Methods for reducing tau expression

Abstract

Provided herein is a method of administering ISIS 814907 to improve Alzheimer's disease, reduce tau RNA, or reduce tau protein in a human subject in need thereof. In certain embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild dementia due to Alzheimer's disease (MCI), and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia). In certain cases, the method is useful for improving at least one symptom or characteristic of a disease or disorder associated with tau protein. In certain cases, the disease or disorder associated with tau protein is a neurodegenerative disease or disorder. In certain cases, the disease or disorder associated with tau protein is Alzheimer's disease or frontotemporal dementia (FTD). In certain embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild dementia due to Alzheimer's disease (MCI), and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia). In certain cases, the disease or disorder associated with tau protein is tauopathy.In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome.Such symptoms or characteristics include memory loss, cognitive decline, loss of ability to understand or speak, abnormal behavior, loss and impairment of motor function, or an increase in the number and / or volume of neurofibrillary inclusions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Applications Nos. 63 / 225,404, 63 / 246,706, 63 / 331,650, and 63 / 345,511, filed on July 23, 2021, September 21, 2021, April 15, 2022, and May 25, 2022, respectively, each of which is incorporated by reference in its entirety herein.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an XML file named 13751-0362WO1.xml. Created on July 11, 2022, this XML file is 149,519 bytes in size. The material in this XML file is incorporated herein by reference in its entirety. Technical Field Provided herein is a method of administering ISIS 814907 to improve Alzheimer's disease, reduce tau RNA, or reduce tau protein in a human subject in need thereof. In certain cases, the method is useful for improving at least one symptom or characteristic of a disease or disorder associated with tau protein. In certain cases, the disease or disorder associated with tau protein is a neurodegenerative disease or disorder. In certain cases, the disease or disorder associated with tau protein is Alzheimer's disease or frontotemporal dementia (FTD). In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild dementia due to Alzheimer's disease (MCI), and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia). In certain cases, the disease or disorder associated with tau protein is a tauopathy. In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome. Symptoms or characteristics of the disease or disorder associated with tau protein include memory loss, cognitive decline, loss of ability to understand or speak, abnormal behavior, impaired motor function, or an increase in the number and / or volume of neurofibrillary inclusions. [Background technology]

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive and functional decline, leading to significant disability (Lane, et al., 2018, Eur. J. Neurol. 25:59-70). Symptom onset typically occurs in patients over the age of 65, with onset before age 65 accounting for less than 5% of all AD patients (Alzheimer's Association, 2021, 2021 Alzheimer's disease facts and figures, Alzheimers Dement. 17:327-406). Current management of AD is limited to multidisciplinary management of symptoms, including pharmacological treatments. Accumulating evidence suggests that aggregated hyperphosphorylated tau may be a key component of neurodegeneration in AD. Tau protein is encoded by the MAPT gene and is a microtubule-associated protein that is primarily expressed in neurons (Dixit, et al., 2008, Science 319:1086-1089). Under pathological conditions, hyperphosphorylated tau accumulates intracellularly and extracellularly, aggregates into oligomers and fibrils, and gives rise to intraneuronal neurofibrillary tangles (NFTs), which spread through specific neural networks via transsynaptic pathways (Braak and Del Tredici, 2016, Cold Spring Harb. Perspect. Biol. 8: a023630; Ossenkoppele, et al., 2019, Neuroimage Clin. 23: 101848), causing neurodegeneration, synaptic dysfunction and loss of synapses (DeVos, et al., 2018, Front. Neurosci. 12: 267; Guo, et al., 2018, Acta Neuropathologica 133: 665-704; Wilcock, et al., 1982, J Neurol. Sci. 56: 343-56; Hanseeuw, et al. 2019, JAMA Neurol.76:915-924, Gordon, et al., 2019, Brain 142:1063-1076).Intraneuronal tau inclusions are a pathological hallmark of other neurodegenerative diseases or disorders, such as tauopathies, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), FTDP-17, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), epilepsy, and Dravet syndrome (GG Kovacs. Chapter 25-Tauopathies. In Handbook of Clinical Neurology, Vol. 145 (3rd series). 2018). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Lane,et al.,2018,Eur.J.Neurol.25:59-70 [Non-Patent Document 2] Alzheimer's Association,2021,2021 Alzheimer's disease facts and figures,Alzheimers Dement.17:327-406 [Non-Patent Document 3] Dixit,et al.,2008,Science 319:1086-1089 [Non-Patent Document 4] Braak and Del Tredici,2016,Cold Spring Harb.Perspect.Biol.8:a023630 [Non-Patent Document 5] Ossenkoppele,et al.,2019,Neuroimage Clin.23:101848 [Non-Patent Document 6] DeVos,et al.,2018,Front.Neurosci.12:267 [Non-Patent Document 7] Guo,et al.,2018,Acta Neuropathologica 133:665-704 [Non-Patent Document 8] Wilcock, et al., 1982, J Neurol. Sci. 56:343-56 [Non-Patent Document 9] Hanseeuw,et al.2019,JAMA Neurol.76:915-924 [Non-Patent Document 10] Gordon,et al.,2019,Brain 142:1063-1076 [Non-Patent Document 11] GGKovacs.Chapter 25-Tauopathies.In Handbook of Clinical Neurology,Vol.145(3rd series).2018 [Brief description of the drawings]

[0005] [Figure 1-1] The concentration of total tau protein in the CSF over time for individual patients in each dose group is shown as absolute values ​​measured in picograms per milliliter (pg / mL). [Figure 1-2] The concentration of total tau protein in the CSF over time for individual patients in each dose group is shown as absolute values ​​measured in picograms per milliliter (pg / mL). [Figure 1-3] The concentration of total tau protein in the CSF over time for individual patients in each dose group is shown as absolute values ​​measured in picograms per milliliter (pg / mL). [Figure 1-4] The concentration of total tau protein in the CSF over time for individual patients in each dose group is shown as absolute values ​​measured in picograms per milliliter (pg / mL). [Figure 1-5] The concentration of total tau protein in the CSF over time for individual patients in each dose group is shown as absolute values ​​measured in picograms per milliliter (pg / mL). [Figure 2-1] The percent change from baseline in total tau protein is shown. Arrowheads indicate days of administration of ISIS 814907 or placebo. [Figure 2-2]The percent change from baseline in total tau protein is shown. Arrowheads indicate days of administration of ISIS 814907 or placebo. [Figure 2-3] The percent change from baseline in total tau protein is shown. Arrowheads indicate days of administration of ISIS 814907 or placebo. [Figure 2-4] The percent change from baseline in total tau protein is shown. Arrowheads indicate days of administration of ISIS 814907 or placebo. [Figure 2-5] The percent change from baseline in total tau protein is shown. Arrowheads indicate days of administration of ISIS 814907 or placebo. [Diagram 3] The percent change from baseline in CSF total tau protein concentration is shown through 56 days after the last dose (day 141), the last available time point. Circles represent individual patients and horizontal lines represent group means. [Figure 4-1] Figure 4A shows the mean concentration of total tau protein in the CSF. Figure 4B shows the mean percent change from baseline in total tau protein in the CSF. Figure 4C shows the mean percent change from baseline in phospho-tau protein over time by dose group. Error bars show the standard error of the mean. [Figure 4-2] Figure 4A shows the mean concentration of total tau protein in the CSF. Figure 4B shows the mean percent change from baseline in total tau protein in the CSF. Figure 4C shows the mean percent change from baseline in phospho-tau protein over time by dose group. Error bars show the standard error of the mean. [Figure 4-3] Figure 4A shows the mean concentration of total tau protein in the CSF. Figure 4B shows the mean percent change from baseline in total tau protein in the CSF. Figure 4C shows the mean percent change from baseline in phospho-tau protein over time by dose group. Error bars show the standard error of the mean. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] (Summary of the invention) Provided herein are methods for improving a disease or disorder associated with tau protein, and methods for reducing tau RNA and / or tau protein in a human subject in need thereof. Also provided herein are methods for treating or preventing a disease or disorder associated with tau protein. In certain embodiments, the disease or disorder associated with tau protein is a neurodegenerative disease or disorder. In certain embodiments, the disease or disorder associated with tau protein is a tauopathy. In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease or frontotemporal dementia (FTD). In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild dementia due to Alzheimer's disease (MCI), and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia). In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome. In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease. In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild dementia due to Alzheimer's disease (MCI), and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia). In certain embodiments, the disease or disorder associated with tau protein is FTD. In certain embodiments, the method comprises administering a therapeutically effective amount of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is ISIS 814907. In certain embodiments, the therapeutically effective amount is within the range of about 10 mg to about 115 mg. In certain embodiments, the therapeutically effective amount is within the range of about 60 mg to about 115 mg. In certain embodiments, the therapeutically effective amount is about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg. In certain embodiments, the therapeutically effective amount is administered about once every four weeks.In certain embodiments, the therapeutically effective amount is administered monthly. In certain embodiments, the therapeutically effective amount is administered once every other month. In certain embodiments, the therapeutically effective amount is administered once every quarter. In certain embodiments, the therapeutically effective amount is administered once about every 8 weeks. In certain embodiments, the therapeutically effective amount is administered once about every 12 weeks. In certain embodiments, the therapeutically effective amount is administered once about every 16 weeks. In certain embodiments, the therapeutically effective amount is administered once about every 24 weeks. In certain embodiments, the therapeutically effective amount is administered once about every 6 months. In certain embodiments, the therapeutically effective amount is administered monthly. In certain embodiments, the therapeutically effective amount is administered once every 2 months. In certain embodiments, the therapeutically effective amount is administered once every 3 months. In certain embodiments, the therapeutically effective amount is administered quarterly. In certain embodiments, the therapeutically effective amount is administered twice a year (semi-annually). In certain embodiments, the therapeutically effective amount is administered annually. In certain embodiments, the therapeutically effective amount is administered once every two years.

[0007] In some embodiments, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof, comprising administering a dose of ISIS 814907 to the human subject. In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (MCI), and / or Alzheimer's dementia (e.g., mild Alzheimer's dementia). In some embodiments, the dose is 10 mg of ISIS 814907 once a month. In some embodiments, the dose is 30 mg of ISIS 814907 once a month. In some embodiments, the dose is 60 mg of ISIS 814907 once a month. In some embodiments, the dose is 115 mg of ISIS 814907 once every three months, once a quarter, or four times a year. The administration is performed intrathecally (e.g., bolus IT administration). In some embodiments, the human subject is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more than 24 monthly doses. In some embodiments, the human subject is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more than 24 quarterly doses. In some embodiments, the human subject is over 90 years old. In some embodiments, the human subject is between 40 and 90 years old. In some embodiments, the human subject is between 50 and 80 years old. In some embodiments, the human subject is between 50 and 74 years old.In some embodiments, the human subject has one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following criteria: 1) mild Alzheimer's disease; 2) Recurrent Neuropsychiatric Assessment Battery (RBANS) Delayed Memory Index score of 85 or less showing objective evidence of memory impairment; 3) CDR total score of 0.5 for MCI with AD or 0.5 or 1 for mild AD dementia; 4) CDR total score of 0.5 or less for MCI with AD; ) a CDR memory box score of 0.5 or greater; 5) an MMSE score between 22 and 30; 6) an MMSE score between 20 and 27; 7) a CDR memory box score of 0.5 or greater; 8) evidence of amyloid pathology as measured by positive emission tomography (PET) or cerebrospinal fluid (CSF) sampling; 9) a cerebrospinal fluid (CSF) pattern of low Aβ42 and elevated t-tau and phosphorylated tau (p-tau); and 10) a probable diagnosis of Alzheimer's disease based on the National Institute of Aging-Alzheimer Association (NIA-AA) criteria.

[0008] In some embodiments, the disclosure features other methods of treating Alzheimer's disease in a human subject in need thereof, comprising administering a dose of ISIS 814907 to the human subject. In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (MCI), and / or Alzheimer's dementia (e.g., mild Alzheimer's dementia). In some embodiments, the dose is 60 mg of ISIS 814907. In some embodiments, the dose is 115 mg of ISIS 814907. In some embodiments, the dose is administered once every 24 weeks (Q24W). In some embodiments, the dose is administered once every 12 weeks (Q12W). In some embodiments, the 60 mg dose is administered Q12W. In some embodiments, the 60 mg dose is administered Q24W. In some embodiments, the 115 mg dose is administered Q24W. In some embodiments, a dose of 115mg is administered Q12W. Administration is performed intrathecally (e.g., bolus IT administration). In some embodiments, human subjects are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more than 24 doses of Q12W. In some embodiments, the human subject is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more than 24 doses of Q24W. In some embodiments, the human subject is over 90 years old. In some embodiments, doses are administered for up to 72 weeks. In some embodiments, the human subject is between 40 and 90 years old. In some embodiments, the human subject is between 50 and 80 years old. In some embodiments, the human subject is between 50 and 72 years old.In some embodiments, the human subject has one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following criteria: 1) mild Alzheimer's disease; 2) Recurrent Neuropsychiatric Assessment Battery (RBANS) Delayed Memory Index score of 85 or less showing objective evidence of memory impairment; 3) CDR total score of 0.5 for MCI with AD or 0.5 or 1 for mild AD dementia; 4) CDR overall score of 0.0 or less for MCI with AD or 0.0 or less for mild AD dementia; 1) total score of 1, or total score of 0.5 and memory score of 1; 5) MMSE score ≥22 and ≤30; 6) MMSE score ≥20 and ≤27; 7) CDR memory box score ≥0.5; and 8) evidence of amyloid pathology as measured by positive emission tomography (PET) or cerebrospinal fluid (CSF) sampling; 9) cerebrospinal fluid (CSF) pattern of low Aβ42 and elevated t-tau and phosphorylated tau (p-tau); and 10) a probable diagnosis of Alzheimer's disease based on National Institute of Aging-Alzheimer Association (NIA-AA) criteria.

[0009] In certain embodiments, the method comprises administering a loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 4 weeks, followed by administration of a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 8 weeks, once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In certain embodiments, the method comprises administering a loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 8 weeks, followed by a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In certain embodiments, the method comprises administering a loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 12 weeks, followed by a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In some embodiments, the methods include administering at least two loading doses, at least three loading doses, at least four loading doses, at least five loading doses, or at least six loading doses.

[0010] In certain embodiments, the method comprises administering ISIS 814907 at a loading dose of about 60 mg to about 115 mg once about every 4 weeks, followed by a maintenance dose of about 60 mg to about 115 mg once about every 8 weeks, once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In certain embodiments, the method comprises administering ISIS 814907 at a loading dose of about 60 mg to about 115 mg once about every 8 weeks, followed by a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of ISIS 814907 once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In certain embodiments, the method comprises administering a loading dose of about 60 mg to about 115 mg of ISIS 814907 once about every 12 weeks, followed by administration of a maintenance dose of about 60 mg to about 115 mg of ISIS 814907 once about every 16 weeks, once about every 24 weeks, or once about every 6 months.

[0011] In certain embodiments, the method comprises administering a loading dose of about 60 mg of ISIS 814907 once about every 12 weeks, followed by a maintenance dose of about 60 mg of ISIS 814907 once about every 6 months. In certain embodiments, the method comprises administering a loading dose of about 115 mg of ISIS 814907 once about every 12 weeks, followed by a maintenance dose of about 115 mg of ISIS 814907 once about every 6 months. In certain embodiments, the method comprises administering a loading dose of about 60 mg to about 115 mg of ISIS 814907 once about every 12 weeks, followed by a maintenance dose of about 60 mg to about 115 mg of ISIS 814907 once about every 6 months. (Mode for carrying out the invention)

[0012] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" as well as other forms such as "includes" and "included" is not limiting. Additionally, terms such as "element" or "component" include both elements and components that include one unit as well as elements and components that include multiple subunits unless specifically stated otherwise.

[0013] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, and papers, are expressly incorporated herein in their entirety by reference to the portions of such documents discussed herein.

[0014] definition Unless otherwise defined, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those commonly used and well known in the art. Where permitted, all patents, applications, published applications, and other publications and other data referred to throughout this disclosure are incorporated herein by reference in their entirety.

[0015] Unless otherwise indicated, the following terms have the following meanings.

[0016] As used herein, "2'-deoxyribonucleoside" refers to a nucleoside that includes a 2'-H(H) deoxyribosyl sugar moiety. In certain embodiments, a 2'-deoxyribonucleoside is a 2'-β-D deoxyribonucleoside, which includes a 2'-β-D-deoxyribosyl sugar moiety having the β-D configuration found in naturally occurring deoxyribonucleic acid (DNA). In certain embodiments, a 2'-deoxyribonucleoside may include a modified nucleobase or may include an RNA nucleobase (uracil).

[0017] As used herein, "2'-MOE" refers to a 2'-OCH substituted for the 2'-OH group of a ribosyl sugar moiety. 2 CH 2 OCH 3 A "2'-MOE sugar moiety" refers to a 2'-OCH group in place of the 2'-OH group of a ribosyl sugar moiety. 2 CH 2 OCH 3 The 2'-MOE sugar moiety is a sugar moiety having a 2'-MOE group. Unless otherwise indicated, the 2'-MOE sugar moiety is in the β-D configuration. "MOE" means O-methoxyethyl.

[0018] As used herein, "2'-MOE nucleoside" means a nucleoside that includes a 2'-MOE sugar moiety.

[0019] As used herein, "5-methylcytosine" means a cytosine modified with a methyl group attached to position 5. 5-methylcytosine is a modified nucleobase.

[0020] As used herein, "about" means plus or minus 7% of the value provided.

[0021] As used herein, "administering" means providing a pharmaceutical agent to a human subject.

[0022] As used herein, "ameliorate" in reference to treatment means an improvement in at least one symptom or characteristic compared to the same symptom or characteristic in the absence of treatment. In certain embodiments, the improvement is a reduction in the severity or frequency of the symptom or characteristic, or a delay in the onset or slowing of the progression of the severity or frequency of the symptom or characteristic.

[0023] As used herein, "CAG repeat" means one of a plurality of consecutive triplet units, each triplet consisting of three consecutive nucleosides having a 5' to 3' nucleobase sequence of cytosine (C), adenine (A), and guanine (G).

[0024] As used herein, "dose" means the amount of a pharmaceutical agent administered.

[0025] As used herein, the term "internucleoside linkage" refers to the covalent bond between consecutive nucleosides in an oligonucleotide.As used herein, "modified internucleoside linkage" refers to any internucleoside linkage other than phosphodiester internucleoside linkage.A "phosphorothioate internucleoside linkage" is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of the phosphodiester internucleoside linkage is replaced with a sulfur atom.

[0026] As used herein, "loading dose" refers to a therapeutically effective amount of a pharmaceutical agent administered during the initial dosing phase in which a steady state concentration of the pharmaceutical agent is achieved. "Initial loading dose" refers to the first loading dose administered. "Final loading dose" refers to the most recent loading dose administered prior to administration of the first maintenance dose.

[0027] As used herein, "maintenance dose" means a therapeutically effective amount of a pharmaceutical agent administered during a dosing phase after a steady state concentration of that pharmaceutical agent has been achieved.

[0028] As used herein, "MAPT Rx" and "ISIS814907" are synonymous.

[0029] As used herein, "nucleobase" refers to an unmodified nucleobase or a modified nucleobase. An "unmodified nucleobase" is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). A "modified nucleobase" is an atomic group other than unmodified A, T, C, U, or G that can pair with at least one unmodified nucleobase. "5-methylcytosine" is a modified nucleobase. As used herein, "nucleobase sequence" refers to the order of consecutive nucleobases in a target nucleic acid or oligonucleotide, regardless of any modification of the sugar or internucleoside linkage.

[0030] As used herein, "nucleoside" refers to a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. As used herein, "modified nucleoside" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. "Linked nucleosides" are nucleosides that are connected in a contiguous sequence (i.e., there are no additional nucleosides between the linked nucleosides). As used herein, "oligonucleotide" refers to a single linked nucleoside connected via an internucleoside bond, each of which may or may not be modified. Unless otherwise indicated, an oligonucleotide consists of 8 to 50 linked nucleosides. As used herein, "modified oligonucleotide" refers to an oligonucleotide in which at least one nucleoside or internucleoside bond is modified.

[0031] As used herein, "pharmaceutical acceptable carrier or diluent" refers to any substance suitable for use in administration to a human subject. Certain such carriers allow the pharmaceutical composition to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and lozenges for oral ingestion by a human subject. In certain embodiments, the pharmaceutical acceptable carrier or diluent is sterile water, sterile saline, sterile buffer or sterile artificial cerebrospinal fluid (aCSF).

