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AssigneeGenzyme Corporation
InventorsLisa M. STANEK, Adam PALERMO, Brenda RICHARDS, Sergio Pablo SARDI, Catherine O'RIORDAN, Antonius SONG
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Provided herein are RNAi molecules including a first strand containing a guide sequence and a second strand comprising a non-guide sequence where the non-guide sequence contains a bulge opposite the seed region of the guide sequences; e.g., opposite the cleavage sequence. In some aspects, the invention provides RNAi for treating Huntington's disease. Further provided herein are expression cassettes, vectors (e.g., rAAV, recombinant adenoviral, recombinant lentiviral, and recombinant HSV vectors), cells, viral particles, and pharmaceutical compositions containing the RNAi. Yet further provided herein are methods and kits related to the use of the RNAi, for example, to treat Huntington's disease.
An RNAi comprising a first strand and a second strand, wherein
An RNAi comprising a first strand and a second strand, wherein
An RNAi comprising a first strand and a second strand, wherein
An RNAi comprising a first strand comprising a guide region which comprises the sequence 5′-UAGACAAUGAUUCACACGGU-3′ (SEQ ID NO:1) and a second strand comprising a non-guide region which comprises the sequence 5′-ACCGUGUGUCAUUGUCUAA-3′ (SEQ ID NO:2), wherein the first strand and second strand form a duplex and wherein the A residue at residue 18 or residue 19 of the second strand forms a bulge in the non-guide region.
An RNAi comprising a first strand comprising a guide region which comprises the sequence 5′-UCGACAAUGAUUCACACGGU-3′ (SEQ ID NO:15) and a second strand comprising a non-guide region which comprises the sequence 5′-ACCGUGUGUCAUUGUCGAA-3′ (SEQ ID NO:16), wherein the first strand and second strand form a duplex and wherein the A residue at residue 18 or residue 19 of the second strand forms a bulge in the non-guide region.
An RNAi comprising a first strand comprising a guide region which comprises the sequence 5′-UAGACGAUGAUUCACACGGU-3′ (SEQ ID NO:17) and a second strand comprising a non-guide region which comprises the sequence 5′-ACCGUGUGUCAUCGUCUAA-3′ (SEQ ID NO:18), wherein the first strand and second strand form a duplex and wherein the A residue at residue 18 or residue 19 of the second strand forms a bulge in the non-guide region.
The RNAi of claim wherein the guide region comprises a nucleic acid sequence having about 90% identity to SEQ ID NO:15 and the non-guide region comprises a nucleic acid sequence having about 90% identity to SEQ ID NO:16 or a nucleic acid sequence having about 90% identity to SEQ ID NO:17 and the non-guide region comprises a nucleic acid sequence having about 90% identity to SEQ ID NO:18.
A method for treating Huntington's disease in a mammal comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UAGACAAUGAUUCACACGGU-3′ (SEQ ID NO:1) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUUGUCUAA-3′ (SEQ ID NO:2), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for inhibiting the expression of htt in a mammal with Huntington's disease comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UAGACAAUGAUUCACACGGU-3′ (SEQ ID NO:1) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUUGUCUAA-3′ (SEQ ID NO:2), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for inhibiting the accumulation of htt in a cell of a mammal with Huntington's disease comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UAGACAAUGAUUCACACGGU-3′ (SEQ ID NO:1) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUUGUCUAA-3′ (SEQ ID NO:2), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for treating Huntington's disease in a mammal comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UCGACAAUGAUUCACACGGU-3′ (SEQ ID NO:15) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUUGUCGAA-3′ (SEQ ID NO:16), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for inhibiting the expression of htt in a mammal with Huntington's disease comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UCGACAAUGAUUCACACGGU-3′ (SEQ ID NO:15) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUUGUCGAA-3′ (SEQ ID NO:16), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for inhibiting the accumulation of htt in a cell of a mammal with Huntington's disease comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UCGACAAUGAUUCACACGGU-3′ (SEQ ID NO:15) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUUGUCGAA-3′ (SEQ ID NO:16), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for treating Huntington's disease in a mammal comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UAGACGAUGAUUCACACGGU-3′ (SEQ ID NO:17) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUCGUCUAA-3′ (SEQ ID NO:18), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for inhibiting the expression of htt in a mammal with Huntington's disease comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UAGACGAUGAUUCACACGGU-3′ (SEQ ID NO:17) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUCGUCUAA-3′ (SEQ ID NO:18), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method for inhibiting the accumulation of htt in a cell of a mammal with Huntington's disease comprising administering to the mammal an RNAi comprising a first strand comprising a first nucleic acid comprising the sequence 5′-UAGACGAUGAUUCACACGGU-3′ (SEQ ID NO:17) and a second strand comprising a second nucleic acid comprising the sequence 5′-ACCGUGUGUCAUCGUCUAA-3′ (SEQ ID NO:18), wherein the A residue at residue 18 or residue 19 of the second strand does not form a basepair with a residue in the first strand.
A method of any one of claims 2226-239, wherein the viral particle of any one of claims 226-233 or the rAAV particle of any one of claims 234-239 is in a composition.
Dependencies are inferred from the claim text.