Inhibition of MAP4K4 through RNAi
AssigneePhio Pharmaceuticals Corp.
InventorsTod M. Woolf, Joanne Kamens, Anastasia Khvorova, William Salomon
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Abstract
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.
Claims9
A blunt-ended double-stranded RNA (dsRNA) for inhibiting expression of a MAP4K4 gene, comprising:
- (1) a sense strand of at least 25 nucleotides in length, having a 5′-end and a 3′-end, wherein the sense strand is modified with 2′OMe-modified ribose sugars, comprising a continuous stretch of 2′OMe-modified ribose sugars on the 5′-end, a continuous stretch of 2′OMe-modified ribose sugars on the 3′-end, and a central region that is unmodified, and,
- an antisense strand of at least 25 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 NOs:
- 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 50, 53, 54, and 56,
- wherein the antisense strand comprises a sequence selected from the group consisting of:
- SEQ ID NO:
- 2, 4, 6, 8, 10, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, and 52,
- wherein the dsRNA does not form a hairpin, and
- wherein the dsRNA is capable of inhibiting expression of a MAP4K4 gene.
Dependencies are inferred from the claim text.