[0032] As used herein, "pharmaceutically acceptable salts" refers to physiologically and pharma- ceutically acceptable salts of a compound that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

[0033] As used herein, "potassium salt" refers to a salt of a modified oligonucleotide in which the cation of the salt is potassium.

[0034] As used herein, "RNA" means RNA transcript, which includes pre-mRNA and mature mRNA, unless otherwise specified.

[0035] As used herein, "sodium salt" refers to a salt of a modified oligonucleotide in which the cation of the salt is sodium.

[0036] As used herein, "subject" refers to a human or non-human animal. In certain embodiments, the subject is a human subject. A "subject in need thereof" is a subject that will benefit from the administration of modified oligonucleotides disclosed herein. In certain embodiments, the subject in need thereof has AD.

[0037] As used herein, "sugar moiety" refers to an unmodified sugar moiety or a modified sugar moiety. "Unmodified sugar moiety" refers to a 2'-OH(H)β-D ribosyl moiety as found in RNA (an "unmodified RNA sugar moiety"), or a 2'-H(H)β-D deoxyribosyl moiety as found in DNA (an "unmodified DNA sugar moiety"). An unmodified sugar moiety has one hydrogen at each of the 1', 3', and 4' positions, one oxygen at the 3' position, and two hydrogens at the 5' position. "Modified sugar moiety" or "modified sugar" refers to a modified furanosyl sugar moiety or sugar surrogate.

[0038] As used herein, "symptom or feature" refers to any physical characteristic or test result that indicates the presence or extent of a disease or disorder. In certain embodiments, the symptom is evident to the subject or to a medical professional examining or testing the subject. In certain embodiments, the feature is evident upon invasive diagnostic testing, including but not limited to postmortem examination. In certain embodiments, the feature is evident on a brain MRI scan.

[0039] As used herein, "tau RNA" is equivalent to "MAPT RNA" and is the RNA expression product of the human gene MAPT. As used herein, "MAPT gene" refers to the genomic sequence that encodes tau RNA.

[0040] As used herein, "tau protein" is the protein expression product of tau RNA.

[0041] As used herein, a "therapeutically effective amount" refers to an amount of a pharmaceutical agent that provides a therapeutic benefit to a human subject, e.g., a therapeutically effective amount ameliorates a symptom or characteristic of a disease or disorder.

[0042] As used herein, "trough concentration" means the concentration of an analyte (e.g., tau protein in a biological sample taken from a human subject receiving a dose immediately before the human subject receives a subsequent dose), or the concentration of the analyte on the final day of testing.

[0043] As used herein, "week" means seven days.

[0044] Specific Embodiments Embodiment 1. A method of ameliorating a disease or disorder associated with tau protein in a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound having the following chemical structure: [ka] (SEQ ID NO: 4), or a salt thereof, to the human subject.

[0045] Embodiment 2. The method of embodiment 1, wherein the modified oligonucleotide is a sodium or potassium salt.

[0046] Embodiment 3. A method of ameliorating a disease or disorder associated with tau protein in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of the following chemical structure: [ka] The method comprises administering to the human subject a modified oligonucleotide according to (SEQ ID NO: 4).

[0047] Embodiment 4. A method of ameliorating a disease or disorder associated with tau protein in a human subject in need thereof, comprising administering to said human subject a therapeutically effective amount of a modified oligonucleotide, said modified oligonucleotide having the following chemical designation (5' to 3'): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (SEQ ID NO: 4), wherein: A = adenine nucleobase, mC = 5-methylcytosine nucleobase, G = guanine nucleobase, T=thymine nucleobase, e=2'-MOE sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, s=phosphorothioate internucleoside linkage, and The method wherein o=phosphodiester internucleoside linkage.

[0048] Embodiment 5. The method of any one of embodiments 1 to 4, wherein the disease or disorder associated with tau protein is a neurodegenerative disease or disorder.

[0049] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the disease or disorder associated with tau protein is a tauopathy.

[0050] Embodiment 7. The method according to any one of embodiments 1 to 6, wherein the disease or disorder associated with tau protein is any of Alzheimer's disease or frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome. In some embodiments, the Alzheimer's disease is mild cognitive impairment (MCI) and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia).

[0051] Embodiment 8. The disease or disorder associated with tau protein is Down's syndrome, prion diseases (sCJD, vCJD, gCJD, GSS, FFI), diffuse neurofibrillary tangle disease with calcification, familial British dementia and familial Danish dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, myotonic dystrophy (DM1) and PROMM (DM2), age-related tau astrogliopathy, traumatic brain injury, chronic traumatic encephalopathy, IgLON5-associated tauopathy, Guadeloupean parkinsonism, Guam parkinsonism-dementia complex, Non-Guamanian motor neuron disease with NFTs. 7. The method of any of embodiments 1-6, wherein the patient is any of the following diseases or disorders associated with a genetic mutation in any of LRRK2, PRKN, SNCA, TARDBP, or C9orf72: amyotrophic lateral sclerosis of Guam, X-linked parkinsonism with spasticity, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, PANK2-associated neurodegeneration with brain iron deposition (NBIA), PLA2G6-associated NBIA, SLC9A6 mental retardation, or a disease or disorder associated with a genetic mutation in any of LRRK2, PRKN, SNCA, TARDBP, or C9orf72.

[0052] Embodiment 9. The method of any of embodiments 1-8, wherein the disease is Alzheimer's disease. In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (MCI), and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia).

[0053] Embodiment 10. The method of any one of embodiments 1 to 8, wherein the disease is FTD.

[0054] Embodiment 11. The method of any one of embodiments 1 to 10, wherein at least one symptom or feature of a disease or disorder associated with the tau protein is ameliorated.

[0055] Embodiment 12. The method of embodiment 11, wherein the at least one symptom or characteristic comprises memory loss, decline in cognitive function, loss of ability to understand or speak, abnormal behavior, impaired motor function, loss of cognitive function, neuropsychiatric behavioral dysfunction, general dysfunction, loss of motor function, impaired cognitive function, neuropsychiatric dysfunction, impairment of daily living function, impaired attention, impaired visual-perceptual processing, impaired memory, impaired independence, increased apathy, impaired learning ability, impaired concentration, impaired understanding and speech, impaired behavior, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, convulsions, suicidal thoughts, suicidal behavior, or an increase in the number and / or volume of neurofibrillary inclusions.

[0056] Embodiment 13. A method of reducing tau RNA in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of the following chemical structure: [ka] (SEQ ID NO: 4), or a salt thereof, to the human subject.

[0057] Embodiment 14 The method of embodiment 13, wherein the modified oligonucleotide is a sodium or potassium salt.

[0058] Embodiment 15. A method of reducing tau RNA in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of the following chemical structure: [ka] The method comprises administering to the human subject a modified oligonucleotide according to (SEQ ID NO: 4).

[0059] Embodiment 16. A method of reducing tau RNA in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide, wherein the modified oligonucleotide has the following chemical designation (5' to 3'): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (SEQ ID NO: 4), wherein: A = adenine nucleobase, mC = 5-methylcytosine nucleobase, G = guanine nucleobase, T=thymine nucleobase, e=2'-MOE sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, s=phosphorothioate internucleoside linkage, and The method wherein o=phosphodiester internucleoside linkage.

[0060] Embodiment 17. A method of reducing tau protein in a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound having the following chemical structure: [ka] (SEQ ID NO: 4), or a salt thereof, to the human subject.

[0061] Embodiment 18 The method of embodiment 17, wherein the modified oligonucleotide is a sodium or potassium salt.

[0062] Embodiment 19. A method of reducing tau protein in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of the following chemical structure: [ka] The method comprises administering to the human subject a modified oligonucleotide according to (SEQ ID NO: 4).

[0063] Embodiment 20. A method of reducing tau protein in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide, wherein the modified oligonucleotide has the following chemical designation (5' to 3'): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (SEQ ID NO: 4), wherein: A = adenine nucleobase, mC = 5-methylcytosine nucleobase, G = guanine nucleobase, T=thymine nucleobase, e=2'-MOE sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, s=phosphorothioate internucleoside linkage, and The method wherein o=phosphodiester internucleoside linkage.

[0064] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is 10 mg.

[0065] Embodiment 22 The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is 30 mg.

[0066] Embodiment 23 The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is 60 mg.

[0067] Embodiment 24. The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is 90 mg.

[0068] Embodiment 25 The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is 115 mg.

[0069] Embodiment 26 The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is about 10 mg.

[0070] Embodiment 27. The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is about 30 mg.

[0071] Embodiment 28. The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is about 60 mg.

[0072] Embodiment 29. The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is about 90 mg.

[0073] Embodiment 30 The method of any one of embodiments 1 to 20, wherein the therapeutically effective amount is about 115 mg.

[0074] Embodiment 31. The therapeutically effective amount is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 20 ... 21. The method of any one of embodiments 1-20, wherein the amount of the active ingredient is any one of 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, and 350 mg.

[0075] Embodiment 32. The therapeutically effective amount is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. g, approx. 105 mg, approx. 110 mg, approx. 115 mg, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. The method according to any one of embodiments 1 to 20, wherein the amount of the active ingredient is any one of about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, and about 350 mg.

[0076] Embodiment 33. The therapeutically effective amount is 50 mg, 50.1 mg, 50.2 mg, 50.3 mg, 50.4 mg, 50.5 mg, 50.6 mg, 50.7 mg, 50.8 mg, 50.9 mg, 51 mg, 51.1 mg, 51.2 mg, 51.3 mg, 51.4 mg, 51.5 mg, 51.6 mg, 51.7 mg, 51.8 mg, 51.9 mg, 52 mg, 52.1 mg, 52.2 mg, 52.3 mg, 52.4 mg, 52.5 mg, 52.6 mg, 52.7 mg, 52.8 mg, 52.9 mg, 53 mg, 53.1 mg, 53.2 mg, 53.3 mg, 53.4 mg, 53.5mg, 53.6mg, 53.7mg, 53.8mg, 53.9mg, 54mg, 54.1mg, 54.2mg, 54.3mg, 54.4mg, 54.5mg, 54.6mg, 54.7mg, 54.8mg, 54.9mg, 55mg, 55.1mg, 55.2mg, 55 .3mg, 55.4mg, 55.5mg, 55.6mg, 55.7mg, 55.8mg, 55.9mg, 56mg, 56.1mg, 56.2mg, 56.3mg, 56.4mg, 56.5mg, 56.6mg, 56.7mg, 56.8mg, 56.9mg, 57mg, 57.1 mg, 57.2mg, 57.3mg, 57.4mg, 57.5mg, 57.6mg, 57.7mg, 57.8mg, 57.9mg, 58mg, 58.1mg, 58.2mg, 58.3mg, 58.4mg, 58.5mg, 58.6mg, 58.7mg, 58.8mg, 58.9 mg, 59mg, 59.1mg, 59.2mg, 59.3mg, 59.4mg, 59.5mg, 59.6mg, 59.7mg, 59.8mg, 59.9mg, 60mg, 60.1mg, 60.2mg, 60.3mg, 60.4mg, 60.5mg, 60.6mg, 60.7mg , 60.8mg, 60.9mg, 61mg, 61.1mg, 61.2mg, 61.3mg, 61.4mg, 61.5mg, 61.6mg, 61.7mg, 61.8mg, 61.9mg, 62mg, 62.1mg, 62.2mg, 62.3mg, 62.4mg, 62.5mg, 6 2.6mg, 62.7mg, 62.8mg, 62.9mg, 63mg, 63.1mg, 63.2mg, 63.3mg, 63.4mg, 63.5mg, 63.6mg, 63.7mg, 63.8mg, 63.9mg, 64mg, 64.1mg, 64.2mg, 64.3mg, 64.4mg, 64.5mg, 64.6mg, 64.7mg, 64.8mg, 64.9mg, 65mg, 65.1mg, 65.2mg, 65.3mg, 65.4mg, 65.5mg, 65.6mg, 65.7mg, 65.8mg, 65.9 mg, 66mg, 66.1mg, 66.2mg, 66.3mg, 66.4mg, 66.5mg, 66.6mg, 66.7mg, 66.8mg, 66.9mg, 67mg, 67.1mg, 67.2mg, 67.3mg, 67.4mg, 21. The method of any one of embodiments 1-20, wherein the amount of the compound is any one of 67.5 mg, 67.6 mg, 67.7 mg, 67.8 mg, 67.9 mg, 68 mg, 68.1 mg, 68.2 mg, 68.3 mg, 68.4 mg, 68.5 mg, 68.6 mg, 68.7 mg, 68.8 mg, 68.9 mg, 69 mg, 69.1 mg, 69.2 mg, 69.3 mg, 69.4 mg, 69.5 mg, 69.6 mg, 69.7 mg, 69.8 mg, 69.9 mg, and 70 mg.

[0077] Embodiment 34. The therapeutically effective amount is about 50 mg, about 50.1 mg, about 50.2 mg, about 50.3 mg, about 50.4 mg, about 50.5 mg, about 50.6 mg, about 50.7 mg, about 50.8 mg, about 50.9 mg, about 51 mg, about 51.1 mg, about 51.2 mg, about 51.3 mg, about 51.4 mg, about 51.5 mg, about 51.6 mg, about 51.7 mg, about 51.8 mg, about 51.9 mg, about 52 mg, about 52.1 mg, about 52.2 mg, about 52.3 mg, about 52.4 mg, about 52.5 mg, about 52.6 mg, about 52.7 mg, about 52.8 mg, about 52.9 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about mg, approx. 53.1 mg, approx. 53.2 mg, approx. 53.3 mg, approx. 53.4 mg, approx. 53.5 mg, approx. 53.6 mg, approx. 53.7 mg, approx. 4.6mg, about 54.7mg, about 54.8mg, about 54.9mg, about 55mg, about 55.1mg, about 55.2mg, about 55.3mg, about 55.4mg, about 55.5mg, about 55.6mg, about 55.7mg, about 55.8mg, about 55.9mg, about 56mg, about 56.1mg, about 5 6.2mg, 56.3mg, 56.4mg, 56.5mg, 56.6mg, 56.7mg, 56.8mg, 56.9mg, 57mg, 57.1mg, 57.2mg, 57.3mg, 57.4mg, 57.5mg, 57.6mg, 57.7mg , about 57.8mg, about 57.9mg, about 58mg, about 58.1mg, about 58.2mg, about 58.3mg, about 58.4mg, about 58.5mg, about 58.6mg, about 58.7mg, about 58.8mg, about 58.9mg, about 59mg, about 59.1mg, about 59.2mg, about 59.3mg , about 59.4mg, about 59.5mg, about 59.6mg, about 59.7mg, about 59.8mg, about 59.9mg, about 60mg, about 60.1mg, about 60.2mg, about 60.3mg, about 60.4mg, about 60.5mg, about 60.6mg, about 60.7mg, about 60.8mg, about 60.9mg, about 61mg, about 61.1mg, about 61.2mg, about 61.3mg, about 61.4mg, about 61.5mg, about 61.6mg, about 61.7mg, about 61.8mg, about 61.9mg, about 62mg, about 62.1mg, about 62.2mg, about 62.3mg, about 62.4mg, about 62.5mg, about 62.6mg, about 62.7mg, about 62.8mg, about 62.9mg, about 63mg, about 63.1mg, about 63.2mg, about 63.3mg, about 63.4mg, about 63.5mg, about 63.6mg, about 63.7mg, about 63.8mg, about 63.9mg, about 64mg, about 64.1mg, about 64.2mg, about 64.3mg, about 64.4mg, about 64 .5mg, about 64.6mg, about 64.7mg, about 64.8mg, about 64.9mg, about 65mg, about 65.1mg, about 65.2mg, about 65.3mg, about 65.4mg, about 65.5mg, about 65.6mg, about 65.7mg, about 65.8mg, about 65.9mg, about 66mg, about 66.1mg, about 66.2mg, about 66.3mg, about 66.4mg, about 6 6.5mg, about 66.6mg, about 66.7mg, about 66.8mg, about 66.9mg, about 67mg, about 67.1mg, about 67.2mg, about 67.3mg, about 67.4mg, about 67.5mg, about 67.6mg, about 67.7mg, about 67.8mg, about 67.9mg, about 68mg, about 68.1mg, about 68.2mg, about 68.3mg, about 68.4mg, about 21. The method of any one of embodiments 1-20, wherein the amount of the compound is any one of about 68.5 mg, about 68.6 mg, about 68.7 mg, about 68.8 mg, about 68.9 mg, about 69 mg, about 69.1 mg, about 69.2 mg, about 69.3 mg, about 69.4 mg, about 69.5 mg, about 69.6 mg, about 69.7 mg, about 69.8 mg, about 69.9 mg, and about 70 mg.

[0078] Embodiment 35. The therapeutically effective amount is 80 mg, 80.1 mg, 80.2 mg, 80.3 mg, 80.4 mg, 80.5 mg, 80.6 mg, 80.7 mg, 80.8 mg, 80.9 mg, 81 mg, 81.1 mg, 81.2 mg, 81.3 mg, 81.4 mg, 81.5 mg, 81.6 mg, 81.7 mg, 81.8 mg, 81.9 mg, 82 mg, 82.1 mg, 82.2 mg, 82.3 mg, 82.4 mg, 82.5 mg, 82.6 mg, 82.7 mg, 82.8 mg, 82.9 mg, 83 mg, 83.1 mg, 83.2 mg, 83.3 mg, 83.4 mg, 83.5mg, 83.6mg, 83.7mg, 83.8mg, 83.9mg, 84mg, 84.1mg, 84.2mg, 84.3mg, 84.4mg, 84.5mg, 84.6mg, 84.7mg, 84.8mg, 84.9mg, 85mg, 85.1mg, 85.2mg, 85 .3mg, 85.4mg, 85.5mg, 85.6mg, 85.7mg, 85.8mg, 85.9mg, 86mg, 86.1mg, 86.2mg, 86.3mg, 86.4mg, 86.5mg, 86.6mg, 86.7mg, 86.8mg, 86.9mg, 87mg, 87.1 mg, 87.2mg, 87.3mg, 87.4mg, 87.5mg, 87.6mg, 87.7mg, 87.8mg, 87.9mg, 88mg, 88.1mg, 88.2mg, 88.3mg, 88.4mg, 88.5mg, 88.6mg, 88.7mg, 88.8mg, 88.9 mg, 89mg, 89.1mg, 89.2mg, 89.3mg, 89.4mg, 89.5mg, 89.6mg, 89.7mg, 89.8mg, 89.9mg, 90mg, 90.1mg, 90.2mg, 90.3mg, 90.4mg, 90.5mg, 90.6mg, 90.7mg , 90.8mg, 90.9mg, 91mg, 91.1mg, 91.2mg, 91.3mg, 91.4mg, 91.5mg, 91.6mg, 91.7mg, 91.8mg, 91.9mg, 92mg, 92.1mg, 92.2mg, 92.3mg, 92.4mg, 92.5mg, 9 2.6mg, 92.7mg, 92.8mg, 92.9mg, 93mg, 93.1mg, 93.2mg, 93.3mg, 93.4mg, 93.5mg, 93.6mg, 93.7mg, 93.8mg, 93.9mg, 94mg, 94.1mg, 94.2mg, 94.3mg, 94.4mg, 94.5mg, 94.6mg, 94.7mg, 94.8mg, 94.9mg, 95mg, 95.1mg, 95.2mg, 95.3mg, 95.4mg, 95.5mg, 95.6mg, 95.7mg, 95.8mg, 95.9 mg, 96mg, 96.1mg, 96.2mg, 96.3mg, 96.4mg, 96.5mg, 96.6mg, 96.7mg, 96.8mg, 96.9mg, 97mg, 97.1mg, 97.2mg, 97.3mg, 97.4mg, 9 21. The method of any one of embodiments 1-20, wherein the amount of the compound is any one of 7.5 mg, 97.6 mg, 97.7 mg, 97.8 mg, 97.9 mg, 98 mg, 98.1 mg, 98.2 mg, 98.3 mg, 98.4 mg, 98.5 mg, 98.6 mg, 98.7 mg, 98.8 mg, 98.9 mg, 99 mg, 99.1 mg, 99.2 mg, 99.3 mg, 99.4 mg, 99.5 mg, 99.6 mg, 99.7 mg, 99.8 mg, 99.9 mg, and 100 mg.

