US2016115483A1PendingUtilityA1

Silencing of polo-like kinase expression using interfering rna

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Assignee: PROTIVA BIOTHERAPEUTICS INCPriority: Dec 27, 2007Filed: Mar 4, 2015Published: Apr 28, 2016
Est. expiryDec 27, 2027(~1.4 yrs left)· nominal 20-yr term from priority
Inventors:Ian MaclachlanAdam Judge
A61P 35/00A61P 43/00C12N 15/1137A61K 9/127A61K 9/1272C12Y 207/11021C12N 2310/322C12N 2310/14C12N 2310/3231C12N 2310/3521C12N 2310/321A61K 9/1271A61K 9/0019C12N 2320/30C12N 2310/3525C12N 2310/3533C12N 15/88C12N 2310/335
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Claims

Abstract

The present invention provides compositions comprising interfering RNA (e.g., siRNA, aiRNA, miRNA) that target polo-like kinase 1 (PLK-1) expression and methods of using such compositions to silence PLK-1 expression. More particularly, the present invention provides unmodified and chemically modified interfering RNA molecules which silence PLK-1 expression and methods of use thereof. The present invention also provides serum-stable nucleic acid-lipid particles (e.g., SNALP) comprising an interfering RNA molecule described herein, a cationic lipid, and a non-cationic lipid, which can further comprise a conjugated lipid that inhibits aggregation of particles. The present invention further provides methods of silencing PLK-1 gene expression by administering an interfering RNA molecule described herein to a mammalian subject. The present invention additionally provides methods of identifying and/or modifying PLK-1 interfering RNA having immunostimulatory properties. Methods for sensitizing a cell such as a cancer cell to the effects of a chemotherapy drug comprising sequentially delivering PLK-1 interfering RNA followed by the chemotherapy drug are also provided.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A modified siRNA molecule comprising a double-stranded region of about 15 to about 60 nucleotides in length,
 wherein one or more of the nucleotides in the double-stranded region comprise modified nucleotides, and   wherein the modified siRNA molecule is capable of silencing polo-like kinase 1 (PLK-1) expression.   
     
     
         2 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises modified nucleotides selected from the group consisting of 2′-O-methyl (2′OMe) nucleotides, 2′-deoxy-2′-fluoro (2′F) nucleotides, 2′-deoxy nucleotides, 2′-O-(2-methoxyethyl) (MOE) nucleotides, locked nucleic acid (LNA) nucleotides, and mixtures thereof. 
     
     
         3 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises 2′OMe nucleotides. 
     
     
         4 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises a sense strand having one or more modified nucleotides in the double-stranded region. 
     
     
         5 . The modified siRNA molecule of  claim 4 , wherein the modified siRNA molecule further comprises an antisense strand having one or more modified nucleotides in the double-stranded region. 
     
     
         6 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises an antisense strand having one or more modified nucleotides in the double-stranded region. 
     
     
         7 . The modified siRNA molecule of  claim 6 , wherein the modified siRNA molecule further comprises a sense strand having one or more modified nucleotides in the double-stranded region. 
     
     
         8 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises a 3′ overhang in one or both strands of the modified siRNA molecule. 
     
     
         9 . The modified siRNA molecule of  claim 8 , wherein one or more of the nucleotides in the 3′ overhang comprise modified nucleotides. 
     
     
         10 . The modified siRNA molecule of  claim 1 , wherein less than about 25% of the nucleotides in the double-stranded region comprise modified nucleotides. 
     
     
         11 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule is less immunostimulatory than a corresponding unmodified siRNA sequence. 
     
     
         12 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises an antisense strand comprising the nucleic acid sequence of SEQ ID NO:2. 
     
     
         13 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises a sense strand comprising the nucleic acid sequence of SEQ ID NO:1. 
     
     
         14 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises an antisense strand comprising the nucleic acid sequence of SEQ ID NO:4. 
     
     
         15 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises a sense strand comprising the nucleic acid sequence of SEQ ID NO:3. 
     
     
         16 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises an antisense strand consisting of the nucleic acid sequence of SEQ ID NO:403. 
     
     
         17 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule comprises a sense strand consisting of the nucleic acid sequence of SEQ ID NO:400. 
     
     
         18 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule is selected from the group consisting of PLK1424 2/6, PLK1424 U4/GU, PLK1424 U4/G, PLK773 G/GU, PLK1425 3/5, and a mixture thereof. 
     
     
         19 . The modified siRNA molecule of  claim 1 , wherein the modified siRNA molecule is PLK1424 2/6. 
     
     
         20 . The modified siRNA molecule of  claim 1 , further comprising a carrier system. 
     
     
         21 - 113 . (canceled)

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