Compositions and uses for treatment thereof
First Claim
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1. An isolated nuclease-resistant oligonucleotide comprising a nucleic acid sequence that hybridizes to a complementary target nucleic acid sequence of a gene or gene product to modulate the expression of a component of a mismatch repair (MMR) complex, wherein the component of the MMR complex comprises exon 7 of MLH3 of MutLgamma, further wherein the isolated nuclease resistant oligonucleotide does not impact the total cellular ratios of MLH1 and its binding partners.
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Abstract
The invention is directed generally to oligonucleotide compositions for the treatment of DNA repeat expansion diseases. The invention also relates to oligonucleotides directed to subunits of the DNA mismatch repair system.
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15 Claims
- 1. An isolated nuclease-resistant oligonucleotide comprising a nucleic acid sequence that hybridizes to a complementary target nucleic acid sequence of a gene or gene product to modulate the expression of a component of a mismatch repair (MMR) complex, wherein the component of the MMR complex comprises exon 7 of MLH3 of MutLgamma, further wherein the isolated nuclease resistant oligonucleotide does not impact the total cellular ratios of MLH1 and its binding partners.
- 7. A pharmaceutical composition comprising a nuclease-resistant oligonucleotide 15 to 30 nucleotide bases in length targeted to a complementary nucleic acid sequence of exon 7 a gene encoding a MLH3 subunit of MutLgamma, wherein the oligonucleotide hybridizes with and modulates the expression of the human MutL subunit by at least 20%, wherein the oligonucleotide comprises at least one modification, and further wherein the nuclease resistant oligonucleotide does not impact the total cellular ratios of MLH1 and its binding partners.
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9. An oligonucleotide complex for modulating the expression or activity of a gene or gene product encoding a component of a mismatch repair (MMR) system, the complex comprising a first oligonucleotide and a second oligonucleotide, wherein the first oligonucleotide comprises a sequence complementary to an acceptor region of exon 7 of a gene encoding a MLH3 subunit, and wherein the first oligonucleotide comprises a nuclease-resistant modification, and wherein the second oligonucleotide comprises a sequence complementary to a donor region of exon 7 of a gene encoding a MLH3 subunit, and wherein the second oligonucleotide comprises a nuclease-resistant modification.
- 10. An oligonucleotide complex for modulating the expression or activity of a gene or gene product encoding a component of a mismatch repair (MMR) system, the complex comprising a first oligonucleotide and a second oligonucleotide, wherein the first oligonucleotide comprises a sequence complementary to an acceptor region of exon 7 of a gene encoding a MLH3 subunit, and wherein the first oligonucleotide comprises a nuclease-resistant modification, and wherein the second oligonucleotide comprises a sequence complementary to a donor region of exon 7 of a gene encoding a MLH3 subunit.
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11. An oligonucleotide complex for modulating the expression or activity of a gene or gene product encoding a component of a mismatch repair (MMR) system, the complex comprising a first oligonucleotide and a second oligonucleotide, wherein the first oligonucleotide comprises a sequence complementary to an acceptor region of exon 7 of a gene encoding a MLH3 subunit, and wherein the second oligonucleotide comprises a sequence complementary to a donor region of exon 7 of a gene encoding a MLH3 subunit, and wherein the second oligonucleotide comprises a nuclease-resistant modification.
Specification