[0079] Embodiment 36. The therapeutically effective amount is about 80 mg, about 80.1 mg, about 80.2 mg, about 80.3 mg, about 80.4 mg, about 80.5 mg, about 80.6 mg, about 80.7 mg, about 80.8 mg, about 80.9 mg, about 81 mg, about 81.1 mg, about 81.2 mg, about 81.3 mg, about 81.4 mg, about 81.5 mg, about 81.6 mg, about 81.7 mg, about 81.8 mg, about 81.9 mg, about 82 mg, about 82.1 mg, about 82.2 mg, about 82.3 mg, about 82.4 mg, about 82.5 mg, about 82.6 mg, about 82.7 mg, about 82.8 mg, about 82.9 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 122 mg, about 124 mg, about 1 mg, approx. 83.1 mg, approx. 83.2 mg, approx. 83.3 mg, approx. 83.4 mg, approx. 83.5 mg, approx. 83.6 mg, approx. 83.7 mg, approx. 83.8 mg, approx. 4.6mg, about 84.7mg, about 84.8mg, about 84.9mg, about 85mg, about 85.1mg, about 85.2mg, about 85.3mg, about 85.4mg, about 85.5mg, about 85.6mg, about 85.7mg, about 85.8mg, about 85.9mg, about 86mg, about 86.1mg, about 8 6.2mg, about 86.3mg, about 86.4mg, about 86.5mg, about 86.6mg, about 86.7mg, about 86.8mg, about 86.9mg, about 87mg, about 87.1mg, about 87.2mg, about 87.3mg, about 87.4mg, about 87.5mg, about 87.6mg, about 87.7mg , about 87.8mg, about 87.9mg, about 88mg, about 88.1mg, about 88.2mg, about 88.3mg, about 88.4mg, about 88.5mg, about 88.6mg, about 88.7mg, about 88.8mg, about 88.9mg, about 89mg, about 89.1mg, about 89.2mg, about 89.3mg , about 89.4mg, about 89.5mg, about 89.6mg, about 89.7mg, about 89.8mg, about 89.9mg, about 90mg, about 90.1mg, about 90.2mg, about 90.3mg, about 90.4mg, about 90.5mg, about 90.6mg, about 90.7mg, about 90.8mg, about 90.9mg, about 91mg, about 91.1mg, about 91.2mg, about 91.3mg, about 91.4mg, about 91.5mg, about 91.6mg, about 91.7mg, about 91.8mg, about 91.9mg, about 92mg, about 92.1mg, about 92.2mg, about 92.3mg, about 92.4mg, about 92.21. The method of any one of embodiments 1-20, wherein the amount of the glycerol in ...

[0080] Embodiment 37. The therapeutically effective amount is 105 mg, 105.1 mg, 105.2 mg, 105.3 mg, 105.4 mg, 105.5 mg, 105.6 mg, 105.7 mg, 105.8 mg, 105.9 mg, 106 mg, 106.1 mg, 106.2 mg, 106.3 mg, 106.4 mg, 106.5 mg, 106.6 mg, 106.7 mg, 106.8 mg, 106.9 mg, 107 mg, 107.1 mg, 107.2 mg, 107.3 mg, 107.4 mg, 107.5 mg, 107.6 mg, 107.7 mg, 107.8 mg, 107.9 mg, 108 ... mg, 108.1mg, 108.2mg, 108.3mg, 108.4mg, 108.5mg, 108.6mg, 108.7mg, 108.8mg, 108.9mg, 109mg, 109.1mg, 109.2mg, 109.3mg, 109.4mg, 109.5mg, 10 9.6mg, 109.7mg, 109.8mg, 109.9mg, 110mg, 110.1mg, 110.2mg, 110.3mg, 110.4mg, 110.5mg, 110.6mg, 110.7mg, 110.8mg, 110.9mg, 111mg, 111.1mg, 11 1.2mg, 111.3mg, 111.4mg, 111.5mg, 111.6mg, 111.7mg, 111.8mg, 111.9mg, 112mg, 112.1mg, 112.2mg, 112.3mg, 112.4mg, 112.5mg, 112.6mg, 112.7mg , 112.8mg, 112.9mg, 113mg, 113.1mg, 113.2mg, 113.3mg, 113.4mg, 113.5mg, 113.6mg, 113.7mg, 113.8mg, 113.9mg, 114mg, 114.1mg, 114.2mg, 114.3mg , 114.4mg, 114.5mg, 114.6mg, 114.7mg, 114.8mg, 114.9mg, 115mg, 115.1mg, 115.2mg, 115.3mg, 115.4mg, 115.5mg, 115.6mg, 115.7mg, 115.8mg, 115. 9mg, 116mg, 116.1mg, 116.2mg, 116.3mg, 116.4mg, 116.5mg, 116.6mg, 116.7mg, 116.8mg, 116.9mg, 117mg, 117.1mg, 117.2mg, 117.3mg, 117.4mg, 117.5mg, 117.6mg, 117.7mg, 117.8mg, 117.9mg, 118mg, 118.1mg, 118.2mg, 118.3mg, 118.4mg, 118 .5mg, 118.6mg, 118.7mg, 118.8mg, 118.9mg, 119mg, 119.1mg, 119.2mg, 119.3mg, 119.4mg, 119 .5mg, 119.6mg, 119.7mg, 119.8mg, 119.9mg, 120mg, 120.1mg, 120.2mg, 120.3mg, 120.4mg, 12 0.5mg, 120.6mg, 120.7mg, 120.8mg, 120.9mg, 121mg, 121.1mg, 121.2mg, 121.3mg, 121.4mg, 12 1.5mg, 121.6mg, 121.7mg, 121.8mg, 121.9mg, 122mg, 122.1mg, 122.2mg, 122.3mg, 122.4mg, 1 22.5mg, 122.6mg, 122.7mg, 122.8mg, 122.9mg, 123mg, 123.1mg, 123.2mg, 123.3mg, 123.4mg, 1 21. The method of any one of embodiments 1 to 20, wherein the amount of the active ingredient is any one of 23.5 mg, 123.6 mg, 123.7 mg, 123.8 mg, 123.9 mg, 124 mg, 124.1 mg, 124.2 mg, 124.3 mg, 124.4 mg, 124.5 mg, 124.6 mg, 124.7 mg, 124.8 mg, 124.9 mg, and 125 mg.

[0081] Embodiment 38. The therapeutically effective amount is about 105 mg, about 105.1 mg, about 105.2 mg, about 105.3 mg, about 105.4 mg, about 105.5 mg, about 105.6 mg, about 105.7 mg, about 105.8 mg, about 105.9 mg, about 106 mg, about 106.1 mg, about 106.2 mg, about 106.3 mg, about 106.4 mg, about 106.5 mg, about 106.6 mg, about 106.7 mg, about 106.8 mg, about 106.9 mg, about 107 mg, about 107.1 mg, about 107.2 mg, about 107.3 mg, about 107.4 mg, about 107.5 mg, about 107.6 mg, about 107.7mg, about 107.8mg, about 107.9mg, about 108mg, about 108.1mg, about 108.2mg, about 108.3mg, about 108.4mg, about 108.5mg, about 108.6mg, about 108.7mg, about 108.8mg, about 108.9mg, about 109mg, about 109.1mg, about 109.2mg, about 109.3mg, about 109.4mg, about 109.5mg, about 109.6mg, about 109.7mg, about 109.8mg, about 109.9mg, about 110mg, about 110.1mg, about 110.2mg, about 110.3mg, about 110.4mg, about 1 10.5mg, about 110.6mg, about 110.7mg, about 110.8mg, about 110.9mg, about 111mg, about 111.1mg, about 111.2mg, about 111.3mg, about 111.4mg, about 111.5mg, about 111.6mg, about 111.7mg, about 111.8mg, about 111.9mg, about 112mg, about 112.1mg, about 112.2mg, about 112.3mg, about 112.4mg, about 112.5mg, about 112.6mg, about 112.7mg, about 112.8mg, about 112.9mg, about 113mg, about 113.1mg, about 113.2mg, about 11 3.3mg, about 113.4mg, about 113.5mg, about 113.6mg, about 113.7mg, about 113.8mg, about 113.9mg, about 114mg, about 114.1mg, about 114.2mg, about 114.3mg, about 114.4mg, about 114.5mg, about 114.6mg, about 114.7mg, about 114.8mg, about 114.9mg, about 115mg, about 115.1mg, about 115.2mg, about 115.3mg, about 115.4mg, about 115.5mg, about 115.6mg, about 115.7mg, about 115.8mg, about 115.9mg, about 116mg, about 116.1mg, about 116.2mg, about 116.3mg, about 116.4mg, about 116.5mg, about 116.6mg, about 116.7mg, about 116.8mg, about 116.9mg, about 117mg, about 117.1mg, about 117.2mg, about 117.3mg, about 117.4mg, about 117.5mg, about 117.6mg, about 117.7mg, about 117.8mg, about 117.9mg, about 118mg, about 118.1mg, about 118.2mg, about 118.3mg, about 118.4m g, about 118.5mg, about 118.6mg, about 118.7mg, about 118.8mg, about 118.9mg, about 119mg, about 119.1mg, about 119.2mg, about 119.3mg, about 119.4mg, about 119.5mg, about 11 9.6mg, about 119.7mg, about 119.8mg, about 119.9mg, about 120mg, about 120.1mg, about 120.2mg, about 120.3mg, about 120.4mg, about 120.5mg, about 120.6mg, about 120.7mg, about 120.8mg, about 120.9mg, about 121mg, about 121.1mg, about 121.2mg, about 121.3mg, about 121.4mg, about 121.5mg, about 121.6mg, about 121.7mg, about 121.8mg, about 121.9mg, about 122mg, about 122.1mg, about 122.2mg, about 122.3mg, about 122.4mg, about 122.5mg, about 122.6mg, about 122.7mg, about 122.8mg, about 122.9mg, about 123mg, about 123 21. The method of any one of embodiments 1-20, wherein the amount of the active ingredient is any one of about 123.1 mg, about 123.2 mg, about 123.3 mg, about 123.4 mg, about 123.5 mg, about 123.6 mg, about 123.7 mg, about 123.8 mg, about 123.9 mg, about 124 mg, about 124.1 mg, about 124.2 mg, about 124.3 mg, about 124.4 mg, about 124.5 mg, about 124.6 mg, about 124.7 mg, about 124.8 mg, about 124.9 mg, and about 125 mg.

[0082] Embodiment 39. The therapeutically effective amount is 40 mg to 200 mg, 40 mg to 190 mg, 40 mg to 180 mg, 40 mg to 170 mg, 40 mg to 160 mg, 40 mg to 150 mg, 40 mg to 140 mg, 40 mg to 120 mg, 40 mg to 110 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 70 mg, 40 mg to 60 mg, 40 mg to 50 mg, 50 mg to 200 mg, 50 mg to 190 mg, 50 mg to 180 mg, 50 mg to 170 mg, 50 mg to 160 mg, 50 mg to 150 mg, 50 mg to 140 mg, 50 mg to 120 mg. g, 50mg~110mg, 50mg~100mg, 50mg~80mg, 50mg~70mg, 50mg~60mg, 60mg~200mg, 60mg~190mg, 60mg~180mg, 60mg~170mg, 60mg~160mg, 60mg~150mg, 60m g~140mg, 60mg~120mg, 60mg~110mg, 60mg~100mg, 60mg~80mg, 60mg~70mg, 70mg~200mg, 70mg~190mg, 70mg~180mg, 70mg~170mg, 70mg~160mg, 70mg~15 0mg, 70mg~140mg, 70mg~120mg, 70mg~110mg, 70mg~100mg, 70mg~80mg, 80mg~200mg, 80mg~190mg, 80mg~180mg, 80mg~170mg, 80mg~160mg, 80mg~150mg , 80mg~140mg, 80mg~120mg, 80mg~110mg, 80mg~100mg, 80mg~90mg, 90mg~200mg, 90mg~190mg, 90mg~180mg, 90mg~170mg, 90mg~160mg, 90mg~150mg, 90 mg~140mg, 90mg~120mg, 90mg~110mg, 90mg~100mg, 100mg~200mg, 100mg~190mg, 100mg~180mg, 100mg~170mg, 100mg~160mg, 100mg~150mg, 100mg~140 mg, 100mg~120mg, 100mg~110mg, 110mg~200mg, 110mg~190mg, 110mg~180mg, 110mg~170mg, 110mg~160mg, 110mg~150mg, 110mg~140mg, 110mg~130mg,110mg~120mg、120mg~200mg、120mg~190mg、120mg~180mg、120mg~170mg、120mg~160mg、120mg~150mg、120mg~140mg、120mg~130mg、130mg~200mg、130mg~190mg、130mg~180mg、130mg~170mg、130mg~160mg、130mg~150mg、130mg~140mg、140mg~200mg、140mg~190mg、140mg~180mg、140mg~170mg、140mg~160mg、140mg~150mg、150mg~200mg、150mg~190mg、150mg~180mg、150mg~170mg、150mg~160mg、160mg~200mg、160mg~190mg、160mg~180mg、160mg~170mg、180mg~200mg、180mg~190mg、190mg~200mg、105mg~135mg、105mg~130mg、105mg~125mg、105mg~120mg、110mg~135mg、110mg~130mg、110mg~125mg、110mg~120mg、115mg~135mg、115mg~130mg、115mg~125mg、115mg~120mg、115mg~125mg、115mg~120mg、120mg~135mg、120mg~125mg、125mg~140mg、125mg~130mg、130mg~135mg、135mg~140mg、120mg~129mg、120mg~128mg、120mg~127mg、120mg~86mg、120mg~124mg、120mg~123mg、120mg~122mg、120mg~121mg、121mg~130mg、122mg~129mg、122mg~128mg、122mg~127mg、122mg~126mg、122mg~125mg、122mg~124mg、122mg~123mg、123mg~130mg、123mg~129mg、123mg~128mg、123mg~127mg、123mg~126mg、123mg~125mg、123mg~124mg、124mg~130mg、124mg~129mg、124mg~128mg、124mg~127mg、124mg~126mg、124mg~125mg、The method according to any one of embodiments 1 to 20, wherein the amount of the glycerol in the glycerol is within any one of the following ranges: 125 mg to 129 mg, 125 mg to 128 mg, 125 mg to 127 mg, 125 mg to 126 mg, 126 mg to 130 mg, 126 mg to 129 mg, 126 mg to 128 mg, 126 mg to 127 mg, 127 mg to 130 mg, 127 mg to 129 mg, 127 mg to 128 mg, 128 mg to 130 mg, 128 mg to 129 mg, and 129 mg to 130 mg.

[0083] Embodiment 40. The therapeutically effective amount is less than 350 mg, less than 345 mg, less than 340 mg, less than 335 mg, less than 330 mg, less than 325 mg, less than 320 mg, less than 315 mg, less than 310 mg, less than 305 mg, less than 300 mg, less than 295 mg, less than 290 mg, less than 285 mg, less than 280 mg, less than 275 mg, less than 270 mg, less than 265 mg, less than 260 mg, less than 255 mg, less than 250 mg, less than 245 mg, less than 240 mg, less than 235 mg, less than 230 mg, less than 225 mg, less than 220 mg, less than 215 mg, less than 210 mg, less than 205 mg, less than 200 mg, less than 195 mg, less than 190 mg, less than 185 mg, less than 180 mg 21. The method of any one of embodiments 1-20, wherein the amount of the active ingredient is any one of less than, 175 mg, less than 170 mg, less than 165 mg, less than 160 mg, less than 150 mg, less than 145 mg, less than 140 mg, less than 135 mg, less than 130 mg, less than 125 mg, less than 120 mg, less than 115 mg, less than 110 mg, less than 105 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, less than 10 mg, and less than 5 mg.

[0084] Embodiment 41. The therapeutically effective amount is less than about 350 mg, less than about 345 mg, less than about 340 mg, less than about 335 mg, less than about 330 mg, less than about 325 mg, less than about 320 mg, less than about 315 mg, less than about 310 mg, less than about 305 mg, less than about 300 mg, less than about 295 mg, less than about 290 mg, less than about 285 mg, less than about 280 mg, less than about 275 mg, less than about 270 mg. less than about 265 mg, less than about 260 mg, less than about 255 mg, less than about 250 mg, less than about 245 mg, less than about 240 mg, less than about 235 mg, less than about 230 mg, less than about 225 mg, less than about 220 mg, less than about 215 mg, less than about 210 mg, less than about 205 mg, less than about 200 mg, less than about 195 mg, less than about 190 mg, less than about 185 mg, less than about 180 mg 21. The method of any one of embodiments 1-20, wherein the amount of the active ingredient is any one of less than about 175 mg, less than about 170 mg, less than about 165 mg, less than about 160 mg, less than about 150 mg, less than about 145 mg, less than about 140 mg, less than about 135 mg, less than about 130 mg, less than about 125 mg, less than about 120 mg, less than about 115 mg, less than about 110 mg, less than about 105 mg, less than about 100 mg, less than about 95 mg, less than about 90 mg, less than about 85 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, and less than about 5 mg.

[0085] Embodiment 42. The method of any one of embodiments 1-20, wherein the therapeutically effective amount is at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least about 100 mg, at least 105 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185, at least 190 mg, at least 195 mg, and at least 200 mg.

[0086] Embodiment 43. The therapeutically effective amount is at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 105 mg, at least about 21. The method of any one of embodiments 1-20, wherein the amount of the sucrose hydrate is at least about 115 mg, at least about 120 mg, at least about 125 mg, at least about 130 mg, at least about 135 mg, at least about 140 mg, at least about 145 mg, or at least about 150 mg, at least about 155 mg, at least about 160 mg, at least about 165 mg, at least about 170 mg, at least about 175 mg, at least about 180 mg, at least about 185 mg, at least about 190 mg, at least about 195 mg, and at least about 200 mg.

[0087] Embodiment 44. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every four weeks.

[0088] Embodiment 45. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every 8 weeks.

[0089] Embodiment 46 The method of any one of embodiments 1 to 43, comprising administering the modified oligonucleotide once every 12 weeks.

[0090] Embodiment 47. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every 16 weeks.

[0091] Embodiment 48. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every 20 weeks.

[0092] Embodiment 49. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every 24 weeks.

[0093] Embodiment 50. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every six months.

[0094] Embodiment 51. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every four weeks.

[0095] Embodiment 52. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every 8 weeks.

[0096] Embodiment 53 The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every 12 weeks.

[0097] Embodiment 54. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every 16 weeks.

[0098] Embodiment 55. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every 20 weeks.

[0099] Embodiment 56 The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every 24 weeks.

[0100] Embodiment 57. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide about once every six months.

[0101] Embodiment 58. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once a month.

[0102] Embodiment 59. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every two months.

[0103] Embodiment 60. The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every three months.

[0104] Embodiment 61 The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide quarterly.

[0105] Embodiment 62 The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide semi-annually.

[0106] Embodiment 63 The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once a year.

[0107] Embodiment 64 The method of any one of embodiments 1-43, comprising administering the modified oligonucleotide once every two years.

[0108] Embodiment 65. The modified oligonucleotide is administered once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks, 44. The method of any of embodiments 1-43, comprising administering the therapeutic agent once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, or once every year.

[0109] Embodiment 66. The modified oligonucleotide is administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, about once every 16 weeks, about once every 17 weeks, about once every 18 weeks, about once every 19 weeks, about 44. The method of any of embodiments 1-43, comprising administering any of the following: once every 21 weeks, once about every 22 weeks, once about every 23 weeks, once about every 24 weeks, about once every month, once about every 2 months, once about every 3 months, once about every 4 months, once about every 5 months, and about once every 6 months, once about every 7 months, once about every 8 months, once about every 9 months, once about every 10 months, once about every 11 months, or about once every year.

[0110] Embodiment 67. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 10 mg of the modified oligonucleotide once every four weeks.

[0111] Embodiment 68. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 30 mg of the modified oligonucleotide once every four weeks.

[0112] Embodiment 69. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 60 mg of the modified oligonucleotide once every four weeks.

[0113] Embodiment 70. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every 12 weeks.

[0114] Embodiment 71 The method of any one of embodiments 67-70, wherein four doses of the modified oligonucleotide are administered.

[0115] Embodiment 72 The method of any one of embodiments 71, wherein two doses of the modified oligonucleotide are administered.

