Treatment of neurological diseases using modulators of unc13a gene transcripts
AssigneeQuralis Corporation
InventorsSANDRA HINCKLEY, DUNCAN BROWN, DANIEL ELBAUM, MARISA ELIZABETH KAMELGARN
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Abstract
Disclosed herein are UNC13A oligonucleotides with one or more spacers or without a spacer. In various embodiments, UNC13A oligonucleotides with spacer(s) reduce mis-spliced UNC13A transcripts and increase full length UNC13A transcripts, thereby imparting therapeutic efficacy against neurological diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or Alzheimer's disease (AD).
Claims212
A compound comprising a modified oligonucleotide comprising a sequence that is at least 85% complementary to an equal length portion of any one of SEQ ID NO:
- 5057-5065 or SEQ ID NOs:
- 5206-5208, a sequence having 90% identity thereof, or to a 15 to 50 contiguous nucleobase portion thereof, wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is a non-natural linkage.
A compound comprising a modified oligonucleotide comprising a sequence that is at least 85% complementary to an equal length portion of any one of SEQ ID NO:
- 5057-5065 or SEQ ID NOs:
- 5206-5208, a sequence having 90% identity thereof, or to a 15 to 50 contiguous nucleobase portion thereof, wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is a non-natural linkage, and further wherein the oligonucleotide comprises a spacer.
An oligonucleotide comprising a sequence that is at least 85% complementary to an equal length portion of any one of SEQ ID NO:
- 5057-5065 or SEQ ID NOs:
- 5206-5208, a sequence having 90% identity thereof, or to a 15 to 50 contiguous nucleobase portion thereof, wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is a non-natural linkage.
An oligonucleotide comprising a sequence that is at least 85 98% complementary to an equal length portion of any one of SEQ ID NO:
- 5057-5065 or SEQ ID NOs:
- 5206-5208, a sequence having 90% identity thereof, or to a 15 to 50 contiguous nucleobase portion thereof, wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is a non-natural linkage, and further wherein the oligonucleotide comprises a spacer.
The compound of any one of claims 1-3 or 7-8 or oligonucleotide of any one of claims 44-8, wherein the oligonucleotide comprises a segment with at most 7 linked nucleosides.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide further comprises a locked nucleic acid (LNA).
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide comprising the spacer has a GC content of at least 10%.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide comprising the spacer has a GC content of at least 20%.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide comprising the spacer has a GC content of at least 25%.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide comprising the spacer has a GC content of at least 30%.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide comprising the spacer has a GC content of at least 40%.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide comprising the spacer has a GC content of at least 50%.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide is between 12 and 40 oligonucleotide units in length.
The compound or oligonucleotide of any one of the above claims, wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is independently selected from the group consisting of a phosphodiester linkage, a phosphorothioate linkage, an alkyl phosphate linkage, a phosphorodithioate linkage, a phosphotriester linkage, an alkylphosphonate linkage, a 3-methoxypropyl phosphonate linkage, a methylphosphonate linkage, an aminoalkylphosphotriester linkage, an alkylene phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, a phosphoramidothioate linkage, a thiophosphorodiamidate linkage, a phosphorodiamidate linkage, an aminoalkylphosphoramidate linkage, a thiophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a thiophosphate linkage, a selenophosphate linkage, and a boranophosphate linkage.
A compound comprising an oligonucleotide comprising a nucleobase sequence that shares at least 90% identity to an equal length portion of any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, SEQ ID NOs:
- 5168-5202, SEQ ID NOs:
- 5209-5221, or SEQ ID NOs:
- 5235-5292.
An oligonucleotide comprising a nucleobase sequence that shares at least 90% identity to an equal length portion of any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, or SEQ ID NOs:
- 5168-5202.
The compound or oligonucleotide of any one of the above claims, wherein one or more internucleoside linkage of the oligonucleotide is a modified internucleoside linkage.
The compound or oligonucleotide of any one of the preceding claims, wherein the oligonucleotide comprises at least one modified sugar moiety.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 30%, 40%, 50%, 60%, 70%, 80%, or 90% increase of full length UNC13A protein.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 100% increase of full length UNC13A protein.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 200% increase of full length UNC13A protein.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 300% increase of full length UNC13A protein.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 400% increase of full length UNC13A protein.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% rescue of full length UNC13A protein.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 50%, 60%, 70%, 80%, or 90% reduction of a mis-spliced UNC13A transcript.
