Compositions and methods for decreasing tau expression

Abstract

Provided herein are compositions and methods for decreasing tau mRNA and protein expression. These compositions and methods are useful in treating tau-related diseases and disorders.

1 . A method of decreasing tau expression level in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide comprising a nucleobase sequence that has at least 90% sequence identity to any of the nucleobase sequences provided in Tables 2-17, wherein C in any of the nucleobase sequences is either cytosine or 5-methylcytosine, and wherein at least one nucleotide of the oligonucleotide has a 2′-modification. 
     
     
         2 . The method of  claim 1 , wherein the subject is afflicted with or susceptible to a tau-associated disease. 
     
     
         3 . The method of  claim 2 , wherein the tau-associated disease is selected from Alzheimer's disease (AD), amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, Dravet's Syndrome, epilepsy, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration, ganglioglioma, gangliocytoma, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease (PiD), postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, Tangle-predominant dementia, multi-infarct dementia, ischemic stroke, or tuberous sclerosis. 
     
     
         4 . The method of  claim 1 , wherein the oligonucleotide is administered to the subject through an intrathecal, intracranial, intranasal, oral, intravenous, or subcutaneous route. 
     
     
         5 . The method of  claim 1  further comprising administering a second agent to the subject. 
     
     
         6 . The method of  claim 1 , wherein the subject is a human. 
     
     
         7 . A method of treating a tau-associated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide comprising a nucleobase sequence that has at least 90% sequence identity to any of the nucleobase sequences provided in Tables 2-17, wherein C in any of the nucleobase sequences is either cytosine or 5-methylcytosine, and wherein at least one nucleotide of the oligonucleotide has a 2′-modification. 
     
     
         8 . The method of  claim 7 , wherein the tau-associated disease is selected from Alzheimer's disease (AD), amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, Dravet's Syndrome, epilepsy, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration, ganglioglioma, gangliocytoma, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease (PiD), postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, Tangle-predominant dementia, multi-infarct dementia, ischemic stroke, or tuberous sclerosis. 
     
     
         9 . The method of  claim 7 , wherein the oligonucleotide is administered to the subject through an intrathecal, intracranial, intranasal, oral, intravenous, or subcutaneous route. 
     
     
         10 . The method of  claim 7  further comprising administering a second agent to the subject. 
     
     
         11 . The method of  claim 7 , wherein the subject is a human. 
     
     
         12 . The method of  claim 7 , wherein the oligonucleotide comprises a nucleobase sequence that has at least 90% sequence identity to any of the sequences provided in Tables 2-8, wherein C in any of the nucleobase sequences is either cytosine or 5-methylcytosine, and wherein each nucleotide of the oligonucleotide has a 2′-modification. 
     
     
         13 . The method of  claim 12 , wherein the oligonucleotide comprises any of the nucleobase sequences provided in Tables 2-8, or a nucleobase sequence that has at least 90% sequence identity thereto. 
     
     
         14 . The method of  claim 12 , wherein the internucleoside linkage of the oligonucleotide is either phosphodiester or phosphorothioate linkage. 
     
     
         15 . The method of  claim 12 , wherein the oligonucleotide comprises a linker attached to the 3′ end of the oligonucleotide through a phosphate bridge, and the oligonucleotide has any of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 12 , wherein the oligonucleotide decreases tau mRNA or protein expression independent of RNAse H. 
     
     
         17 . The method of  claim 7 , wherein the oligonucleotide comprises a nucleobase sequence that has at least 90% sequence identity to any of the sequences provided in Tables 9-15 and 17, wherein C in any of the nucleobase sequences is either cytosine or 5-methylcytosine, and wherein at least one nucleotide of the oligonucleotide has a 2′-modification. 
     
     
         18 . The method of  claim 17 , wherein the oligonucleotide comprises any of the nucleobase sequences provided in Tables 9-15 and 17, or a nucleobase sequence that has at least 90% sequence identity thereto. 
     
     
         19 . The method of  claim 17 , wherein the internucleoside linkage of the oligonucleotide is phosphorothioate linkage. 
     
     
         20 . The method of  claim 17 , wherein the oligonucleotide comprises at least five, at least seven or ten contiguous 2′-deoxynucleosides. 
     
     
         21 . The method of  claim 7 , wherein each C in any of the nucleobase sequences is 5-methylcytosine. 
     
     
         22 . The method of  claim 7 , wherein the oligonucleotide comprises a nucleobase sequence that is 100% complementary to at least 12 contiguous nucleobases of any one of SEQ ID NOs: 487-506. 
     
     
         23 . The method of  claim 22 , wherein the oligonucleotide comprises one or more 5-methylcytosines. 
     
     
         24 . The method of  claim 22 , wherein each nucleotide of the oligonucleotide has a 2′-modification. 
     
     
         25 . The method of  claim 22 , wherein the oligonucleotide comprises at least five, at least seven, or ten contiguous 2′-deoxynucleosides. 
     
     
         26 . The method of  claim 22 , wherein the oligonucleotide comprises 12 to 30, 12 to 25, or 15 to 20 nucleobases. 
     
     
         27 . The method of  claim 7 , wherein the 2′-modification is selected from the group consisting of 2′-fluoro, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA). 
     
     
         28 . The method of  claim 7 , wherein the 2′-modification is 2′-O-methoxyethyl (2′-O-MOE). 
     
     
         29 . The method of  claim 7 , wherein the oligonucleotide is capable of decreasing tau mRNA or protein expression level by at least 30% in vitro and/or in vivo.