[0116] Embodiment 73. The method of any one of embodiments 1-43, comprising administering to the human subject a 10 mg dose of the modified oligonucleotide once every four weeks for a total of four doses, followed by administration of a 60 mg dose of the modified oligonucleotide once every 12 weeks.

[0117] Embodiment 74. The method of any one of embodiments 1-43, comprising administering to the human subject a 30 mg dose of the modified oligonucleotide once every four weeks for a total of four doses, followed by administration of a 60 mg dose of the modified oligonucleotide once every 12 weeks.

[0118] Embodiment 75. The method of any one of embodiments 1-43, comprising administering to the human subject a 60 mg dose of the modified oligonucleotide once every four weeks for a total of four doses, followed by administration of a 60 mg dose of the modified oligonucleotide once every 12 weeks.

[0119] Embodiment 76 The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every 12 weeks.

[0120] Embodiment 77. The method of any of embodiments 1-43, comprising administering to the human subject a 60 mg dose of the modified oligonucleotide once every three months, once every six months, or twice a year, once a quarter, or four times a year.

[0121] Embodiment 78. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every three months, once every quarter, or four times a year.

[0122] Embodiment 79. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every six months or twice a year.

[0123] Embodiment 80. The method of any one of embodiments 1-43, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every 12 weeks, once every three months, or once quarterly.

[0124] Embodiment 81. The method of any of embodiments 1-43, wherein the human subject has progressive supranuclear palsy (PSP), and the method comprises administering to the subject a first dosing regimen comprising administering a 115 mg dose of the modified oligonucleotide once every 12 weeks, once every 3 months, once every quarter, or four times a year.

[0125] Embodiment 82. The dosing regimen is monitored for safety, the administration of the first dosing regimen is discontinued, and the subject is then administered a second dosing regimen, a) a dose of 60 mg of the modified oligonucleotide every 8 weeks or every 2 months; b) a dose of 90 mg of the modified oligonucleotide every 12 weeks, every 3 months, or once quarterly; or 82. The method of embodiment 81, further comprising: c) administering said second dosing regimen comprising administering a dose of 60 mg of said modified oligonucleotide every 4 weeks or every month.

[0126] Embodiment 83. The method of any of embodiments 67-82, wherein 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 doses are administered.

[0127] Embodiment 84 The method of any one of embodiments 1-43, comprising administering to the human subject an initial loading dose of 10 mg of the modified oligonucleotide.

[0128] Embodiment 85. The method of embodiment 84, comprising administering to the human subject a second loading dose of 10 mg of the modified oligonucleotide 4 weeks after the initial loading dose.

[0129] Embodiment 86 The method of embodiment 85, comprising administering to the human subject a maintenance dose of 10 mg of the modified oligonucleotide 4 weeks after the second loading dose.

[0130] Embodiment 87. The method of embodiment 85, comprising administering to the human subject a maintenance dose of 10 mg of the modified oligonucleotide 8 weeks after the second loading dose.

[0131] Embodiment 88. The method of embodiment 85, comprising administering to the human subject a maintenance dose of 10 mg of the modified oligonucleotide 12 weeks after the second loading dose.

[0132] Embodiment 89. The method of embodiment 85, comprising administering to the human subject a maintenance dose of 10 mg of the modified oligonucleotide 16 weeks after the second loading dose.

[0133] Embodiment 90. The method of embodiment 85, comprising administering to the human subject a maintenance dose of 10 mg of the modified oligonucleotide 24 weeks after the second loading dose.

[0134] Embodiment 91. The method of embodiment 85, comprising administering to the human subject a maintenance dose of 10 mg of the modified oligonucleotide 6 months after the second loading dose.

[0135] Embodiment 92 The method of any one of embodiments 1-43, comprising administering to the human subject an initial loading dose of 30 mg of the modified oligonucleotide.

[0136] Embodiment 93 The method of embodiment 92, comprising administering to the human subject a second loading dose of 30 mg of the modified oligonucleotide 4 weeks after the initial loading dose.

[0137] Embodiment 94. The method of embodiment 93, comprising administering to the human subject a maintenance dose of 30 mg of the modified oligonucleotide 4 weeks after the second loading dose.

[0138] Embodiment 95. The method of embodiment 93, comprising administering to the human subject a maintenance dose of 30 mg of the modified oligonucleotide 8 weeks after the second loading dose.

[0139] Embodiment 96 The method of embodiment 93, comprising administering to the human subject a maintenance dose of 30 mg of the modified oligonucleotide 12 weeks after the second loading dose.

[0140] Embodiment 97. The method of embodiment 93, comprising administering to the human subject a maintenance dose of 30 mg of the modified oligonucleotide 16 weeks after the second loading dose.

[0141] Embodiment 98. The method of embodiment 93, comprising administering to the human subject a maintenance dose of 30 mg of the modified oligonucleotide 24 weeks after the second loading dose.

[0142] Embodiment 99. The method of embodiment 93, comprising administering to the human subject a maintenance dose of 30 mg of the modified oligonucleotide 6 months after the second loading dose.

[0143] Embodiment 100. The method of any one of embodiments 1-43, comprising administering to the human subject an initial loading dose of 60 mg of the modified oligonucleotide.

[0144] Embodiment 101. The method of embodiment 100, comprising administering to the human subject a second loading dose of 60 mg of the modified oligonucleotide 4 weeks after the initial loading dose.

[0145] Embodiment 102. The method of embodiment 101, comprising administering to the human subject a maintenance dose of 60 mg of the modified oligonucleotide 4 weeks after the second loading dose.

[0146] Embodiment 103. The method of embodiment 101, comprising administering to the human subject a maintenance dose of 60 mg of the modified oligonucleotide 8 weeks after the second loading dose.

[0147] Embodiment 104. The method of embodiment 101, comprising administering to the human subject a maintenance dose of 60 mg of the modified oligonucleotide 12 weeks after the second loading dose.

[0148] Embodiment 105. The method of embodiment 101, comprising administering to the human subject a maintenance dose of 60 mg of the modified oligonucleotide 16 weeks after the second loading dose.

[0149] Embodiment 106 The method of embodiment 101, comprising administering to the human subject a maintenance dose of 60 mg of the modified oligonucleotide 24 weeks after the second loading dose.

[0150] Embodiment 107. The method of embodiment 101, comprising administering to the human subject a maintenance dose of 60 mg of the modified oligonucleotide 6 months after the second loading dose.

[0151] Embodiment 108. The method of any one of embodiments 1-43, comprising administering to the human subject an initial loading dose of 90 mg of the modified oligonucleotide.

[0152] Embodiment 109. The method of embodiment 108, comprising administering to the human subject a second loading dose of 90 mg of the modified oligonucleotide 4 weeks after the initial loading dose.

[0153] Embodiment 110. The method of embodiment 109, comprising administering to the human subject a maintenance dose of 90 mg of the modified oligonucleotide 4 weeks after the second loading dose.

[0154] Embodiment 111. The method of embodiment 109, comprising administering to the human subject a maintenance dose of 90 mg of the modified oligonucleotide 8 weeks after the second loading dose.

[0155] Embodiment 112. The method of embodiment 109, comprising administering to the human subject a maintenance dose of 90 mg of the modified oligonucleotide 12 weeks after the second loading dose.

[0156] Embodiment 113 The method of embodiment 109, comprising administering to the human subject a maintenance dose of 90 mg of the modified oligonucleotide 16 weeks after the second loading dose.

[0157] Embodiment 114 The method of embodiment 109, comprising administering to the human subject a maintenance dose of 90 mg of the modified oligonucleotide 24 weeks after the second loading dose.

[0158] Embodiment 115. The method of embodiment 109, comprising administering to the human subject a maintenance dose of 90 mg of the modified oligonucleotide 6 months after the second loading dose.

[0159] Embodiment 116 The method of any one of embodiments 1-43, comprising administering to the human subject an initial loading dose of 115 mg of the modified oligonucleotide.

[0160] Embodiment 117. The method of embodiment 116, comprising administering to the human subject a second loading dose of 115 mg of the modified oligonucleotide 12 weeks after the initial loading dose.

[0161] Embodiment 118. The method of embodiment 117, comprising administering to the human subject a maintenance dose of 115 mg of the modified oligonucleotide 12 weeks after the second loading dose.

[0162] Embodiment 119. The method of embodiment 117, comprising administering to the human subject a maintenance dose of 115 mg of the modified oligonucleotide 16 weeks after the second loading dose.

[0163] Embodiment 120. The method of embodiment 117, comprising administering to the human subject a maintenance dose of 115 mg of the modified oligonucleotide 24 weeks after the second loading dose.

[0164] Embodiment 121. The method of embodiment 117, comprising administering to the human subject a maintenance dose of 115 mg of the modified oligonucleotide 6 months after the second loading dose.

[0165] Embodiment 122. The method of any of embodiments 85, 93, 101, 109, or 117, comprising administering to the human subject a maintenance dose of 10 mg, 30 mg, 60 mg, 90 mg, or 115 mg of the modified oligonucleotide 4 weeks after the second loading dose, and every 4 weeks thereafter.

[0166] Embodiment 123. The method of any of embodiments 85, 93, 101, 109, or 117, comprising administering to the human subject a maintenance dose of 10 mg, 30 mg, 60 mg, 90 mg, or 115 mg of the modified oligonucleotide 8 weeks after the second loading dose, and every 4 weeks thereafter.

[0167] Embodiment 124. The method of any of embodiments 85, 93, 101, 109, or 117, comprising administering to the human subject a maintenance dose of 10 mg, 30 mg, 60 mg, 90 mg, or 115 mg of the modified oligonucleotide 12 weeks after the second loading dose, and every 4 weeks thereafter.

[0168] Embodiment 125. The method of any of embodiments 85, 93, 101, 109, or 117, comprising administering to the human subject a maintenance dose of 10 mg, 30 mg, 60 mg, 90 mg, or 115 mg of the modified oligonucleotide 16 weeks after the second loading dose, and every 4 weeks thereafter.

[0169] Embodiment 126. The method of any of embodiments 85, 93, 101, 109, or 117, comprising administering to the human subject a maintenance dose of 10 mg, 30 mg, 60 mg, 90 mg, or 115 mg of the modified oligonucleotide 24 weeks after the second loading dose, and every 4 weeks thereafter.

[0170] Embodiment 127. The method of any of embodiments 85, 93, 101, 109, or 117, comprising administering to the human subject a maintenance dose of 10 mg, 30 mg, 60 mg, 90 mg, or 115 mg of the modified oligonucleotide 6 months after the second loading dose, and every 4 weeks thereafter.

[0171] Embodiment 128. The method of any of embodiments 122-127, wherein at least two, at least three, at least four, at least five, or at least six maintenance doses are administered to the human subject.

[0172] Embodiment 129. A method of ameliorating Alzheimer's disease (e.g., mild Alzheimer's disease, mild Alzheimer's dementia, and / or mild Alzheimer's dementia), reducing tau RNA, or reducing tau protein in a human subject in need thereof, comprising administering to said subject a compound having the following chemical structure: [ka] The method comprises intrathecally administering to the human subject a therapeutically effective amount of a modified oligonucleotide according to (SEQ ID NO: 4), or a salt thereof, of 10 mg, 30 mg, 60 mg, 90 mg, 115 mg, or about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg, or about 60 mg to about 115 mg.

[0173] Embodiment 130. The method of embodiment 129, wherein the modified oligonucleotide is a sodium or potassium salt.

[0174] Embodiment 131. A method of ameliorating Alzheimer's disease (e.g., mild Alzheimer's disease, mild Alzheimer's dementia, and / or mild Alzheimer's dementia), reducing tau RNA, or reducing tau protein in a human subject in need thereof, comprising administering to said subject a compound having the following chemical structure: [ka] The method comprises intrathecally administering to the human subject a therapeutically effective amount of a modified oligonucleotide according to (SEQ ID NO: 4) of 10 mg, 30 mg, 60 mg, 90 mg, 115 mg, or about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg, or about 60 mg to about 115 mg.

[0175] Embodiment 132. A method of ameliorating Alzheimer's disease (e.g., mild Alzheimer's disease, mild Alzheimer's dementia, and / or mild Alzheimer's dementia), reducing tau RNA, or reducing tau protein in a human subject in need thereof, comprising intrathecally administering to the human subject 10 mg, 30 mg, 60 mg, 90 mg, 115 mg, or about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg, or about 60 mg to about 115 mg of a therapeutically effective amount of a modified oligonucleotide, wherein the modified oligonucleotide has the following chemical designation (5' to 3'): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (SEQ ID NO: 4), wherein A = adenine nucleobase, mC = 5-methylcytosine nucleobase, G = guanine nucleobase, T=thymine nucleobase, e=2'-MOE sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, s=phosphorothioate internucleoside linkage, and The method wherein o=phosphodiester internucleoside linkage.

[0176] Embodiment 133 The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every four weeks.

[0177] Embodiment 134. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every 8 weeks.

[0178] Embodiment 135. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every 12 weeks.

[0179] Embodiment 136 The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every 16 weeks.

[0180] Embodiment 137. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every 24 weeks.

[0181] Embodiment 138. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every six months.

[0182] Embodiment 139. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide about once every six months.

[0183] Embodiment 140. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide once a month.

[0184] Embodiment 141. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide once every two months.

[0185] Embodiment 142. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide once every three months.

[0186] Embodiment 143 The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide quarterly.

[0187] Embodiment 144. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide semi-annually.

[0188] Embodiment 145. The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide once a year.

[0189] Embodiment 146 The method of any one of embodiments 129-133, comprising administering the modified oligonucleotide once every two years.

[0190] Embodiment 147. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 10 mg of the modified oligonucleotide once every four weeks.

[0191] Embodiment 148. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 30 mg of the modified oligonucleotide once every four weeks.

[0192] Embodiment 149. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 60 mg of the modified oligonucleotide once every four weeks.

[0193] Embodiment 150. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every 12 weeks.

[0194] Embodiment 151 The method of any one of embodiments 147-150, wherein four doses of the modified oligonucleotide are administered.

[0195] Embodiment 152 The method of embodiment 151, wherein two doses of the modified oligonucleotide are administered.

[0196] Embodiment 153. The method of any of embodiments 129-133, comprising administering to the human subject a 10 mg dose of the modified oligonucleotide once every 4 weeks for a total of four doses, followed by administration of a 60 mg dose of the modified oligonucleotide once every 12 weeks.

[0197] Embodiment 154. The method of any of embodiments 129-133, comprising administering to the human subject a 30 mg dose of the modified oligonucleotide once every 4 weeks for a total of four doses, followed by administration of a 60 mg dose of the modified oligonucleotide once every 12 weeks.

[0198] Embodiment 155. The method of any of embodiments 129-133, comprising administering to the human subject a 60 mg dose of the modified oligonucleotide once every 4 weeks for a total of four doses, followed by administration of a 60 mg dose of the modified oligonucleotide once every 12 weeks.

[0199] Embodiment 156 The method of any of embodiments 129-133, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every 12 weeks.

[0200] Embodiment 157. The method of any of embodiments 129-133, comprising administering to the human subject a 60 mg dose of the modified oligonucleotide once every three months, once every quarter, or four times a year.

[0201] Embodiment 158. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every three months, once every quarter, or four times a year.

[0202] Embodiment 159. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every six months or twice a year.

[0203] Embodiment 160. The method of any of embodiments 129-133, comprising administering to the human subject a dose of 115 mg of the modified oligonucleotide once every 12 weeks, once every 3 months, or once quarterly.

[0204] Embodiment 161. The method of any of embodiments 129-133, wherein the human subject has progressive supranuclear palsy (PSP), and the method comprises administering to the subject a first dosing regimen comprising administering a 115 mg dose of the modified oligonucleotide once every 12 weeks, once every 3 months, once every quarter, or four times a year.

[0205] Embodiment 162. The safety of the dosing regimen is monitored, the administration of the first dosing regimen is discontinued, and the subject is then administered a second dosing regimen, a) a dose of 60 mg of the modified oligonucleotide every 8 weeks or every 2 months; b) a dose of 90 mg of the modified oligonucleotide every 12 weeks, every 3 months, or once quarterly; or c) administering said second dosing regimen comprising administering a dose of 60 mg of said modified oligonucleotide every 4 weeks or every month.

[0206] Embodiment 163. The method of any of embodiments 153-162, wherein 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 doses are administered.

[0207] Embodiment 164. The human subject is administered a) an initial loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide; b) a second loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide about 4 weeks, about 8 weeks, or about 12 weeks after administration of the initial loading dose; c) about 8 weeks or about 12 weeks after administration of the second loading dose, a first maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide; d) administering a second maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide about 8 weeks or about 12 weeks after the first maintenance dose.

[0208] Embodiment 165. The human subject is administered a) an initial loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide; b) a second loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide about 4 weeks, about 8 weeks, or about 12 weeks after administration of the initial loading dose; c) about 12 weeks after administration of the second loading dose, a first maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide; d) about 12 weeks after the first maintenance dose, administering a second maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of the modified oligonucleotide.

[0209] Embodiment 166. The method of any of embodiments 129-165, wherein the subject has AD (e.g., mild Alzheimer's disease, mild dementia due to Alzheimer's disease, and / or mild Alzheimer's dementia), FTD, or PSP, and at least one symptom or feature of AD, FTD, or PSP is ameliorated.

[0210] Embodiment 167. The method of embodiment 166, wherein the at least one symptom or characteristic comprises memory loss, decline in cognitive function, loss of ability to understand or speak, abnormal behavior, impaired motor function, loss of cognitive function, neuropsychiatric behavioral dysfunction, general dysfunction, loss of motor function, impaired cognitive function, impaired neuropsychiatric dysfunction, impairment in daily living function, impaired attention, impaired visual-perceptual processing, impaired memory, impaired independence, increased apathy, impaired learning ability, impaired concentration, impaired understanding and speech, impaired behavior, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, convulsions, suicidal thoughts, suicidal behavior, or an increase in the number and / or volume of neurofibrillary inclusions.

[0211] Embodiment 168. The method of any one of embodiments 1 to 167, wherein the human subject has a mutation in at least one gene selected from MAPT, APOE, APP, PSEN1, PSEN2, LRRK2, STX6, EIF2AK3, and MOBP.

[0212] Embodiment 169. The method of any one of embodiments 1 to 167, further comprising identifying a mutation in at least one gene selected from MAPT, APOE, APP, PSEN1, and PSEN2 in the human subject.

[0213] Embodiment 170 The method of any one of embodiments 1-169, wherein the modified oligonucleotide is administered to the CNS of the human subject.

[0214] Embodiment 171. The method of any one of embodiments 1-170, wherein the modified oligonucleotide is administered by intrathecal administration.

[0215] Embodiment 172 The method of any one of embodiments 1-170, wherein the modified oligonucleotide is administered by intrathecal bolus injection.

[0216] Embodiment 173. The method of any one of embodiments 1 to 172, wherein tau RNA is reduced.

[0217] Embodiment 174. The method of any one of embodiments 1 to 173, wherein tau protein is reduced.

[0218] Embodiment 175. The method of any one of embodiments 1 to 174, comprising detecting the amount of tau RNA in a biological sample from the human subject.

[0219] Embodiment 176 The method of any one of embodiments 1 to 175, comprising detecting the amount of tau protein in a biological sample from the human subject.

[0220] Embodiment 177 The method of embodiment 175 or embodiment 176, wherein the biological sample comprises cerebrospinal fluid.

[0221] Embodiment 178. The method of any one of embodiments 175 to 177, wherein the detection occurs prior to the administration.

[0222] Embodiment 179. The method of any one of embodiments 175 to 177, wherein the detecting is performed after the administering.

[0223] Embodiment 180. The method of any one of embodiments 175 to 177, wherein the detection is performed before or after the administration.

[0224] Embodiment 181. The method of any one of embodiments 175-180, comprising adjusting the loading dose, the loading dose, the maintenance dose, or the therapeutically effective amount administered following detection of the amount of tau RNA, tau protein, or a combination thereof.

[0225] Embodiment 182. The method of any of embodiments 1 to 181, comprising analyzing the subject's brain activity, brain size, neurofibrillary inclusion size, neurofibrillary inclusion volume, amount or concentration of total tau protein, phosphorylated tau protein, or amyloid beta protein in cerebrospinal fluid, or a combination thereof, by performing magnetic resonance imaging (MRI), positron emission tomography (PET), electroencephalogram (EEG), or CSF analysis.

[0226] Embodiment 183. The method of embodiment 182, wherein the performing of the MRI, PET, EEG, or CSF analysis is performed before administration, after administration, or a combination thereof.