A method for treating a neurological disease in a subject in need thereof, the method comprising administering to the subject an oligonucleotide comprising a segment with at most 7 linked nucleosides, and wherein oligonucleotide shares at least 85% identity with any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, SEQ ID NOs:
- 5168-5202, SEQ ID NOs:
- 5209-5221, or SEQ ID NOs:
- 5235-5292, or a pharmaceutically acceptable salt thereof;
- wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is independently selected from the group consisting of:
- a phosphodiester linkage, a phosphorothioate linkage, an alkyl phosphate linkage, a phosphorodithioate linkage, a phosphotriester linkage, an alkylphosphonate linkage, a 3-methoxypropyl phosphonate linkage, a methylphosphonate linkage, an aminoalkylphosphotriester linkage, an alkylene phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, a phosphoramidothioate linkage, a thiophosphorodiamidate linkage, a phosphorodiamidate linkage, an aminoalkylphosphoramidate linkage, a thiophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a thiophosphate linkage, a selenophosphate linkage, and a boranophosphate linkage, and/or
- wherein at least one (i.e., one or more) nucleoside is substituted with a component selected from the group consisting of a 2′-O-(2-methoxyethyl) nucleoside, a 2′-O-methyl nucleoside, a 2′-O—(N-methylacetamide) nucleoside, a 2′-deoxy-2′-fluoro nucleoside, a 2′-fluoro-β-D-arabinonucleoside, a locked nucleic acid (LNA), a tricyclic nucleic acid, constrained methoxyethyl (cMOE), constrained ethyl (cET), and a peptide nucleic acid (PNA)
- optionally, wherein the oligonucleotide further comprises a spacer.
A method for treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, the method comprising administering to the subject an oligonucleotide comprising a segment with at most 7 linked nucleosides, and wherein oligonucleotide shares at least 85% identity with any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, SEQ ID NOs:
- 5168-5202, SEQ ID NOs:
- 5209-5221, or SEQ ID NOs:
- 5235-5292, or a pharmaceutically acceptable salt thereof;
- wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is independently selected from the group consisting of:
- a phosphodiester linkage, a phosphorothioate linkage, an alkyl phosphate linkage, a phosphorodithioate linkage, a phosphotriester linkage, an alkylphosphonate linkage, a 3-methoxypropyl phosphonate linkage, a methylphosphonate linkage, an aminoalkylphosphotriester linkage, an alkylene phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, a phosphoramidothioate linkage, a thiophosphorodiamidate linkage, a phosphorodiamidate linkage, an aminoalkylphosphoramidate linkage, a thiophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a thiophosphate linkage, a selenophosphate linkage, and a boranophosphate linkage, and/or
- wherein at least one (i.e., one or more) nucleoside is substituted with a component selected from the group consisting of a 2′-O-(2-methoxyethyl) nucleoside, a 2′-O-methyl nucleoside, a 2′-O—(N-methylacetamide) nucleoside, a 2′-deoxy-2′-fluoro nucleoside, a 2′-fluoro-β-D-arabinonucleoside, a locked nucleic acid (LNA), a tricyclic nucleic acid, constrained methoxyethyl (cMOE), constrained ethyl (cET), and a peptide nucleic acid (PNA)
- optionally, wherein the oligonucleotide further comprises a spacer.
A method for treating Alzheimer's Disease (AD) with frontotemporal dementia (FTD) in a subject in need thereof, the method comprising administering to the subject an oligonucleotide comprising a segment with at most 7 linked nucleosides, and wherein oligonucleotide shares at least 85% identity with any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, SEQ ID NOs:
- 5168-5202, SEQ ID NOs:
- 5209-5221, or SEQ ID NOs:
- 5235-5292, or a pharmaceutically acceptable salt thereof,
- wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is independently selected from the group consisting of:
- a phosphodiester linkage, a phosphorothioate linkage, an alkyl phosphate linkage, a phosphorodithioate linkage, a phosphotriester linkage, an alkylphosphonate linkage, a 3-methoxypropyl phosphonate linkage, a methylphosphonate linkage, an aminoalkylphosphotriester linkage, an alkylene phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, a phosphoramidothioate linkage, a thiophosphorodiamidate linkage, a phosphorodiamidate linkage, an aminoalkylphosphoramidate linkage, a thiophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a thiophosphate linkage, a selenophosphate linkage, and a boranophosphate linkage, and/or
- wherein at least one (i.e., one or more) nucleoside is substituted with a component selected from the group consisting of a 2′-O-(2-methoxyethyl) nucleoside, a 2′-O-methyl nucleoside, a 2′-O—(N-methylacetamide) nucleoside, a 2′-deoxy-2′-fluoro nucleoside, a 2′-fluoro-β-D-arabinonucleoside, a locked nucleic acid (LNA), a tricyclic nucleic acid, constrained methoxyethyl (cMOE), constrained ethyl (cET), and a peptide nucleic acid (PNA), optionally, wherein the oligonucleotide further comprises a spacer
