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Compositions and methods for inhibiting expression of the pcsk9 gene

A gene expression and gene technology, applied in the field of pathological process that can be mediated by PCSK9 downregulation, can solve problems such as the reduction of total cholesterol level and LDLc cholesterol level

Inactive Publication Date: 2013-11-06
ALNYLAM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In both cases, PCSK9 loss-of-function resulted in reduced total and LDLc cholesterol levels

Method used

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  • Compositions and methods for inhibiting expression of the pcsk9 gene
  • Compositions and methods for inhibiting expression of the pcsk9 gene
  • Compositions and methods for inhibiting expression of the pcsk9 gene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0109] Gene walking of the PCSK9 gene

[0110] Perform siRNA design for identification in two separate screening groups:

[0111] a) siRNA targeting human and mouse or rat PCSK9 mRNA, and

[0112] b) Predict all reactive human siRNAs specific to the target gene PCSK9.

[0113] The mRNA sequences of human, mouse and rat PCSK9 were used. The human sequence NM_174936.2 was used as the reference sequence in all siRNA selection processes.

[0114] The 19-mer extension is conserved in humans and mice. In the first step, human and rat PCSK9 mRNA sequences were identified, and human-mouse cross-reactive siRNA and human-rat target cross-reactive siRNA were generated. Filter group.

[0115] In the second screening, siRNAs specifically targeting human PCSK9 were identified. Extract all possible 19-mer sequences of human PCSK9 and define them as candidate target sequences. Table 1 and Table 2 list all the sequences that cross-react with humans and monkeys, as well as the sequences that cross-re...

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Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a human PCSK9 gene in a cell, wherein said dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding PCSK9, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said PCSK9, inhibits expression of said PCSK9 gene, wherein (a) said first sequence is the sequence of SEQ ID NO: 1229 and said second sequence is the sequence of SEQ ID NO: 1230; (b) said first sequence is the sequence of SEQ ID NO: 1227 and said second sequence is the sequence of SEQ ID NO: 1228; or (c) said part of said mRNA encoding PCSK9 is the sequence from position 3530 to 3548 of the mRNA sequence of database entry NM_174936.

Description

[0001] Cross references to related applications [0002] This application requires U.S. Provisional Application No. 60 / 799,458 filed on May 11, 2006, U.S. Provisional Application No. 60 / 817,203 filed on June 27, 2006, and U.S. Provisional Application No. 60 / 817,203 filed on August 25, 2006. Application No. 60 / 840,089, U.S. Provisional Application No. 60 / 829,914 filed on October 18, 2006 and U.S. Provisional Application No. 60 / 901,134 filed on February 13, 2007 priority. The contents of all these provisional applications are incorporated herein by reference in their entirety. Technical field [0003] The present invention relates to double-stranded ribonucleic acid (dsRNA) and its use in mediating RNA interference to inhibit PCSK9 gene expression, as well as the use of dsRNA in the treatment of pathological processes mediated by PCSK9 downregulation such as hyperlipidemia. Background technique [0004] Proprotein convertase subtilisin kexin 9 (PCSK9) is a member of the subtilisin se...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12Q1/68A01N43/04C07H21/04A61K31/07C12N15/113
CPCC12N2310/14C12N2310/321C12N2310/3515C12N2310/332C12N2310/322C12N2310/315C12N2310/111C12N15/1137A61K31/713A61P3/06A61P43/00A61P9/00C12N2310/3521A61K48/00C12N15/113
Inventor 帕梅拉·谭比吉特·布拉姆利奇玛丽亚·弗兰克-卡米尼斯基凯文·菲茨杰拉德埃金·阿肯克威克特·E·考特廉斯基
Owner ALNYLAM PHARMA INC