[0227] Embodiment 184 The method of embodiment 183, comprising determining or adjusting the therapeutically effective amount after performing the MRI, PET, EEG, or CSF analysis.

[0228] Embodiment 185. The method of embodiment 184, comprising performing the MRI, PET, EEG, or CSF analysis after administration, and adjusting the frequency of administration after performing the MRI, PET, EEG, or CSF analysis.

[0229] Embodiment 186. The method of any of embodiments 182 to 185, wherein the MRI, PET, EEG, or CSF analysis is performed within 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours of administration.

[0230] Embodiment 187. The method of embodiment 186, comprising administering a loading dose about once every 4 weeks and a maintenance dose about once every 8 or 16 weeks before performing an initial MRI, PET, EEG, or CSF analysis, and administering said maintenance dose less than every 8 weeks or less than every 16 weeks.

[0231] I.MAPT In certain embodiments, methods are described herein for reducing tau RNA and / or tau protein in cells or biological fluids of a subject. Tau RNA is encoded by the human MAPT gene, located at human 17 (17q21.31). Tau protein is the protein expression product of tau RNA. Tau protein is highly expressed in neurons compared to other cell types. A representative nucleobase sequence of the human MAPT gene is provided in GENBANK Accession No. NT_010783.14, a truncated version from nucleotides 2624000 to 2761000, which is incorporated herein as SEQ ID NO:2. A representative nucleobase sequence of human tau RNA is provided in GENBANK Accession No. NM_001377265., which is incorporated herein as SEQ ID NO:1. A representative protein sequence of human tau protein is provided in GENBANK Accession No. NP_001364194.1, which is incorporated herein as SEQ ID NO:3.

[0232] II.ISIS814907 In certain embodiments, the modified oligonucleotide ISIS814907 (MAPT RxDescribed herein are methods for administering ISIS 814907 to a subject in need thereof. In certain embodiments, ISIS 814907 is characterized as a 5-8-5 MOE gapmer having the sequence (5' to 3') CCGTTTTCTTACCACCCT (incorporated herein as SEQ ID NO: 4), where each of nucleosides 1 to 5 and 14 to 18 is a 2'-MOE nucleoside, each of nucleosides 6 to 13 is a 2'-deoxynucleoside, the internucleoside linkages between nucleoside 2 and nucleoside 3 and from nucleoside 15 to nucleoside 16 are phosphodiester internucleoside linkages, the remaining internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methylcytosine.

[0233] In certain embodiments, ISIS 814907 is characterized by the following chemical designation: mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (SEQ ID NO: 4), wherein: A=adenine, mC=5-methylcytosine, G=guanine, T=thymine; e = 2'-MOE nucleoside, d=2'-deoxynucleoside, s=phosphorothioate internucleoside linkage, and o = phosphodiester internucleoside linkage.

[0234] In certain embodiments, ISIS 814907 has the following chemical structure: [ka] It is characterized by:

[0235] In certain embodiments, the sodium salt of ISIS 814907 has the following chemical structure: [ka] It is represented by:

[0236] III. Certain Pharmaceutical Compositions In certain embodiments, a method for administering a pharmaceutical composition comprising modified oligonucleotide ISIS814907 to a subject is described herein. In certain embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition comprises or consists essentially of sterile saline and modified oligonucleotide ISIS814907. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, the pharmaceutical composition comprises or consists essentially of sterile water and modified oligonucleotide ISIS814907. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, the pharmaceutical composition comprises or consists essentially of artificial cerebrospinal fluid (aCSF) and modified oligonucleotide ISIS814907. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade. In certain embodiments, the pharmaceutical composition comprises aCSF in which a certain concentration of modified oligonucleotide ISIS814907 is dissolved, and is diluted with an aCSF diluent to achieve the intended clinical dose. In certain embodiments, ISIS814907 is formulated in aCSF at 30 mg / mL and diluted with aCSF diluent to achieve the intended clinical dose. In certain embodiments, ISIS814907 is formulated in aCSF at 20 mg / mL and diluted with aCSF diluent to achieve the intended clinical dose.

[0237] In certain embodiments, the pharmaceutical composition comprises one or more excipients and the modified oligonucleotide ISIS 814907. In certain embodiments, the excipient is selected from water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0238] In certain embodiments, the pharmaceutical composition comprising the modified oligonucleotide ISIS814907 includes any pharma- ceutically acceptable salt of the modified oligonucleotide ISIS814907, an ester of the modified oligonucleotide ISIS814907, or a salt of such an ester. In certain embodiments, the pharmaceutical composition comprising the modified oligonucleotide ISIS814907 can provide (directly or indirectly) a biologically active metabolite or a residue thereof upon administration to a human subject. Thus, for example, the present disclosure also relates to pharma- ceutically acceptable salts of the modified oligonucleotide ISIS814907, prodrugs of the modified oligonucleotide ISIS814907, pharma- ceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharma- ceutically acceptable salts include, but are not limited to, sodium and potassium salts.

[0239] In certain embodiments, the pharmaceutical composition comprises one or more lipid moieties and modified oligonucleotide ISIS 814907. In certain embodiments, lipid moieties are used to enhance the distribution of ISIS 814907 to certain cells or tissues. In certain such methods, modified oligonucleotide ISIS 814907 is introduced into preformed liposomes or lipoplexes made of a mixture of cationic lipids and neutral lipids. In certain methods, DNA complexes with monocationic or polycationic lipids are formed in the absence of neutral lipids.

[0240] In certain embodiments, the pharmaceutical compositions disclosed herein include a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing pharmaceutical compositions, for example pharmaceutical compositions that include hydrophobic compounds. In certain embodiments, certain organic solvents, such as dimethylsulfoxide, are used.

[0241] In certain embodiments, the pharmaceutical composition comprises one or more tissue-specific delivery molecules designed to deliver the modified oligonucleotides described herein to a particular tissue or cell type. For example, in certain embodiments, the pharmaceutical composition comprises a liposome coated with a tissue-specific antibody.

[0242] In certain embodiments, the pharmaceutical composition includes a co-solvent system. Certain of such co-solvent systems include, for example, benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution in absolute ethanol and includes 3 w / v% benzyl alcohol, 8 w / v% of the non-polar surfactant Polysorbate 80™, and 65 w / v% polyethylene glycol 300. The proportions of such co-solvent systems can be varied widely without significantly changing their solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components can be changed, for example, other surfactants can be used in place of Polysorbate 80™, the fraction size of the polyethylene glycol can be changed, polyethylene glycol can be replaced by other biocompatible polymers, such as polyvinylpyrrolidone, and dextrose can be replaced by other sugars or polysaccharides.

[0243] In certain embodiments, the pharmaceutical composition is prepared for oral administration. In certain embodiments, the pharmaceutical composition is prepared for buccal administration. In certain embodiments, the pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV)). In certain such embodiments, the pharmaceutical composition includes a carrier and is formulated in an aqueous solution, such as aCSF, water, or a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients (e.g., ingredients that aid solubility or act as preservatives) are included. In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents, and the like. Certain injectable pharmaceutical compositions are provided in unit dosage form, e.g., in ampoules or multi-dose containers. Certain injectable pharmaceutical compositions are suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as suspending agents, stabilizing agents, and / or dispersing agents. Certain solvents suitable for use in injectable pharmaceutical compositions include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

[0244] Under certain conditions, the modified oligonucleotide ISIS814907 acts as an acid. ISIS814907 may be depicted or described in a protonated (free acid) form or in an ionized (salt) form associated with a cation, but aqueous solutions of ISIS814907 exist in equilibrium between such forms. For example, the phosphate bond of ISIS814907 in aqueous solution exists in equilibrium between the free acid, anion, and salt forms. Unless otherwise indicated, the term "ISIS814907" is intended to include all such forms. Moreover, ISIS814907 has several such bonds, each of which is in equilibrium. Thus, ISIS814907 exists in solution in a collection of forms at multiple positions, all of which are in equilibrium. The term "ISIS814907" is intended to include all such forms. In the depicted structures, a single form is necessarily depicted. Regardless, unless otherwise indicated, such figures are intended to include the corresponding forms as well. In this specification, when a structure showing the free acid of ISIS814907 is followed by the term "or a salt thereof", all such forms, whether fully or partially protonated / deprotonated / associated with a cation, are expressly included. In certain cases, one or more specific cations are identified.

[0245] In certain embodiments, ISIS 814907 is in an aqueous solution containing sodium. In certain embodiments, ISIS 814907 is in an aqueous solution containing potassium. In certain embodiments, ISIS 814907 is in PBS. In certain embodiments, ISIS 814907 is in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and / or HCl to reach the desired pH.

[0246] Certain specific doses are described herein. For clarity, the dose of ISIS 814907 in milligrams refers to the mass of the free acid form of ISIS 814907. As mentioned above, in aqueous solution, the free acid is in equilibrium between anion form and salt form. However, for the purpose of dose calculation, it is assumed that ISIS 814907 exists as anhydrous free acid without solvent and without sodium acetate. For example, when ISIS 814907 is in a solution containing sodium (e.g., saline), ISIS 814907 may be partially or completely deprotonated and associated with Na+ ions. However, the mass of the protons is still added to the weight of the dose, and the mass of the Na+ ions is not added to the weight of the dose. Thus, for example, a 60 mg dose of ISIS 814907 is equivalent to the number of fully protonated molecules that weigh 60 mg. This is considered to be equivalent to 63.48 mg of solvent-free, sodium acetate-free anhydrous sodiated ISIS 814907. Similarly, a 115 mg dose of ISIS 814907 is equivalent to a fully protonated molecule weighing 115 mg. This is considered to be equivalent to 121.67 mg of solvent-free, sodium acetate-free anhydrous sodiated ISIS 814907.

[0247] IV. Specific Dosages In certain embodiments, the present disclosure provides a method for administering a therapeutically effective amount of modified oligonucleotide ISIS814907 to a subject.In certain embodiments, the therapeutically effective amount is 10mg.In certain embodiments, the therapeutically effective amount is 30mg.In certain embodiments, the therapeutically effective amount is 60mg.In certain embodiments, the therapeutically effective amount is 90mg.In certain embodiments, the therapeutically effective amount is 115mg.

[0248] In certain embodiments, a therapeutically effective amount is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 650 mg, 660 mg, 670 mg 85mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, or 350mg.

[0249] In certain embodiments, a therapeutically effective amount is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg , about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, and about 350 mg.

[0250] In certain embodiments, the therapeutically effective amount is 50 mg, 50.1 mg, 50.2 mg, 50.3 mg, 50.4 mg, 50.5 mg, 50.6 mg, 50.7 mg, 50.8 mg, 50.9 mg, 51 mg, 51.1 mg, 51.2 mg, 51.3 mg, 51.4 mg, 51.5 mg, 51.6 mg, 51.7 mg, 51.8 mg, 51.9 mg, 52 mg, 52.1 mg, 52.2 mg, 52.3 mg, 52.4 mg, 52.5 mg, 52.6 mg, 52.7 mg, 52.8 mg, 52.9 mg, 53 mg, 53.1 mg, 53.2 mg, 53.3 mg, 53.4mg, 53.5mg, 53.6mg, 53.7mg, 53.8mg, 53.9mg, 54mg, 54.1mg, 54.2mg, 54.3mg, 54.4mg, 54.5mg, 54.6mg, 54.7mg, 54.8mg, 54.9mg, 55mg, 55.1mg, 55. 2mg, 55.3mg, 55.4mg, 55.5mg, 55.6mg, 55.7mg, 55.8mg, 55.9mg, 56mg, 56.1mg, 56.2mg, 56.3mg, 56.4mg, 56.5mg, 56.6mg, 56.7mg, 56.8mg, 56.9mg, 57mg , 57.1mg, 57.2mg, 57.3mg, 57.4mg, 57.5mg, 57.6mg, 57.7mg, 57.8mg, 57.9mg, 58mg, 58.1mg, 58.2mg, 58.3mg, 58.4mg, 58.5mg, 58.6mg, 58.7mg, 58.8mg, 58.9mg, 59mg, 59.1mg, 59.2mg, 59.3mg, 59.4mg, 59.5mg, 59.6mg, 59.7mg, 59.8mg, 59.9mg, 60mg, 60.1mg, 60.2mg, 60.3mg, 60.4mg, 60.5mg, 60.6mg, 60. 7mg, 60.8mg, 60.9mg, 61mg, 61.1mg, 61.2mg, 61.3mg, 61.4mg, 61.5mg, 61.6mg, 61.7mg, 61.8mg, 61.9mg, 62mg, 62.1mg, 62.2mg, 62.3mg, 62.4mg, 62.5mg , 62.6mg, 62.7mg, 62.8mg, 62.9mg, 63mg, 63.1mg, 63.2mg, 63.3mg, 63.4mg, 63.5mg, 63.6mg, 63.7mg, 63.8mg, 63.9mg, 64mg, 64.1mg, 64.2mg, 64.3mg, 64.4mg, 64.5mg, 64.6mg, 64.7mg, 64.8mg, 64.9mg, 65mg, 65.1mg, 65.2mg, 65.3mg, 65.4mg, 65.5mg, 65.6mg, 65.7mg, 65.8mg , 65.9mg, 66mg, 66.1mg, 66.2mg, 66.3mg, 66.4mg, 66.5mg, 66.6mg, 66.7mg, 66.8mg, 66.9mg, 67mg, 67.1mg, 67.2mg, 67.3 mg, 67.4 mg, 67.5 mg, 67.6 mg, 67.7 mg, 67.8 mg, 67.9 mg, 68 mg, 68.1 mg, 68.2 mg, 68.3 mg, 68.4 mg, 68.5 mg, 68.6 mg, 68.7 mg, 68.8 mg, 68.9 mg, 69 mg, 69.1 mg, 69.2 mg, 69.3 mg, 69.4 mg, 69.5 mg, 69.6 mg, 69.7 mg, 69.8 mg, 69.9 mg, and 70 mg.

[0251] In certain embodiments, a therapeutically effective amount is about 50 mg, about 50.1 mg, about 50.2 mg, about 50.3 mg, about 50.4 mg, about 50.5 mg, about 50.6 mg, about 50.7 mg, about 50.8 mg, about 50.9 mg, about 51 mg, about 51.1 mg, about 51.2 mg, about 51.3 mg, about 51.4 mg, about 51.5 mg, about 51.6 mg, about 51.7 mg, about 51.8 mg, about 51.9 mg, about 52 mg, about 52.1 mg, about 52.2 mg, about 52.3 mg, about 52.4 mg, about 52.5 mg, about 52.6 mg, about 52.7 mg, about 52.8 mg, about 52.9 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 9 .9mg, about 53mg, about 53.1mg, about 53.2mg, about 53.3mg, about 53.4mg, about 53.5mg, about 53.6mg, about 53.7mg, about 53.8mg, about 53.9mg, about 54mg, about 54.1mg, about 54.2mg, about 54.3mg, about 54.4mg, about 54.5mg, about 54.6mg, about 54.7mg, about 54.8mg, about 54.9mg, about 55mg, about 55.1mg, about 55.2mg, about 55.3mg, about 55.4mg, about 55.5mg, about 55.6mg, about 55.7mg, about 55.8mg, about 55.9mg, about 56mg, about 56.1 mg, approx. 56.2 mg, approx. 56.3 mg, approx. 56.4 mg, approx. 56.5 mg, approx. 56.6 mg, approx. 56.7 mg, approx. 56.8 mg, approx. 56.9 mg, approx. .7mg, about 57.8mg, about 57.9mg, about 58mg, about 58.1mg, about 58.2mg, about 58.3mg, about 58.4mg, about 58.5mg, about 58.6mg, about 58.7mg, about 58.8mg, about 58.9mg, about 59mg, about 59.1mg, about 59.2mg, about 59. 3mg, about 59.4mg, about 59.5mg, about 59.6mg, about 59.7mg, about 59.8mg, about 59.9mg, about 60mg, about 60.1mg, about 60.2mg, about 60.3mg, about 60.4mg, about 60.5mg, about 60.6mg, about 60.7mg, about 60.8mg, about 60.9mg, about 61mg, about 61.1mg, about 61.2mg, about 61.3mg, about 61.4mg, about 61.5mg, about 61.6mg, about 61.7mg, about 61.8mg, about 61.9mg, about 62mg, about 62.1mg, about 62.2mg, about 62.3mg, about 62.4mg, about 62.5mg, about 62.6mg, about 62.7mg, about 62.8mg, about 62.9mg, about 63mg, about 63.1mg, about 63.2mg, about 63.3mg, about 63.4mg, about 63.5mg, about 63.6mg, about 63.7mg, about 63.8mg, about 63.9mg, about 64mg, about 64.1mg, about 64.2mg, about 64.3mg, about 64.4m g, about 64.5 mg, about 64.6 mg, about 64.7 mg, about 64.8 mg, about 64.9 mg, about 65 mg, about 65.1 mg, about 65.2 mg, about 65.3 mg, about 65 .4mg, about 65.5mg, about 65.6mg, about 65.7mg, about 65.8mg, about 65.9mg, about 66mg, about 66.1mg, about 66.2mg, about 66.3mg, About 66.4 mg, about 66.5 mg, about 66.6 mg, about 66.7 mg, about 66.8 mg, about 66.9 mg, about 67 mg, about 67.1 mg, about 67.2 mg, about 67.3 mg, about 67.4 mg, about 67.5 mg, about 67.6 mg, about 67.7 mg, about 67.8 mg, about 67.9 mg, about 68 mg, about 68.1 mg, about 68.2 mg, about 6 8.3 mg, about 68.4 mg, about 68.5 mg, about 68.6 mg, about 68.7 mg, about 68.8 mg, about 68.9 mg, about 69 mg, about 69.1 mg, about 69.2 mg, about 69.3 mg, about 69.4 mg, about 69.5 mg, about 69.6 mg, about 69.7 mg, about 69.8 mg, about 69.9 mg, and about 70 mg.

[0252] In certain embodiments, the therapeutically effective amount is 80 mg, 80.1 mg, 80.2 mg, 80.3 mg, 80.4 mg, 80.5 mg, 80.6 mg, 80.7 mg, 80.8 mg, 80.9 mg, 81 mg, 81.1 mg, 81.2 mg, 81.3 mg, 81.4 mg, 81.5 mg, 81.6 mg, 81.7 mg, 81.8 mg, 81.9 mg, 82 mg, 82.1 mg, 82.2 mg, 82.3 mg, 82.4 mg, 82.5 mg, 82.6 mg, 82.7 mg, 82.8 mg, 82.9 mg, 83 mg, 83.1 mg, 83.2 mg, 83.3 mg, 83.4mg, 83.5mg, 83.6mg, 83.7mg, 83.8mg, 83.9mg, 84mg, 84.1mg, 84.2mg, 84.3mg, 84.4mg, 84.5mg, 84.6mg, 84.7mg, 84.8mg, 84.9mg, 85mg, 85.1mg, 85. 2mg, 85.3mg, 85.4mg, 85.5mg, 85.6mg, 85.7mg, 85.8mg, 85.9mg, 86mg, 86.1mg, 86.2mg, 86.3mg, 86.4mg, 86.5mg, 86.6mg, 86.7mg, 86.8mg, 86.9mg, 87mg , 87.1mg, 87.2mg, 87.3mg, 87.4mg, 87.5mg, 87.6mg, 87.7mg, 87.8mg, 87.9mg, 88mg, 88.1mg, 88.2mg, 88.3mg, 88.4mg, 88.5mg, 88.6mg, 88.7mg, 88.8mg, 88.9mg, 89mg, 89.1mg, 89.2mg, 89.3mg, 89.4mg, 89.5mg, 89.6mg, 89.7mg, 89.8mg, 89.9mg, 90mg, 90.1mg, 90.2mg, 90.3mg, 90.4mg, 90.5mg, 90.6mg, 90. 7mg, 90.8mg, 90.9mg, 91mg, 91.1mg, 91.2mg, 91.3mg, 91.4mg, 91.5mg, 91.6mg, 91.7mg, 91.8mg, 91.9mg, 92mg, 92.1mg, 92.2mg, 92.3mg, 92.4mg, 92.5mg , 92.6mg, 92.7mg, 92.8mg, 92.9mg, 93mg, 93.1mg, 93.2mg, 93.3mg, 93.4mg, 93.5mg, 93.6mg, 93.7mg, 93.8mg, 93.9mg, 94mg, 94.1mg, 94.2mg, 94.3mg, 94.4mg, 94.5mg, 94.6mg, 94.7mg, 94.8mg, 94.9mg, 95mg, 95.1mg, 95.2mg, 95.3mg, 95.4mg, 95.5mg, 95.6mg, 95.7mg, 95.8mg , 95.9mg, 96mg, 96.1mg, 96.2mg, 96.3mg, 96.4mg, 96.5mg, 96.6mg, 96.7mg, 96.8mg, 96.9mg, 97mg, 97.1mg, 97.2mg, 97.3m g, 97.4 mg, 97.5 mg, 97.6 mg, 97.7 mg, 97.8 mg, 97.9 mg, 98 mg, 98.1 mg, 98.2 mg, 98.3 mg, 98.4 mg, 98.5 mg, 98.6 mg, 98.7 mg, 98.8 mg, 98.9 mg, 99 mg, 99.1 mg, 99.2 mg, 99.3 mg, 99.4 mg, 99.5 mg, 99.6 mg, 99.7 mg, 99.8 mg, 99.9 mg, and 100 mg.

