RNA interference for the treatment of gain-of-function disorders
First Claim
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1. A method of treating a subject having or at risk for Huntington'"'"'s disease characterized or caused by a mutant huntingtin (htt) protein, comprising:
- administering to the subject an effective amount of an siRNA or shRNA targeting a heterozygous single nucleotide polymorphism (SNP) within a gene encoding the mutant htt protein, wherein the SNP has an allelic frequency of at least 30% in a sample population and is present at a genomic site selected from the group consisting of RS362331, RS4690077, RS362268, RS362267, RS362307, and RS362306, such that sequence-specific interference of said gene occurs;
thereby treating said disease in said subject.
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Abstract
The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington'"'"'s disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease.
124 Citations
17 Claims
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1. A method of treating a subject having or at risk for Huntington'"'"'s disease characterized or caused by a mutant huntingtin (htt) protein, comprising:
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administering to the subject an effective amount of an siRNA or shRNA targeting a heterozygous single nucleotide polymorphism (SNP) within a gene encoding the mutant htt protein, wherein the SNP has an allelic frequency of at least 30% in a sample population and is present at a genomic site selected from the group consisting of RS362331, RS4690077, RS362268, RS362267, RS362307, and RS362306, such that sequence-specific interference of said gene occurs; thereby treating said disease in said subject. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11)
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2. A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with an effective amount of an siRNA or shRNA targeting a heterozygous single nucleotide polymorphism (SNP) within the target mRNA, such that RNA silencing of said mRNA occurs, wherein the SNP has an allelic frequency of at least 30% in a sample population and is present at a genomic site selected from the group consisting of RS362331, RS4690077, RS362268, RS362267, RS362307, and RS362306.
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12. A method of treating a subject having or at risk for Huntington'"'"'s disease characterized or caused by a mutant huntingtin (htt) protein, comprising administering to the subject an effective amount of a siRNA targeting a heterozygous single nucleotide polymorphism (SNP) within a gene encoding the mutant htt protein, such that RNA silencing of said gene occurs, wherein the siRNA comprises (i) an antisense strand or a variant thereof having sufficient complementarity to the SNP at genomic site RS362307 to direct target-specific RNA interference of the gene encoding the mutant htt protein;
- and (ii) a sense strand or a variant thereof that is substantially complementary to the antisense strand, such that the sense and antisense strands are capable of annealing together, said variant comprising at least one nucleotide analog or backbone modification.
- View Dependent Claims (13, 14)
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15. A method of treating a subject having or at risk for Huntington'"'"'s disease characterized or caused by a mutant huntingtin (htt) protein, comprising administering to the subject an effective amount of a siRNA targeting a heterozygous single nucleotide polymorphism (SNP) within a gene encoding the mutant htt protein, such that RNA silencing of said gene occurs, wherein the siRNA comprises (i) an antisense strand or a variant thereof having sufficient complementarity to the SNP at genomic site RS362331 or RS363125 to direct target-specific RNA interference of the gene encoding the mutant htt protein;
- and (ii) a sense strand or a variant thereof that is substantially complementary to the antisense strand, such that the sense and antisense strands are capable of annealing together, said variant comprising at least one nucleotide analog or backbone modification.
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16. A method of treating a subject having or at risk for a disease characterized or caused by a mutant huntingtin (htt) protein, comprising:
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administering to the subject an effective amount of an siRNA or shRNA targeting a heterozygous single nucleotide polymorphism located at genomic site RS362307 within the gene encoding the mutant htt protein, such that sequence-specific interference of said gene occurs; thereby treating said disease in said subject.
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17. A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with an effective amount of an siRNA or shRNA targeting a heterozygous single nucleotide polymorphism located at genomic site RS362307 within the target mRNA, such that RNA silencing of said mRNA occurs.
Specification