Inhibition of PCSK9 through RNAI
First Claim
1. An RNAi construct for inhibiting expression of a PCSK9 gene, comprising a double-stranded RNA (dsRNA) of 25-27 base pairs in length, the dsRNA comprising:
- (1) a sense strand having a 5′
-end and a 3′
-end, wherein the sense strand comprises SEQ ID NO;
65, and wherein the sense strand comprises 12-14 and 10-12 consecutive 2′
-modified ribose sugars at the 5′
-end and the 3′
-end nucleotides, respectively, and (2) an antisense strand having a 5′
-end and a 3′
-end, which hybridizes to the sense strand.
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Abstract
The invention relates to various PCSK9 RNAi constructs with gene silencing activities, and uses thereof. The construct has a double-stranded region of 19-49 nucleotides, preferably 25, 26, or 27 nucleotides, and preferably blunt-ended. The construct has selective minimal modifications to confer an optimal balance of biological activity, toxicity, stability, and target gene specificity. The sense strand may be modified such that the construct is not cleaved by Dicer or other RNAse III, and the entire length of the antisense strand is loaded into RISC In addition, the antisense strand may also be modified by 2′-O-methyl groups at the 2nd 5′-end nucleotide to greatly reduce off-target silencing. The constructs of the invention largely avoid the interferon response and sequence-independent apoptosis in mammalian cells, exhibits better serum stability, and enhanced target specificity.
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Citations
11 Claims
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1. An RNAi construct for inhibiting expression of a PCSK9 gene, comprising a double-stranded RNA (dsRNA) of 25-27 base pairs in length, the dsRNA comprising:
- (1) a sense strand having a 5′
-end and a 3′
-end, wherein the sense strand comprises SEQ ID NO;
65, and wherein the sense strand comprises 12-14 and 10-12 consecutive 2′
-modified ribose sugars at the 5′
-end and the 3′
-end nucleotides, respectively, and (2) an antisense strand having a 5′
-end and a 3′
-end, which hybridizes to the sense strand. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
- (1) a sense strand having a 5′
Specification