[0253] In certain embodiments, a therapeutically effective amount is about 80 mg, about 80.1 mg, about 80.2 mg, about 80.3 mg, about 80.4 mg, about 80.5 mg, about 80.6 mg, about 80.7 mg, about 80.8 mg, about 80.9 mg, about 81 mg, about 81.1 mg, about 81.2 mg, about 81.3 mg, about 81.4 mg, about 81.5 mg, about 81.6 mg, about 81.7 mg, about 81.8 mg, about 81.9 mg, about 82 mg, about 82.1 mg, about 82.2 mg, about 82.3 mg, about 82.4 mg, about 82.5 mg, about 82.6 mg, about 82.7 mg, about 82.8 mg, about 82.9 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 12 .9mg, about 83mg, about 83.1mg, about 83.2mg, about 83.3mg, about 83.4mg, about 83.5mg, about 83.6mg, about 83.7mg, about 83.8mg, about 83.9mg, about 84mg, about 84.1mg, about 84.2mg, about 84.3mg, about 84.4mg, about 84.5mg, about 84.6mg, about 84.7mg, about 84.8mg, about 84.9mg, about 85mg, about 85.1mg, about 85.2mg, about 85.3mg, about 85.4mg, about 85.5mg, about 85.6mg, about 85.7mg, about 85.8mg, about 85.9mg, about 86mg, about 86.1 mg, approx. 86.2 mg, approx. 86.3 mg, approx. 86.4 mg, approx. 86.5 mg, approx. 86.6 mg, approx. 86.7 mg, approx. 86.8 mg, approx. 86.9 mg, approx. 87 mg, approx. 87.1 mg, approx. .7mg, about 87.8mg, about 87.9mg, about 88mg, about 88.1mg, about 88.2mg, about 88.3mg, about 88.4mg, about 88.5mg, about 88.6mg, about 88.7mg, about 88.8mg, about 88.9mg, about 89mg, about 89.1mg, about 89.2mg, about 89. 3mg, about 89.4mg, about 89.5mg, about 89.6mg, about 89.7mg, about 89.8mg, about 89.9mg, about 90mg, about 90.1mg, about 90.2mg, about 90.3mg, about 90.4mg, about 90.5mg, about 90.6mg, about 90.7mg, about 90.8mg, about 90.9mg, about 91mg, about 91.1mg, about 91.2mg, about 91.3mg, about 91.4mg, about 91.5mg, about 91.6mg, about 91.7mg, about 91.8mg, about 91.9mg, about 92mg, about 92.1mg, about 92.2mg, about 92.3mg, about 92.4mg, about 92.5mg, about 92.6mg, about 92.7mg, about 92.8mg, about 92.9mg, about 93mg, about 93.1mg, about 93.2mg, about 93.3mg, about 93.4mg, about 93.5mg, about 93.6mg, about 93.7mg, about 93.8mg, about 93.9mg, about 94mg, about 94.1mg, about 94.2mg, about 94.3mg, about 94.4m g, about 94.5 mg, about 94.6 mg, about 94.7 mg, about 94.8 mg, about 94.9 mg, about 95 mg, about 95.1 mg, about 95.2 mg, about 95.3 mg, about 95 .4mg, about 95.5mg, about 95.6mg, about 95.7mg, about 95.8mg, about 95.9mg, about 96mg, about 96.1mg, about 96.2mg, about 96.3mg, about 96.4mg, about 96.5mg, about 96.6mg, about 96.7mg, about 96.8mg, about 96.9mg, about 97mg, about 97.1mg, about 97.2mg, about 97.3mg, about 97.4mg, about 97.5mg, about 97.6mg, about 97.7mg, about 97.8mg, about 97.9mg, about 98mg, about 98.1mg, about 98.2mg, about 98 0.3 mg, about 98.4 mg, about 98.5 mg, about 98.6 mg, about 98.7 mg, about 98.8 mg, about 98.9 mg, about 99 mg, about 99.1 mg, about 99.2 mg, about 99.3 mg, about 99.4 mg, about 99.5 mg, about 99.6 mg, about 99.7 mg, about 99.8 mg, about 99.9 mg, and about 100 mg.

[0254] In certain embodiments, the therapeutically effective amount is 105 mg, 105.1 mg, 105.2 mg, 105.3 mg, 105.4 mg, 105.5 mg, 105.6 mg, 105.7 mg, 105.8 mg, 105.9 mg, 106 mg, 106.1 mg, 106.2 mg, 106.3 mg, 106.4 mg, 106.5 mg, 106.6 mg, 106.7 mg, 106.8 mg, 106.9 mg, 107 mg, 107.1 mg, 107.2 mg, 107.3 mg, 107.4 mg, 107.5 mg, 107.6 mg, 107.7 mg, 107.8 mg, 107.9 mg, 108 ... .9mg, 108mg, 108.1mg, 108.2mg, 108.3mg, 108.4mg, 108.5mg, 108.6mg, 108.7mg, 108.8mg, 108.9mg, 109mg, 109.1mg, 109.2mg, 109.3mg, 109.4mg, 109. 5mg, 109.6mg, 109.7mg, 109.8mg, 109.9mg, 110mg, 110.1mg, 110.2mg, 110.3mg, 110.4mg, 110.5mg, 110.6mg, 110.7mg, 110.8mg, 110.9mg, 111mg, 111.1 mg, 111.2mg, 111.3mg, 111.4mg, 111.5mg, 111.6mg, 111.7mg, 111.8mg, 111.9mg, 112mg, 112.1mg, 112.2mg, 112.3mg, 112.4mg, 112.5mg, 112.6mg, 112 .7mg, 112.8mg, 112.9mg, 113mg, 113.1mg, 113.2mg, 113.3mg, 113.4mg, 113.5mg, 113.6mg, 113.7mg, 113.8mg, 113.9mg, 114mg, 114.1mg, 114.2mg, 114. 3mg, 114.4mg, 114.5mg, 114.6mg, 114.7mg, 114.8mg, 114.9mg, 115mg, 115.1mg, 115.2mg, 115.3mg, 115.4mg, 115.5mg, 115.6mg, 115.7mg, 115.8mg, 115 .9mg, 116mg, 116.1mg, 116.2mg, 116.3mg, 116.4mg, 116.5mg, 116.6mg, 116.7mg, 116.8mg, 116.9mg, 117mg, 117.1mg, 117.2mg, 117.3mg, 117.4mg, 117.5mg, 117.6mg, 117.7mg, 117.8mg, 117.9mg, 118mg, 118.1mg, 118.2mg, 118.3mg, 118.4mg, 1 18.5mg, 118.6mg, 118.7mg, 118.8mg, 118.9mg, 119mg, 119.1mg, 119.2mg, 119.3mg, 119.4m g, 119.5mg, 119.6mg, 119.7mg, 119.8mg, 119.9mg, 120mg, 120.1mg, 120.2mg, 120.3mg, 120 .4mg, 120.5mg, 120.6mg, 120.7mg, 120.8mg, 120.9mg, 121mg, 121.1mg, 121.2mg, 121.3mg, 121.4mg, 121.5mg, 121.6mg, 121.7mg, 121.8mg, 121.9mg, 122mg, 122.1mg, 122.2mg, 122.3 mg, 122.4mg, 122.5mg, 122.6mg, 122.7mg, 122.8mg, 122.9mg, 123mg, 123.1mg, 123.2mg, 12 3.3mg, 123.4mg, 123.5mg, 123.6mg, 123.7mg, 123.8mg, 123.9mg, 124mg, 124.1mg, 124.2mg, 124.3mg, 124.4mg, 124.5mg, 124.6mg, 124.7mg, 124.8mg, 124.9mg, and 125mg.

[0255] In certain embodiments, a therapeutically effective amount is about 105 mg, about 105.1 mg, about 105.2 mg, about 105.3 mg, about 105.4 mg, about 105.5 mg, about 105.6 mg, about 105.7 mg, about 105.8 mg, about 105.9 mg, about 106 mg, about 106.1 mg, about 106.2 mg, about 106.3 mg, about 106.4 mg, about 106.5 mg, about 106.6 mg, about 106.7 mg, about 106.8 mg, about 106.9 mg, about 107 mg, about 107.1 mg, about 107.2 mg, about 107.3 mg, about 107.4 mg, about 107.5 mg, about 107.6 mg, about 107.7 mg, about 107.8 mg, about 107.9 ...9 mg, about 107.1 mg, about 107.2 mg, about 107.3 mg, about 107.4 mg, about 107.5 mg, about 1 07.6mg, about 107.7mg, about 107.8mg, about 107.9mg, about 108mg, about 108.1mg, about 108.2mg, about 108.3mg, about 108.4mg, about 108.5mg, about 108.6mg, about 108.7mg, about 108.8mg, about 108.9mg, about 109mg, about 109.1mg, about 109.2mg, about 109.3mg, about 109.4mg, about 109.5mg, about 109.6mg, about 109.7mg, about 109.8mg, about 109.9mg, about 110mg, about 110.1mg, about 110.2mg, about 110.3mg, about 110.4 mg, approx. 110.5 mg, approx. 110.6 mg, approx. 110.7 mg, approx. 110.8 mg, approx. 110.9 mg, approx. 111 mg, approx. 111.1 mg, approx. 111.2 mg, approx. 111.3 mg, approx. g, approx. 111.9mg, approx. 112mg, approx. 112.1mg, approx. 112.2mg, approx. 112.3mg, approx. 112.4mg, approx. 112.5mg, approx. 113.3mg, about 113.4mg, about 113.5mg, about 113.6mg, about 113.7mg, about 113.8mg, about 113.9mg, about 114mg, about 114.1mg, about 114.2mg, about 114.3mg, about 114.4mg, about 114.5mg, about 114.6mg, about 114.7mg, about 114.8mg, about 114.9mg, about 115mg, about 115.1mg, about 115.2mg, about 115.3mg, about 115.4mg, about 115.5mg, about 115.6mg, about 115.7mg, about 115.8mg, about 115.9mg, about 116mg, about 116.1mg, about 116.2mg, about 116.3mg, about 116.4mg, about 116.5mg, about 116.6mg, about 116.7mg, about 116.8mg, about 116.9mg, about 117mg, about 117.1mg, about 117.2mg , about 117.3mg, about 117.4mg, about 117.5mg, about 117.6mg, about 117.7mg, about 117.8mg, about 117.9mg, about 118mg, about 118.1mg, about 118.2mg, about 118.3mg, about 1 18.4mg, about 118.5mg, about 118.6mg, about 118.7mg, about 118.8mg, about 118.9mg, about 119mg, about 119.1mg, about 119.2mg, about 119.3mg, about 119.4mg, about 119.5mg, about 119.6mg, about 119.7mg, about 119.8mg, about 119.9mg, about 120mg, about 120.1mg, about 120.2mg, about 120.3mg, about 120.4mg, about 120.5mg, about 120.6mg , about 120.7mg, about 120.8mg, about 120.9mg, about 121mg, about 121.1mg, about 121.2mg, about 121.3mg, about 121.4mg, about 121.5mg, about 121.6mg, about 121.7mg, about 1 21.8mg, about 121.9mg, about 122mg, about 122.1mg, about 122.2mg, about 122.3mg, about 122.4mg, about 122.5mg, about 122.6mg, about 122.7mg, about 122.8mg, about 122. 9 mg, about 123 mg, about 123.1 mg, about 123.2 mg, about 123.3 mg, about 123.4 mg, about 123.5 mg, about 123.6 mg, about 123.7 mg, about 123.8 mg, about 123.9 mg, about 124 mg, about 124.1 mg, about 124.2 mg, about 124.3 mg, about 124.4 mg, about 124.5 mg, about 124.6 mg, about 124.7 mg, about 124.8 mg, about 124.9 mg, and about 125 mg.

[0256] In certain embodiments, the therapeutically effective amount is from 40 mg to 200 mg, 40 mg to 190 mg, 40 mg to 180 mg, 40 mg to 170 mg, 40 mg to 160 mg, 40 mg to 150 mg, 40 mg to 140 mg, 40 mg to 120 mg, 40 mg to 110 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 70 mg, 40 mg to 60 mg, 40 mg to 50 mg, 50 mg to 200 mg, 50 mg to 190 mg, 50 mg to 180 mg, 50 mg to 170 mg, 50 mg to 160 mg, 50 mg to 150 mg, 50 mg to 14 ... 0mg~120mg, 50mg~110mg, 50mg~100mg, 50mg~80mg, 50mg~70mg, 50mg~60mg, 60mg~200mg, 60mg~190mg, 60mg~180mg, 60mg~170mg, 60mg~160mg, 60mg~15 0mg, 60mg~140mg, 60mg~120mg, 60mg~115mg, 60mg~110mg, 60mg~100mg, 60mg~80mg, 60mg~70mg, 70mg~200mg, 70mg~190mg, 70mg~180mg, 70mg~170mg, 7 0mg~160mg, 70mg~150mg, 70mg~140mg, 70mg~120mg, 70mg~110mg, 70mg~100mg, 70mg~80mg, 80mg~200mg, 80mg~190mg, 80mg~180mg, 80mg~170mg, 80mg~ 160mg, 80mg~150mg, 80mg~140mg, 80mg~120mg, 80mg~110mg, 80mg~100mg, 80mg~90mg, 90mg~200mg, 90mg~190mg, 90mg~180mg, 90mg~170mg, 90mg~160m g, 90mg~150mg, 90mg~140mg, 90mg~120mg, 90mg~110mg, 90mg~100mg, 100mg~200mg, 100mg~190mg, 100mg~180mg, 100mg~170mg, 100mg~160mg, 100mg~1 50mg, 100mg~140mg, 100mg~120mg, 100mg~110mg, 110mg~200mg, 110mg~190mg, 110mg~180mg, 110mg~170mg, 110mg~160mg, 110mg~150mg, 110mg~140mg,110mg~130mg、110mg~120mg、120mg~200mg、120mg~190mg、120mg~180mg、120mg~170mg、120mg~160mg、120mg~150mg、120mg~140mg、120mg~130mg、130mg~200mg、130mg~190mg、130mg~180mg、130mg~170mg、130mg~160mg、130mg~150mg、130mg~140mg、140mg~200mg、140mg~190mg、140mg~180mg、140mg~170mg、140mg~160mg、140mg~150mg、150mg~200mg、150mg~190mg、150mg~180mg、150mg~170mg、150mg~160mg、160mg~200mg、160mg~190mg、160mg~180mg、160mg~170mg、180mg~200mg、180mg~190mg、190mg~200mg、105mg~135mg、105mg~130mg、105mg~125mg、105mg~120mg、110mg~135mg、110mg~130mg、110mg~125mg、110mg~120mg、115mg~135mg、115mg~130mg、115mg~125mg、115mg~120mg、115mg~125mg、115mg~120mg、120mg~135mg、120mg~125mg、125mg~140mg、125mg~130mg、130mg~135mg、135mg~140mg、120mg~129mg、120mg~128mg、120mg~127mg、120mg~86mg、120mg~124mg、120mg~123mg、120mg~122mg、120mg~121mg、121mg~130mg、122mg~129mg、122mg~128mg、122mg~127mg、122mg~126mg、122mg~125mg、122mg~124mg、122mg~123mg、123mg~130mg、123mg~129mg、123mg~128mg、123mg~127mg、123mg~126mg、123mg~125mg、123mg~124mg、124mg~130mg、124mg~129mg、124mg~128mg、124mg~127mg、124mg~126mg、It is any one of 124mg to 125mg, 125mg to 129mg, 125mg to 128mg, 125mg to 127mg, 125mg to 126mg, 126mg to 130mg, 126mg to 129mg, 126mg to 128mg, 126mg to 127mg, 127mg to 130mg, 127mg to 129mg, 127mg to 128mg, 128mg to 130mg, 128mg to 129mg, and 129mg to 130mg.

[0257] In certain embodiments, a therapeutically effective amount is less than 350 mg, less than 345 mg, less than 340 mg, less than 335 mg, less than 330 mg, less than 325 mg, less than 320 mg, less than 315 mg, less than 310 mg, less than 305 mg, less than 300 mg, less than 295 mg, less than 290 mg, less than 285 mg, less than 280 mg, less than 275 mg, less than 270 mg, less than 265 mg, less than 260 mg, less than 255 mg, less than 250 mg, less than 245 mg, less than 240 mg, less than 235 mg, less than 230 mg, less than 225 mg, less than 220 mg, less than 215 mg, less than 210 mg, less than 205 mg, less than 200 mg, less than 195 mg, less than 190 mg. less than 185 mg, less than 180 mg, less than 175 mg, less than 170 mg, less than 165 mg, less than 160 mg, less than 150 mg, less than 145 mg, less than 140 mg, less than 135 mg, less than 130 mg, less than 125 mg, less than 120 mg, less than 115 mg, less than 110 mg, less than 105 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, less than 10 mg, and less than 5 mg.

[0258] In certain embodiments, a therapeutically effective amount is less than about 350 mg, less than about 345 mg, less than about 340 mg, less than about 335 mg, less than about 330 mg, less than about 325 mg, less than about 320 mg, less than about 315 mg, less than about 310 mg, less than about 305 mg, less than about 300 mg, less than about 295 mg, less than about 290 mg, less than about 285 mg, less than about 280 mg, less than about 275 mg, less than about 270 mg, less than about 265 mg, less than about 260 mg, less than about 255 mg, less than about 250 mg, less than about 245 mg, less than about 240 mg, less than about 235 mg, less than about 230 mg, less than about 225 mg, less than about 220 mg, less than about 215 mg, less than about 210 mg, less than about 205 mg, less than about 200 mg, less than about 195 mg, less than about 190 mg, less than about 185 mg, less than about 180 mg, less than about 175 mg, less than about 170 mg, less than about 165 mg, less than about 160 mg, less than about 150 mg, less than about 145 mg, less than about 140 mg, less than about 135 mg, less than about 130 mg, less than about 125 mg, less than about 120 mg, less than about 115 mg, less than about 110 mg, less than about 105 mg, less than about 100 mg, less than about 95 mg, less than about 90 mg, less than about 85 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, and less than about 5 mg.

[0259] In certain embodiments, the therapeutically effective amount is any of at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185, at least 190 mg, at least 195 mg, and at least 200 mg.

[0260] In certain embodiments, a therapeutically effective amount is at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 105 mg, at least about 115 mg, at least about 120 mg, at least about 125 mg, at least about 130 mg, at least about 135 mg, at least about 140 mg, at least about 145 mg, or any of at least about 150 mg, at least about 155 mg, at least about 160 mg, at least about 165 mg, at least about 170 mg, at least about 175 mg, at least about 180 mg, at least about 185, at least about 190 mg, at least about 195 mg, and at least about 200 mg.

[0261] V. Specific Dosing Regimens In certain embodiments, the present invention describes a method for administering therapeutically effective amount of modified oligonucleotide ISIS814907 to a subject one or more times.In certain embodiments, the method includes administering therapeutically effective amount at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 times. In certain embodiments, the method comprises administering a therapeutically effective amount once every 4 weeks. In certain embodiments, the method comprises administering a therapeutically effective amount once every 8 weeks. In certain embodiments, the method comprises administering a therapeutically effective amount once every 12 weeks. In certain embodiments, the method comprises administering a therapeutically effective amount once every 16 weeks. In certain embodiments, the method comprises administering a therapeutically effective amount once every 20 weeks. In certain embodiments, the method comprises administering a therapeutically effective amount once every 24 weeks. In certain embodiments, the method comprises administering a therapeutically effective amount once every 6 months. In certain embodiments, the method comprises administering a therapeutically effective amount once monthly. In certain embodiments, the method comprises administering a therapeutically effective amount once every 2 months. In certain embodiments, the method comprises administering a therapeutically effective amount once every 3 months. In certain embodiments, the method comprises administering a therapeutically effective amount once quarterly. In certain embodiments, the method comprises administering a therapeutically effective amount once every biannually. In certain embodiments, the method comprises administering a therapeutically effective amount once annually. In certain embodiments, the methods comprise administering a therapeutically effective amount once every two years.

