15, 17, 19, 21, 25, 27, 31, 33, 35, 37, 45 and 50, and wherein the dsRNA does not form a hairpin. |
