Oligonucleotides for mapt modulation
AssigneeUniversity of Massachusetts
InventorsAnastasia Khvorova, Chantal Ferguson, Sarah Davis, Kathryn Monopoli
Life of this patent
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Abstract
This disclosure relates to novel MAPT targeting sequences. Novel MAPT targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.
Claims45
A double stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand, each comprising a 5′ end and a 3′ end,
- wherein the antisense strand comprises a sequence substantially complementary to a tau protein (MAPT) nucleic acid sequence of any one of SEQ ID NOs:
- 1-13, 292, and 295, wherein the substantially complementary sequence comprises sufficient complementarity to the MAPT nucleic acid sequence to direct target-specific silencing of an MAPT mRNA.
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A vector comprising a regulatory sequence operably linked to a nucleotide sequence that encodes a double stranded RNA (dsRNA) molecule substantially complementary to a tau protein (MAPT) nucleic acid sequence of any one of SEQ ID NOs:
- 1-13, 292, and 295, wherein the substantially complementary sequence comprises sufficient complementarity to the MAPT nucleic acid sequence to direct target-specific silencing of an MAPT mRNA.
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A branched RNA compound comprising:
- two or more RNA molecules each separately comprising 15 to 35 nucleotides in length, and
- a sequence substantially complementary to a tau protein (MAPT) mRNA, wherein the substantially complementary sequence comprises sufficient complementarity to the MAPT nucleic acid sequence to direct target-specific silencing of an MAPT mRNA,
- wherein two RNA molecules are connected to one another by one or more moieties independently selected from a linker, a spacer, and a branching point.
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A compound of formula (I):
- wherein:
- L comprises an ethylene glycol chain, an alkyl chain, a peptide, an RNA, a DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or combinations thereof,
- N is a double stranded nucleic acid comprising 15 to 35 bases in length comprising a sense strand and an antisense strand;
- wherein:
- the antisense strand comprises a sequence substantially complementary to a tau protein (MAPT) nucleic acid sequence of any one of SEQ ID NOs:
- 1-13, 292, and 295, wherein the substantially complementary sequence comprises sufficient complementarity to the MAPT nucleic acid sequence to direct target-specific silencing of an MAPT mRNA;
- and
- the sense strand and antisense strand each independently comprise one or more chemical modifications;
- and
- n is 2, 3, 4, 5, 6, 7, or 8.
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A delivery system for therapeutic nucleic acids having the structure of Formula (VI):
- wherein:
- L comprises an ethylene glycol chain, an alkyl chain, a peptide, an RNA, a DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or combinations thereof;
- each cNA, independently, is a carrier nucleic acid comprising one or more chemical modifications;
- each cNA, independently, comprises at least 15 contiguous nucleotides of a tau protein (MAPT) nucleic acid sequence of any one of SEQ ID NOs:
- 1-13, 292, and 295;
- and
- n is 2, 3, 4, 5, 6, 7, or 8.
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Dependencies are inferred from the claim text.