[0262] In certain embodiments, the method includes administering a therapeutically effective amount about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, about once every twelve weeks, about once every thirteen weeks, about once every fourteen weeks, about once every fifteen weeks, about once every sixteen weeks, about once every seventeen weeks, about once every eighteen weeks, about once every nineteen weeks, about once every twenty weeks, about once every twenty-one weeks, about once every twenty-two weeks, about once every twenty-three weeks, about once every twenty-four weeks, or about once every six months. In certain embodiments, the method includes administering a therapeutically effective amount about once every two months. In certain embodiments, the method includes administering a therapeutically effective amount about once every three months. In certain embodiments, the method includes administering a therapeutically effective amount about once a quarter. In certain embodiments, the method comprises administering a therapeutically effective amount about once every six months. In certain embodiments, the method comprises administering a therapeutically effective amount about once every year. In certain embodiments, the method comprises administering a therapeutically effective amount about once every two years.

[0263] In certain embodiments, the methods include administering a therapeutically effective amount for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

[0264] In certain embodiments, the method comprises administering ISIS814907 at a dose of 10 mg once a month. In certain embodiments, the method comprises administering ISIS814907 at a dose of 30 mg once a month. In certain embodiments, the method comprises administering ISIS814907 at a dose of 60 mg once a month. In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg once a quarter. In some embodiments, the human subject has mild Alzheimer's disease. In some embodiments, the human subject has MCI due to Alzheimer's disease. In some embodiments, the human subject has mild Alzheimer's dementia.

[0265] In certain embodiments, the method comprises administering ISIS814907 at a dose of 10 mg once every 4 weeks. In certain embodiments, the method comprises administering ISIS814907 at a dose of 30 mg once every 4 weeks. In certain embodiments, the method comprises administering ISIS814907 at a dose of 60 mg once every 4 weeks. In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg once every 3 months. In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg four times a year. In some embodiments, the human subject has mild Alzheimer's disease. In some embodiments, the human subject has MCI due to Alzheimer's disease. In some embodiments, the human subject has mild Alzheimer's dementia. In certain embodiments, the method comprises administering ISIS814907 at a dose of 60 mg once every 24 weeks. In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg once every 24 weeks. In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg once every 12 weeks. In some embodiments, the human subject has mild Alzheimer's disease. In some embodiments, the human subject has MCI due to Alzheimer's disease. In some embodiments, the human subject has mild Alzheimer's disease dementia.

[0266] In certain embodiments, the method comprises administering ISIS814907 at a dose of 60 mg twice a year (i.e., twice a year). In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg twice a year (i.e., twice a year). In certain embodiments, the method comprises administering ISIS814907 at a dose of 115 mg once every three months (i.e., four times a year). In some embodiments, the human subject has mild Alzheimer's disease. In some embodiments, the human subject has MCI due to Alzheimer's disease. In some embodiments, the human subject has mild Alzheimer's disease dementia.

[0267] Loading and maintenance doses In certain embodiments, the therapeutically effective amount is administered as a loading dose and / or a maintenance dose. In certain embodiments, the method includes administering a loading dose(s) and then administering a maintenance dose(s). In certain embodiments, the method includes administering a loading dose once about every 4 weeks and then administering a maintenance dose once about every 4 weeks, once about every 8 weeks, once about every 12 weeks, once about every 16 weeks, once about every 20 weeks, once about every 24 weeks, or once about every 6 months. In certain embodiments, the method includes administering a loading dose once about every 4 weeks and then administering a maintenance dose once about every 6 months. In certain embodiments, the method includes administering a loading dose once about every 12 weeks and then administering a maintenance dose once about every 6 months.

[0268] In certain embodiments, the method includes administering at least two loading doses, at least three loading doses, at least four loading doses, at least five loading doses, or at least six loading doses. In certain embodiments, the method includes administering two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen loading doses. In certain embodiments, the method includes administering the loading dose(s) about every week, about every two weeks, about every three weeks, about every four weeks, about every five weeks, about every six weeks, about every seven weeks, about every eight weeks, about every nine weeks, about every ten weeks, about every eleven weeks, or about every twelve weeks. In certain embodiments, the methods include administering an initial loading dose and administering a second loading dose about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks after administration of the initial loading dose.

[0269] In certain embodiments, the method includes administering at least 2 maintenance doses, at least 3 maintenance doses, at least 4 maintenance doses, at least 5 maintenance doses, or at least 6 maintenance doses. In certain embodiments, the method includes administering 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 maintenance doses. In some cases, the method includes administering a maintenance dose(s) about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, about every 13 weeks, about every 14 weeks, about every 15 weeks, about every 16 weeks, about every 17 weeks, about every 18 weeks, about every 19 weeks, about every 20 weeks, about every 21 weeks, about every 22 weeks, about every 23 weeks, about every 24 weeks, or about every 6 months. In certain embodiments, the method comprises administering a first maintenance dose and administering a second maintenance dose about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, or about 6 months after administration of the first maintenance dose.

[0270] In certain embodiments, the method includes administering the first maintenance dose(s) about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks after administration of the final loading dose.

[0271] VI. Efficacy and Effectiveness In certain embodiments, methods are described herein for reducing tau RNA and / or tau protein in cells or biological fluids of a human subject, comprising administering to the subject a therapeutically effective amount of ISIS 814907. In certain embodiments, the method reduces tau RNA and / or tau protein in cerebrospinal fluid of a human subject. Whether the method reduces tau RNA and / or tau protein can be determined, for example, by detecting / quantifying a first amount of tau RNA or tau protein in a first biological sample obtained before administration, then detecting / quantifying a second amount of tau RNA or tau protein in a second biological sample obtained after administration, and comparing the first amount to the second amount to detect or quantify the reduction in tau RNA or tau protein.

[0272] In certain embodiments, the methods include reducing tau RNA and / or tau protein by 1-100%, or a range defined by any two of these values. In certain embodiments, the methods include reducing tau RNA and / or tau protein by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 102%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 120%, 130%, 140%, %, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% reduction.

[0273] In certain embodiments, the methods include reducing Tau RNA or Tau protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0274] In certain embodiments, the methods include reducing tau RNA or tau protein by about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to 100%.

[0275] In certain embodiments, the method comprises administering ISIS814907 to a subject and detecting or quantifying the amount of tau RNA or tau protein in the subject's cells or biological fluid. In certain embodiments, the method comprises detecting / quantifying a first amount of tau RNA or tau protein in a first biological sample obtained before administration, then detecting / quantifying a second amount of tau RNA or tau protein in a second biological sample obtained after administration, and comparing the first amount to the second amount to detect or quantify a decrease in tau RNA or tau protein. In certain embodiments, the second biological sample is obtained less than about 24 hours after administration. In certain embodiments, the second biological sample is obtained less than about 1 week after administration. In certain embodiments, the second biological sample is obtained about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, or about 18 weeks after administration. In certain embodiments, the method comprises increasing or decreasing the dose after comparing the first amount to the second amount. In certain embodiments, the method comprises administering more or less frequently after comparing the first amount to the second amount.

[0276] Efficacy evaluation of ISIS814907 In certain embodiments, the methods described herein are sufficiently effective to improve at least one symptom or characteristic of a disease or disorder associated with tau protein in a human subject.In certain embodiments, the methods described herein are sufficiently effective to prevent or slow down the progression or delay the onset of at least one symptom or characteristic associated with tau protein in a human subject.In certain embodiments, the at least one symptom or characteristic is memory loss, cognitive decline, loss of ability to understand or speak, abnormal behavior, motor dysfunction, falls, balance disorders, swallowing disorders, feeding tube placement, hospitalization, death, increase in the number and / or volume of neurofibrillary inclusions, memory loss, loss of cognitive function, neuropsychiatric behavioral dysfunction, or loss of motor function. In certain embodiments, the at least one symptom or characteristic is cognitive loss, neuropsychiatric behavioral dysfunction, general dysfunction, motor function loss disorder, cognitive dysfunction, neuropsychiatric dysfunction, daily life function disorder, attention disorder, visual perceptual processing disorder, working memory disorder, psychomotor speed disorder, impaired verbal motor output, impaired independence, increased apathy, learning ability disorder, mental concentration disorder, speech comprehension and speech disorder, impaired behavior, depression, irritability, anger, mobility disorder, self-care disorder, pain, discomfort, anxiety, convulsions, suicidal ideation, or suicidal behavior. In certain embodiments, the disease or disorder associated with tau protein is a neurodegenerative disease or disorder. In certain embodiments, the disease or disorder associated with tau protein is a tauopathy. In certain embodiments, the disease or disorder associated with tau protein is any of Alzheimer's disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or frontotemporal dementia (FTD). The clinical criteria for MCI due to AD or mild AD dementia follow those of the National Institute on Aging at the National Institutes of Health and the Alzheimer's Association (NIA-AA).In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), non-fluent primary progressive aphasia, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome. In certain embodiments, the disease or disorder associated with tau protein is Down's syndrome, prion diseases (sCJD, vCJD, gCJD, GSS, FFI), diffuse neurofibrillary tangle disease with calcification, familial British dementia and familial Danish dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, myotonic dystrophy (DM1) and PROMM (DM2), age-related tau astrogliopathy, traumatic brain injury, chronic traumatic encephalopathy, IgLON5-associated tauopathy, Guadeloupe parkinsonism, and the like. The disease or disorder associated with tau protein is any of the following: Parkinsonism, Parkinsonism-Dementia Complex of Guam, Non-Guam Motor Neuron Disease with NFTs, Amyotrophic Lateral Sclerosis of Guam, X-linked Parkinsonism with Spasticity, Cerebrotendinous Xanthomatosis, Niemann-Pick Disease Type C, Neurodegeneration with Brain Iron Accumulation (NBIA) associated with PANK2, NBIA associated with PLA2G6, SLC9A6 Mental Retardation, or a disease or disorder associated with any of the following genetic mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease or FTD.

[0277] In certain embodiments, the methods described herein are effective enough to maintain memory, improve memory, maintain cognitive function, improve cognitive function, maintain neuropsychiatric behavior, improve neuropsychiatric behavior, maintain motor function, improve motor function, reduce falls, improve balance, improve swallowing, improve feeding, reduce feeding tube placement, reduce hospitalization, prolong survival, maintain number and / or volume of neurofibrillary inclusions, or reduce number and / or volume of neurofibrillary inclusions in a human subject with a disease or disorder associated with tau protein. In certain embodiments, the disease or disorder associated with tau protein is tauopathy. In certain embodiments, the disease or disorder associated with tau protein is any of Alzheimer's disease (e.g., mild AD, MCI due to AD, mild AD dementia) or frontotemporal dementia (FTD). In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome.In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease or FTD.In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease.

[0278] In certain embodiments, the method described herein is sufficiently effective to improve at least one symptom or characteristic of a disease or disorder associated with tau protein in a human subject having a disease or disorder associated with tau protein compared to a healthy control subject.In certain embodiments, the method described herein is sufficiently effective to prevent or slow down the progression or delay the onset of at least one symptom or characteristic of a disease or disorder associated with tau protein in a human subject having a disease or disorder associated with tau protein compared to a healthy control subject.In certain embodiments, the disease or disorder associated with tau protein is tauopathy.In certain embodiments, the disease or disorder associated with tau protein is any of Alzheimer's disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or frontotemporal dementia (FTD). In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome.In certain embodiments, the disease or disorder associated with tau protein is Down's syndrome, prion diseases (sCJD, vCJD, gCJD, GSS, FFI), diffuse neurofibrillary tangle disease with calcification, familial British dementia and familial Danish dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, myotonic dystrophy (DM1) and PROMM (DM2), age-related tau astrogliopathy, traumatic brain injury, chronic traumatic encephalopathy, IgLON5-associated tauopathy, Guadeloupe parkinsonism, and the like. The disease or disorder associated with tau protein is any of the following: Parkinsonism, Parkinsonism-Dementia Complex of Guam, Non-Guam Motor Neuron Disease with NFTs, Amyotrophic Lateral Sclerosis of Guam, X-linked Parkinsonism with Spasticity, Cerebrotendinous Xanthomatosis, Niemann-Pick Disease Type C, Neurodegeneration with Brain Iron Deposition (NBIA) associated with PANK2, NBIA associated with PLA2G6, SLC9A6 Mental Retardation, or any of the diseases or disorders associated with genetic mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease. In certain embodiments, the healthy control subject is a subject who does not have a disease or disorder associated with tau protein.

[0279] In certain embodiments, the method is sufficiently effective to improve the amount or concentration of total tau protein, phosphorylated tau protein, neurofilament light chain (NfL), or amyloid beta protein in the cerebrospinal fluid of a human subject with a disease or disorder associated with tau protein, as determined by CSF analysis.In certain embodiments, the method is sufficiently effective to maintain the amount or concentration of total tau protein, phosphorylated tau protein, or amyloid beta protein in the cerebrospinal fluid of a human subject with a disease or disorder associated with tau protein, as determined by CSF analysis.In certain embodiments, the method is sufficiently effective to delay the amount or concentration of total tau protein, phosphorylated tau protein, or amyloid beta protein in the cerebrospinal fluid of a human subject with a disease or disorder associated with tau protein, as determined by CSF analysis.In certain embodiments, the method is sufficiently effective to reduce the amount or concentration of total tau protein, phosphorylated tau protein, or amyloid beta protein in the cerebrospinal fluid of a human subject with a disease or disorder associated with tau protein, as determined by CSF analysis. Methods for CSF analysis are known to those of skill in the art, and examples of such methods are described in Example 1.

[0280] In certain embodiments, the method is sufficiently effective to improve the increase in the number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with tau protein, as determined by performing magnetic resonance imaging (MRI) and / or positron emission tomography (PET) on the human subject. In certain embodiments, the method is sufficiently effective to maintain the number and / or volume of neurofibrillary inclusions, delay the onset of the increase in the number and / or volume of neurofibrillary inclusions, slow down the increase in the number and / or volume of neurofibrillary inclusions, or reduce the number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with tau protein, as determined by performing magnetic resonance imaging (MRI) and / or positron emission tomography (PET) on the human subject. In certain embodiments, the disease or disorder associated with tau protein is a tauopathy. In certain embodiments, the disease or disorder associated with tau protein is any of Alzheimer's disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or frontotemporal dementia (FTD). In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome.In certain embodiments, the disease or disorder associated with tau protein is Down's syndrome, prion diseases (sCJD, vCJD, gCJD, GSS, FFI), diffuse neurofibrillary tangle disease with calcification, familial British dementia and familial Danish dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, myotonic dystrophy (DM1) and PROMM (DM2), age-related tau astrogliopathy, traumatic brain injury, chronic traumatic encephalopathy, IgLON5-associated tauopathy, Guadeloupe parkinsonism, and the like. The disease or disorder associated with tau protein is any of the following: Parkinsonism, Parkinsonism-Dementia Complex of Guam, Non-Guam Motor Neuron Disease with NFTs, Amyotrophic Lateral Sclerosis of Guam, X-linked Parkinsonism with Spasticity, Cerebrotendinous Xanthomatosis, Niemann-Pick Disease Type C, Neurodegeneration with Brain Iron Accumulation (NBIA) associated with PANK2, NBIA associated with PLA2G6, SLC9A6 Mental Retardation, or a disease or disorder associated with any of the following genetic mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease. In certain embodiments, the method provides for a reduction in the number of neurofibrillary inclusions or the volume of neurofibrillary inclusions of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 108%, 109%, 110%, 111%, 112%, 113 %, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% decrease.

[0281] In certain embodiments, the methods described herein are sufficiently effective to improve at least one symptom or characteristic of a disease or disorder associated with tau protein in a human subject, as assessed by a clinically relevant test, score or scale. In certain embodiments, the disease or disorder associated with tau protein is a tauopathy. In certain embodiments, the disease or disorder associated with tau protein is any of Alzheimer's disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or frontotemporal dementia (FTD). In certain cases, the disease or disorder associated with tau protein is frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, and / or Dravet syndrome. In certain embodiments, the disease or disorder associated with tau protein is Down's syndrome, prion diseases (sCJD, vCJD, gCJD, GSS, FFI), diffuse neurofibrillary tangle disease with calcification, familial British dementia and familial Danish dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, myotonic dystrophy (DM1) and PROMM (DM2), age-related tau astrogliopathy, traumatic brain injury, chronic traumatic encephalopathy, IgLON5-associated tauopathy, Guadeloupe parkinsonism, and the like. The disease or disorder associated with tau protein is any of the following: Parkinsonism, Parkinsonism-Dementia Complex of Guam, Non-Guam Motor Neuron Disease with NFTs, Amyotrophic Lateral Sclerosis of Guam, X-linked Parkinsonism with Spasticity, Cerebrotendinous Xanthomatosis, Niemann-Pick Disease Type C, Neurodegeneration with Brain Iron Accumulation (NBIA) associated with PANK2, NBIA associated with PLA2G6, SLC9A6 Mental Retardation, or a disease or disorder associated with any of the following genetic mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In certain embodiments, the disease or disorder associated with tau protein is Alzheimer's disease.In certain embodiments, the at least one symptom or characteristic is memory loss, cognitive impairment, loss of speech comprehension or speech, abnormal behavior, motor dysfunction, or an increase in the number and / or volume of neurofibrillary inclusions.In certain embodiments, the at least one symptom or characteristic is cognitive loss, neuropsychiatric behavioral dysfunction, general dysfunction, motor function loss, cognitive dysfunction, neuropsychiatric dysfunction, daily life dysfunction, attention disorder, visual-perceptual processing disorder, memory disorder, impaired independence, increased apathy, impaired learning ability, impaired concentration, impaired speech comprehension and speech, impaired behavior, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, convulsions, suicidal ideation, or suicidal behavior.Non-limiting examples of such clinically relevant tests, scores, and scales include the following:

[0282] Sign-digit modality testing In certain embodiments, the methods described herein are sufficiently effective to improve attention deficits, visual-perceptual processing deficits, working memory deficits, psychomotor speed deficits, or combinations thereof, in subjects with a disease or disorder associated with tau protein, as assessed by the Symbol Digit Modalities Test (SDMT). In the SMDT, subjects pair abstract symbols with specific digits according to a conversion key. The test measures the number of correctly paired items in 90 seconds (maximum of 110 correct pairs). The SDMT has been shown to have strong reliability and validity. The SDMT is described in more detail by Smith, A. Symbol Digit Modalities Test (SDMT). Manual (rev.) Los Angeles: Western Psychological Services, 1982. In certain embodiments, the methods improve the number of correctly paired items by at least 1 item, 2 items, 3 items, 4 items, 5 items, 6 items, 7 items, 8 items, 9 items, or 10 items.

[0283] Stroop Word Reading Test In certain embodiments, the methods described herein are sufficiently effective to improve attention deficits, processing deficits, psychomotor speed deficits, speech motor output deficits, or combinations thereof, in subjects with a disease or disorder associated with tau protein, as assessed by the Stroop Word Reading Test (SWR) test. During the SWR test, subjects are presented with a page of color names (i.e., "blue," "red," or "green") printed in black ink and asked to read as many words as possible within a given time (45 seconds). The number of correctly read words is counted, with higher scores indicating better cognitive function. See Stroop, JR, J. Exp. Psychol. 1935, 18, 643-662 for additional description of the SWR Test. In certain embodiments, the methods improve the number of words a subject can read aloud within a given time by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 words.

[0284] Global Impression, Severity and Change Scales In certain embodiments, the methods described herein are sufficiently effective to improve the subject's Global Impression, Severity and Change Scale scores. This assessment can be performed by a clinician (CGI-S), a companion (CrGI-S), or the subject (PGI-S). The subject is assessed using an 11-point Numeric Rating Scale (NRS), with higher scores indicating greater severity. The CGI-S is described in more detail by Guy W: ECDEU Assessment Manual for Psychopharmacology Rockville, MD: USDepartment of Health, Education, and Welfare; 1976. In certain embodiments, the methods reduce the subject's NRS score by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points.

