RNA SILENCING COMPOSITIONS AND METHODS FOR THE TREATMENT OF HUNTINGTON'S DISEASE
First Claim
1. A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with effective amount of a RNA silencing agent 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 35% in a sample population.
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Abstract
The present invention relates to the discovery of an effective treatment for a variety of Huntington'"'"'s disease (HD). The present invention utilizes RNA silencing technology (e.g. RNAi) against single nucleotide polymorphisms (SNPs) in the Huntingtin (htt) gene encoding the dominant, gain-of-function mutant Huntington protein, thereby resulting in an effective treatment for the gain-of-function disease.
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Citations
23 Claims
- 1. A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with effective amount of a RNA silencing agent 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 35% in a sample population.
- 3. The method of claim 3, wherein the target mRNA comprises the sequence set forth as SEQ ID NO:
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8. A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with effective amount of a siRNA targeting a heterozygous single nucleotide polymorphism (SNP) within the target mRNA, such that RNA silencing of said mRNA occurs, wherein the siRNA is selected from the group consisting of:
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a. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
3 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
4 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification;b. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
7 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
8 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification,c. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
9 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
10 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification, andd. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
13 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
14 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification.
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- 11. An RNA silencing agent comprising an antisense strand comprising about 16-25 nucleotides homologous to a region of an mRNA encoding a mutant huntingtin (htt) protein, said region comprising a heterozygous single nucleotide polymorphism (SNP) having an allelic frequency of at least 35% in a sample population, wherein the RNA silencing agent is capable of directing RNA silencing of said mRNA.
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21. An siRNA is selected from the group consisting of:
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a. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
3 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
4 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification;b. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
7 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
8 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification,c. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
9 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
10 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification, andd. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO;
13 or a variant thereof; and
(ii) an antisense strand comprising the sequence set forth as SEQ ID NO;
14 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification. - View Dependent Claims (22, 23)
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Specification