Inhibitor nucleic acids
First Claim
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1. A double-stranded nucleic acid for inhibiting expression of a target gene by an RNA interference mechanism, comprising:
- a) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides; and
b) an RNA antisense polynucleotide strand having a designated sequence that hybridizes to at least a portion of a transcript of the target gene and is sufficient to inhibit expression of the target gene.
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Abstract
The present invention provides methods and compositions for attenuating expression of a target gene in vivo. In general, the method includes administering RNAi constructs (such as small-interfering RNAs (i.e., siRNAs) that are targeted to particular mRNA sequences, or nucleic acid material that can produce siRNAs in a cell), in an amount sufficient to attenuate expression of a target gene by an RNA interference mechanism. In particular, the RNAi constructs include one or more modifications to improve serum stability and cellular uptake and to avoid non-specific effect.
19 Citations
43 Claims
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1. A double-stranded nucleic acid for inhibiting expression of a target gene by an RNA interference mechanism, comprising:
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a) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides; and
b) an RNA antisense polynucleotide strand having a designated sequence that hybridizes to at least a portion of a transcript of the target gene and is sufficient to inhibit expression of the target gene. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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15. A pharmaceutical preparation for delivery of an RNAi nucleic acid to an organism, the composition comprising a pharmaceutically acceptable carrier and a double-stranded nucleic acid, comprising:
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a) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides; and
b) an RNA antisense polynucleotide strand having a designated sequence that hybridizes to at least a portion of a transcript of a target gene and is sufficient to inhibit expression of the target gene. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23)
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24. A method for decreasing the expression of a target gene in a cell, the method comprising contacting the cell with a composition comprising a double-stranded nucleic acid, the double-stranded nucleic acid comprising:
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a) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides; and
b) an RNA antisense polynucleotide strand having a designated sequence that hybridizes to at least a portion of a transcript of the target gene and is sufficient to inhibit expression of the target gene. - View Dependent Claims (26, 27, 28, 29, 30, 31)
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25. A method for decreasing the expression of a target gene in one or more cells of a subject, the method comprising administering to the subject a composition comprising a double-stranded nucleic acid, the double-stranded nucleic acid comprising:
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a) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides; and
b) an RNA antisense polynucleotide strand having a designated sequence that hybridizes to at least a portion of a transcript of the target gene and is sufficient to inhibit expression of the target gene.
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32. A coating for use on a surface of a medical device, comprising a polymer matrix having RNAi constructs dispersed therein, which RNAi constructs are eluted from the matrix when implanted at site in a patient'"'"'s body and alter the growth, survival or differentiation of cells in the vicinity of the implanted device, wherein at least one of the the RNAi constructs is a double-stranded nucleic acid comprising:
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a) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides; and
b) an RNA antisense polynucleotide strand having a designated sequence that hybridizes to at least a portion of a transcript of the target gene and is sufficient to inhibit expression of the target gene. - View Dependent Claims (33, 34, 35)
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36. A method of optimizing an RNAi construct for pharmaceutical uses comprising:
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a) identifying an RNAi construct having a designated sequence which inhibits the expression of a target gene in vivo;
b) designing one or more modified RNAi constructs having the designated sequence and comprising one or more modified nucleic acids;
c) testing the one or more modified RNAi constructs of (b) for uptake into cells and/or serum half-life;
d) conducting therapeutic profiling of the RNAi constructs of (a) and (b) for efficacy and toxicity in animals;
e) selecting one or more modified RNAi constructs having desirable uptake properties and desirable therapeutic properties; and
f) formulating a pharmaceutical preparation including one or more RNAi constructs selected in step (e). - View Dependent Claims (38)
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37. A method of optimizing an RNAi construct for pharmaceutical uses comprising:
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a) identifying an siRNA construct having a designated sequence which inhibits the expression of a target gene in vivo;
b) making RNAi constructs by replacing the sense RNA polynucleotide strand of the siRNA constructs of a) with a sense DNA polynucleotide strand that hybridizes with the antisense RNA strand of a);
c) testing the RNAi constructs of b) for uptake into cells and/or serum half-life;
d) conducting therapeutic profiling of the RNAi construct of b) for efficacy and toxicity in animals;
e) selecting one or more modified RNAi constructs by repeating steps a)-d) having desirable uptake properties and desirable therapeutic properties; and
f) formulating a pharmaceutical preparation including one or more RNAi constructs selected in step e).
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39. A method of optimizing an RNAi construct comprising:
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a) generating a plurality of test RNAi constructs, each of the construct comprising a double-stranded nucleic acid that comprises;
i) a DNA sense polynucleotide strand comprising one or more modifications or modified nucleotides;
ii) an RNA antisense polynucleotide strand. b) determining gene silencing effect of the test RNAi constructs. - View Dependent Claims (40, 41, 42, 43)
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Specification