A method for treating frontotemporal dementia (FTD) in a subject in need thereof, the method comprising administering to the subject an oligonucleotide comprising a segment with at most 7 linked nucleosides, and wherein oligonucleotide shares at least 85% identity with any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, SEQ ID NOs:
- 5168-5202, SEQ ID NOs:
- 5209-5221, or SEQ ID NOs:
- 5235-5292, or a pharmaceutically acceptable salt thereof;
- wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is independently selected from the group consisting of:
- a phosphodiester linkage, a phosphorothioate linkage, an alkyl phosphate linkage, a phosphorodithioate linkage, a phosphotriester linkage, an alkylphosphonate linkage, a 3-methoxypropyl phosphonate linkage, a methylphosphonate linkage, an aminoalkylphosphotriester linkage, an alkylene phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, a phosphoramidothioate linkage, a thiophosphorodiamidate linkage, a phosphorodiamidate linkage, an aminoalkylphosphoramidate linkage, a thiophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a thiophosphate linkage, a selenophosphate linkage, and a boranophosphate linkage, and/or
- wherein at least one (i.e., one or more) nucleoside is substituted with a component selected from the group consisting of a 2′-O-(2-methoxyethyl) nucleoside, a 2′-O-methyl nucleoside, a 2′-O—(N-methylacetamide) nucleoside, a 2′-deoxy-2′-fluoro nucleoside, a 2′-fluoro-β-D-arabinonucleoside, a locked nucleic acid (LNA), a tricyclic nucleic acid, constrained methoxyethyl (cMOE), constrained ethyl (cET), and a peptide nucleic acid (PNA)
- optionally, wherein the oligonucleotide further comprises a spacer.
A method for treating amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) in a subject in need thereof, the method comprising administering to the subject an oligonucleotide comprising a segment with at most 7 linked nucleosides, and wherein oligonucleotide shares at least 85% identity with any one of SEQ ID NOs:
- 1-1264, SEQ ID NOs:
- 2529-3792, SEQ ID NOs;
- 5066-5166, SEQ ID NOs:
- 5168-5202, SEQ ID NOs:
- 5209-5221, or SEQ ID NOs:
- 5235-5292, or a pharmaceutically acceptable salt thereof;
- wherein at least one (i.e., one or more) nucleoside linkage of the oligonucleotide is independently selected from the group consisting of:
- a phosphodiester linkage, a phosphorothioate linkage, an alkyl phosphate linkage, a phosphorodithioate linkage, a phosphotriester linkage, an alkylphosphonate linkage, a 3-methoxypropyl phosphonate linkage, a methylphosphonate linkage, an aminoalkylphosphotriester linkage, an alkylene phosphonate linkage, a phosphinate linkage, a phosphoramidate linkage, a phosphoramidothioate linkage, a thiophosphorodiamidate linkage, a phosphorodiamidate linkage, an aminoalkylphosphoramidate linkage, a thiophosphoramidate linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a thiophosphate linkage, a selenophosphate linkage, and a boranophosphate linkage, and/or
- wherein at least one (i.e., one or more) nucleoside is substituted with a component selected from the group consisting of a 2′-O-(2-methoxyethyl) nucleoside, a 2′-O-methyl nucleoside, a 2′-O—(N-methylacetamide) nucleoside, a 2′-deoxy-2′-fluoro nucleoside, a 2′-fluoro-β-D-arabinonucleoside, a locked nucleic acid (LNA), a tricyclic nucleic acid, constrained methoxyethyl (cMOE), constrained ethyl (cET), and a peptide nucleic acid (PNA)
- optionally, wherein the oligonucleotide further comprises a spacer.
An oligonucleotide and a pharmaceutically acceptable excipient, the oligonucleotide comprising a sequence that is at least 85% complementary to an equal length portion of any one of SEQ ID NOs:
- 5057-5065 or SEQ ID NOs:
- 5206-5208, a sequence having 90% identity thereof, or to a 15 to 50 contiguous nucleobase portion thereof, optionally wherein the oligonucleotide comprises a spacer and wherein the oligonucleotide is capable of increasing, restoring, or stabilizing expression of the UNC13A mRNA capable of translation of a functional UNC13A and/or activity and/or function of UNC13A protein in a cell or a human patient of an immune-mediated demyelinating disease, and wherein the level of increase, restoration, or stabilization of expression and/or activity and/or function is sufficient for use of the oligonucleotide as a medicament for the treatment of the immune-mediated demyelinating disease.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of an UNC13A transcript with a cryptic exon.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 100% reduction of an UNC13A transcript with a cryptic exon.
The compound or oligonucleotide of any one of the above claims, wherein the oligonucleotide exhibits at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction of an UNC13A transcript with a cryptic exon.
Dependencies are inferred from the claim text.