[0285] Montreal Cognitive Assessment In certain embodiments, the methods described herein are sufficiently effective to improve cognitive impairment in a subject having a disease or disorder associated with tau protein as assessed by the Montreal Cognitive Assessment (MoCA). The MoCA is a subject-completed assessment used to detect cognitive impairment. It includes a series of basic assessments, including attention and visuospatial tasks. Total scores range from 0 to 30, with lower scores indicating greater impairment. The MoCA is described in more detail by Nasreddine et al., 2015, J. Am. Geriatr. Soc. 53:695-9. In certain embodiments, the methods increase the subject's MoCA score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

[0286] Work Productivity and Activity Disability Test In certain embodiments, the methods described herein are sufficiently effective to improve overall functional impairment in subjects with a disease or disorder associated with tau protein, as assessed by the Work Productivity and Activity Impairment Examination (WPAI). The WPAI includes six items assessing the impact of the disease on employment status (yes / no), time away from work due to illness, time away from work for other reasons, hours worked, and impact on productivity and daily activities (all using an 11-point NRS, with higher scores indicating greater impact). The WPAI is described in more detail by Reilly et al., 1993, Pharmacoeconomics 4:353-65. In certain embodiments, the methods reduce the subject's WPAI score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

[0287] Apathy Rating Scale In certain embodiments, the methods described herein are sufficiently effective to ameliorate increased apathy in a subject having a disease or disorder associated with tau protein, as assessed by the Apathy Evaluation Scale (AES). The AES is an 18-item assessment of apathy, including overt behavior, cognitive aspects of motivation, and emotional reactivity. Each item is scored on a 4-point Likert scale ranging from 1 ("not at all") to 4 ("a great deal"). The 18 items are summed to produce a total score (range 18-72 points; 3 items are reverse scored), with higher scores indicating greater apathy. The AES is described in more detail by Marin et al., 1991, Psychiatry Res. 38:143-62. In certain embodiments, the methods result in a reduction in the subject's AES score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

[0288] Neuro-Qol cognitive function short form, version 2 In certain embodiments, the methods described herein are sufficiently effective to improve mental concentration and / or learning impairments in subjects with a disease or disorder associated with tau protein, as assessed by the Neuro-Qol Cognitive Abbreviated Version. The Neuro-Qol Cognitive Abbreviated Version includes eight items (e.g., difficulty concentrating and difficulty learning new tasks or instructions), each rated using a five-point Likert scale, with lower scores indicating greater (four items) or more frequent (four items) difficulties. Raw sum scores are converted to a T-score distribution (mean 50, standard deviation 10). See National Institute of Neurological Disorders and Stroke (NINDS). User Manual for the Quality of Life in Neurological Disorders (Neuro-QoL) Measures, Version 2.0, March 2015.

[0289] Major Depressive Disorder Scale Symptoms In certain embodiments, the methods described herein are sufficiently effective to improve depression in subjects with a disease or disorder associated with tau protein, as assessed by symptoms of Major Depressive Disorder Scale (SMDDS). The SMDDS is a self-reported assessment of depression (McCarrier et al., 2016, Patient 9:117-134). It includes 16 items measuring concepts such as sadness, irritability, worry, and sleep disturbance. Each item is rated on a 5-point Likert scale ranging from "never" to "extremely" (9 items) and "never" to "always" (7 items). Item scores from the 15 items (not including the least severe of the two eating items) are summed to produce a score of 0 to 60, with higher scores indicating more severe depressive symptoms. The SMDDS is described in more detail by Bushnell et al., 2019, Value in Health 22:906-915. In certain embodiments, the methods result in a decrease in the subject's score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

[0290] EuroQol 5-Dimension, 5-Level Questionnaire In certain embodiments, the methods described herein are sufficiently effective to improve mobility impairment, self-care impairment, global functional impairment, pain / discomfort, anxiety, depression, or a combination thereof in subjects with a disease or disorder associated with tau protein, as assessed by the EuroQol 5-Dimension, 5-Level questionnaire (EQ-5D-5L). The EQ-5D-5L is a validated self-reported health status questionnaire used to calculate a utility score of health status for use in health economic analysis (Brooks, 1996, Health Policy 37:53-72 and Herdman et al., 2011, Qual Life Res. 20:1727-36). The EQ-5D-5L has two components: a five-item health status profile that assesses mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, and a visual analog scale (VAS) that measures health status. The published weighting method allows for the creation of a single composite score (index score) of the subject's health status from the scores of the five items (i.e., VAS is not included). In certain embodiments, the method improves the subject's EQ-5D-5L score.

[0291] Health utility index In certain embodiments, the methods described herein are sufficiently effective to improve the health status of a subject with a disease or disorder associated with tau protein, as assessed by the Health Utility Index (HUI). The HUI is a multi-attribute measure of health status (Feeny et al., 1995, Pharmacoeconomics 7:490-502). The HUI2 and HUI3 questionnaires (commonly referred to as HUI2 / 3) contain 15 items with Likert-type response options. From these items, two scores can be generated: HUI2 (7 items) and HUI3 (8 items). Both scores are health utility indices, with 0=death and 1=perfect health. In certain embodiments, the methods improve the subject's HUI score.

[0292] Columbia Suicide Severity Rating Scale In certain embodiments, the methods described herein are sufficiently effective to improve suicidal ideation or behavior in subjects with a disease or disorder associated with tau protein, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a structured tool for assessing suicidal ideation and behavior. Four constructs are measured: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempt. Dichotomous (yes / no) data is collected for 10 categories, and a composite endpoint based on the categories is tracked over time to monitor the safety of the subjects (Posner et al., 2011, Am. J. Psychiatry 168:1266-77). This maps to the Columbia Suicidality Assessment classification algorithm and meets the criteria described in the US FDA draft guidance for the assessment of suicidality in clinical trials (FDA 2012). In certain embodiments, the methods improve the subject's C-SSRS score.

[0293] Recurrent Neuropsychological Assessment Battery (RBANS) In certain embodiments, the method described herein is sufficiently effective to improve memory loss, cognitive decline, cognitive impairment or loss of cognitive function in subjects with disease or disorder associated with tau protein, as assessed by Repetitive Neuropsychological Assessment Battery (RBANS) assessment.RBANS is a neurological assessment designed to identify abnormal cognitive decline in elderly people and differentiate between dementias of different etiologies (Randolph et al., J.Clin.Exp.Neuropsychol.1998 20:310-319).RBANS has been shown to correlate with functional limitations in dementia populations (Hobson et al.,2010,Int.J.Geriatr.Psychiatry 25:525-530) and to adequately detect cognitive impairment associated with AD (Duff et al.,Arch.Clin.Neuropsychol.2008 23:603-612).

[0294] The assessment produces five index scores, one for each of the test domains: attention, visuospatial / constructive ability, language, immediate memory, and delayed memory, which can then be used to determine a total scale score.

[0295] Minor Mental Status Examination (MMSE) In certain embodiments, the methods described herein are sufficiently effective to improve memory loss, cognitive decline, impairment or loss of cognitive function in subjects with a disease or disorder associated with tau protein as assessed by the Mental Status Examination Short Form (MMSE) (Tombaugh et al., 2996, Psychological Assessment 8:48-59). The MMSE is used to quantify cognitive function and to screen for cognitive impairment. It is a severity measure rather than a diagnostic measure, which may be confounded with education level, and dementia may be present and diagnosed as such despite a relatively high MMSE score. The test administrator presents the patient with a series of questions and tests related to orientation, attention, calculation, recall, language and motor skills, with a maximum possible score of 30 points.

[0296] Neuropsychiatric Inventory-Questionnaire (NPI-Q) In certain embodiments, the methods described herein are sufficiently effective to improve abnormal behavior, neuropsychiatric behavioral dysfunction, or neuropsychiatric dysfunction in subjects with a disease or disorder associated with tau protein, as assessed by the Neuropsychiatric Inventory (NPI). The NPI assesses behavioral disorders occurring in dementia patients to assess a wide range of psychopathology and to distinguish between dementias of different etiologies (Cummings et al., 1997, Neurology 71:337-343). The NPI Questionnaire (NPI-Q) is a brief questionnaire-style NPI designed to identify clinically significant neuropsychiatric disorders and their associated impact on caregivers (Kaufer et al., 2000, J. Neuropsychiatry Clin. Neuro. 12:233-239). This is completed by the test administrator after discussing with the study partner the presence / absence of 12 behaviors in the patient (e.g., anxiety, disinhibition, agitation / aggression) and, for each behavior present, its severity (on a scale of 1 to 3, with 3 being the most severe) and associated caregiver burden (on a scale of 0 to 5 ranging from no burden to extreme burden).

[0297] Functional Activity Questionnaire (FAQ) In certain embodiments, the methods described herein are sufficiently effective to improve the impaired independence, mobility, or self-care of subjects with a disease or disorder associated with tau protein, as assessed by the Functional Activities Questionnaire (FAQ). The FAQ is a widely used scale to assess activities of daily living in patients with mild AD (Brown et al., 2011, Arch. Gen. Psychiatry 68:617-626; Marshall et al., 2011, Alzheimers Dement. 7:300-308). It is a simple questionnaire in which a test partner assesses the patient's ability in 10 areas, such as managing current events and preparing a balanced meal, on a scale of 0 (normal) to 3 (dependent). A score of 30 represents the highest level of dependency, and a score of 0 represents complete independence (Pfeffer et al., 1982, J. Gerontol. 37:323-329).

[0298] Clinical Dementia Rating (CDR) Scale In certain embodiments, the methods described herein are sufficiently effective to improve memory loss, cognitive decline, cognitive impairment or loss of cognitive function in subjects with a disease or disorder associated with tau protein, as assessed by the Clinical Dementia Rating (CDR). The CDR is a global rating scale used to classify the severity of Alzheimer's dementia (Morris, 1993, Neurol. 43:2412-2414; Morris, 1997, Int. Psychogeriatr. 9 Suppl 1:173-173). It uses a semi-structured interview with the patient and the study partner by the test administrator to obtain the information necessary to evaluate the patient's cognitive function in six areas: memory, orientation, judgment and problem solving, community activities, household and hobbies, and self-care. The categories for each area are scored as 0 (none), 0.5 (doubtful), 1 (mild), 2 (moderate) and 3 (severe). A summed total score (box sum) was generated and a composite score (using the same five dementia grades) was derived from the category scores following the practice described by Morris (Morris 1993).

[0299] In certain embodiments, the methods described herein are sufficiently effective to ameliorate a symptom or characteristic of a disease or disorder associated with tau protein, as assessed by one or more of the following assessments known to those of skill in the art: Alzheimer's Disease Cooperative Study-Mild Dementia Activities of Daily Living (ADCS-ADL MCI), Alzheimer's Disease Rating Scale-Cognitive Function subscale (ADAS Cog13), Alzheimer's Disease Composite Score (ADCOMS), Integrated Alzheimer's Disease Rating Scale (iADRS), Zarit Burden Interview (ZBI), Resource Utilization in Dementia (RUD-Lite), PSP Rating Scale (PSPRS), Unified Parkinson's Disease Rating Scale (revised) funded by the Movement Disorder Society (MDS), or the Movement Disorder Society (MDS)-funded Unified Parkinson's Disease Rating Scale (MPRS). The following tests were included in the Progressive Supranuclear Palsy Quality of Life Scale (MDS-UPDRS) Part II, Clinical Global Impression of Severity and Change (CGI), Progressive Supranuclear Palsy Quality of Life Scale (PSP-QoL), Schwab and England Activities of Daily Living (SEADL) scales, Phoneme Fluency, Letter-Digit Alignment, Colour Draw Test, Montreal Cognitive Assessment (MoCA), European Quality of Life (EuroQol), and Short Form Survey (SF-36).

[0300] VII. Specific Combination Therapies In certain embodiments, the method comprises co-administering ISIS814907 with at least one other pharmaceutical agent.In certain embodiments, the at least one other pharmaceutical agent improves a disease or disorder associated with tau protein or its symptoms or characteristics.In certain embodiments, ISIS814907 is co-administered with at least one other pharmaceutical agent to produce a combined effect.In certain embodiments, ISIS814907 is co-administered with at least one other pharmaceutical agent to produce a synergistic effect.

[0301] In certain embodiments, ISIS814907 and at least one other pharmaceutical agent are administered simultaneously. In certain embodiments, ISIS814907 and at least one other pharmaceutical agent are administered at different times. In certain embodiments, ISIS814907 and at least one other pharmaceutical agent are prepared together in a single formulation. In certain embodiments, ISIS814907 and at least one other pharmaceutical agent are administered and prepared separately.

[0302] In certain embodiments, pharmaceutical agents that may be co-administered with ISIS 814907 include antipsychotics, such as haloperidol, chlorpromazine, clozapine, quetapine, and olanzapine; antidepressants, such as fluoxetine, sertraline hydrochloride, venlafaxine, and nortriptyline; sedatives, such as benzodiazepines, clonazepam, paroxetine, venlafaxine, and beta-blockers; mood stabilizers, such as lithium, valproic acid, lamotrigine, and carbamazepine; paralytics, such as botulinum toxin; and / or other experimental agents, such as, but not limited to, tetrabenazine (Xenazine), creatine, coenzyme Q10, trehalose, docosahexanoic acid, and the like. acid, ACR16, ethyl-EPA, atomoxetine, citalopram, dimebon, memantine, sodium phenylbutyrate, ramelteon, ursodiol, zyprexa, xenasine, tiapride, riluzole, amantadine, [123I]MNI-420, atomoxetine, tetrabenazine, digoxin, detromethorphan, warfarin, alprozam, ketoconazole, omeprazole, and minocycline. EXAMPLES

[0303] The following examples illustrate certain embodiments of the present disclosure, but do not limit them.Furthermore, when specific embodiments are provided, the inventors intend the general application of these specific embodiments.For example, the disclosure of an oligonucleotide having a specific motif provides reasonable support for additional oligonucleotides having the same or similar motifs.Also, for example, when a specific high affinity modification appears at a specific position, other high affinity modifications at the same position are considered to be suitable, unless otherwise indicated.

[0304] Example 1: Phase 1b clinical trial in humans with ISIS 814907 A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b study was conducted in adult human subjects with AD.

[0305] Human subjects were randomly assigned in a 3:1 ratio to receive either an intrathecal bolus of ISIS 814907-containing artificial CSF or placebo (artificial CSF) four times (days 1, 29, 57, and 85) every 4 weeks (Cohorts A, B, and C) or two times (days 1 and 85) every 12 weeks (Cohort D) during a 13-week treatment evaluation (TE) period. There was a 23-week post-treatment (PT) period without study drug. The primary endpoint was safety. Secondary endpoints were the pharmacokinetics of ISIS 814907-containing CSF. Prespecified exploratory endpoints included CSF total tau protein (t-tau) protein concentration.

[0306] Forty-six human subjects were enrolled in the study. Twelve subjects received placebo and 34 received escalating doses of ISIS814907 at 10 mg (Cohort A), 30 mg (Cohort B), or 60 mg (Cohort C) or 115 mg (Cohort D). Each human subject received all protocol-defined doses and completed the 13-week TE period. Three patients, one each from the placebo group, the 60 mg monthly group (Cohort C), and the 115 mg quarterly group (Cohort D), discontinued the study during the 23-week PT period. All adverse events in human subjects receiving ISIS814907 were mild (88%) or moderate (12%) in severity (e.g., procedural pain and post-lumbar puncture headache). No serious adverse events were observed in human subjects receiving ISIS 814907. There were no clinically relevant adverse changes in laboratory parameters.

[0307] Male or female patients aged 50–74 years with mild AD, defined at screening by a Clinical Dementia Rating (CDR) global composite score of 1 or a composite score of 0.5 with a memory score of 1, an MMSE score of ≥20 and ≤27, and confirmed positive AD biomarkers (amyloid, tau, and phospho-tau via CSF), were considered eligible.

[0308] Baseline patient characteristics were generally similar across study groups, with patients younger and with mild AD (Table 1). Baseline mean CDR Sum of Boxes scores were numerically lower in the 60 mg and 115 mg ISIS 814907 groups due to an amendment during the study that allowed for the inclusion of patients with a CDR total score of 0.5 and a memory score of 1 in addition to patients with a CDR total score of 1.0. Table 1 shows the characteristics of the human subjects at baseline. [Table 1-1] [Table 1-2]

[0309] To obtain total tau (t-tau) protein concentrations in CSF, CSF (20 mL) was obtained from patients using a standard lumbar puncture collection kit immediately prior to dosing on days 1, 29, 57, and 85 (Cohorts A, B, and C) or immediately prior to dosing on days 1 and 85 (Cohort D). CSF was similarly collected during the post-treatment period on study days 113, 141, and 253 (Cohorts A and B) or on study days 141, 197, and 253 (Cohorts C and D). CSF samples obtained at screening and day 1 were analyzed and the results averaged to serve as baseline samples, and CSF samples on days 29, 57, and 85 were used as trough samples 28 days after dosing.

[0310] CSF was obtained by lumbar puncture from patients receiving ISIS814907 or placebo, and tau protein concentrations were measured with the Elecsys Total-Tau CSF. The Elecsys Total-Tau CSF assay is an in vitro diagnostic immunoassay for the quantitative determination of total tau protein in human CSF. Intended uses include: 1. The Elecsys Total-Tau CSF Assay is intended to be used alone or in combination with the Elecsys β-Amyloid (1-42) CSF Assay as a ratio in adult subjects with mild cognitive impairment (MCI) as an aid to identify subjects at low and high risk of cognitive decline as defined by change in clinical score within two years. 2. The Elecsys Total-Tau CSF Assay is intended for use in combination with the Elecsys β-Amyloid (1-42) CSF Assay as a ratio in cognitively impaired adult subjects being evaluated for AD and other causes of cognitive impairment, where positive and negative CSF results will be concordant with positive and negative amyloid PET scan results, respectively.

[0311] In patients receiving ISIS 814907, there was a dose-dependent decrease in the concentration of t-tau in the CSF 8 weeks after the last dose, with mean changes from baseline of -30%, -40%, -49% and -42% in ISIS 814907 cohorts A, B, C and D, respectively. CSF t-tau continued to decrease in patients treated with ISIS 814907 in cohorts C (60 mg) and D (115 mg) 16 weeks after the last dose (-55% and -49%, respectively; CSF was not collected in cohorts A (10 mg) and B (30 mg) 16 weeks after the last dose, and the maximum decrease in all individual patients in cohort D (115 mg) was 69%; Figures 1A and 1B). In patients receiving placebo, the mean percent change from baseline ranged from -1% to -2.4% at all post-baseline visits depicted in Figure 1A. The maximum decrease in steady-state CSF t-tau concentrations did not appear to be reached during the 3-month treatment-emergence (TE) period. During the 6-month post-treatment (PT) period (starting on day 113), a stable decrease in CSF total tau was observed in the 60 mg monthly group, whereas a sustained decrease in CSF concentrations of t-tau was observed in the 115 mg quarterly group. [Table 2]

[0312] Additional exploratory endpoints included assessment of CSF concentrations of p-tau, Aβ42, neurofilament light chain (NfL), neurofilament heavy chain (NfH), neurogranin (NRGN), and YKL-40, with results shown in Table 3. CSF from participants was analyzed with the following assays: Elecsys β-Amyloid (1-42) CSF, Elecsys Total-Tau CSF, and Elecsys Phospho-Tau (181P) CSF (performed at Roche Diagnostics, Indianapolis, IN); NfL (Uman), NfH (Protein Simple, ELLA), YKL40 (Protein Simple, ELLA), and neurogranin (Euroimmune) (at Immunologix, Tampa, FL). Exploratory CSF parameters such as neurofilament light (NfL) and heavy (NfH) chains, neurogranin (NRGN) and YKL-40 did not show a dose-response effect following treatment with MAPTRx (data not shown).

[0313] Similar reductions to those observed in t-tau were observed in CSF p-tau 181 concentrations and the ratio of t-tau to A42. In participants receiving ISIS 814907, there was a dose-dependent reduction in CSF p-tau 181 concentrations 8 weeks after the last dose, with mean changes from baseline of -35%, -44%, -52% and -49% in the 10 mg monthly, 30 mg monthly and 60 mg monthly groups and the 115 mg quarterly group, respectively. 24 weeks after the last dose (Day 1 of Part 2 LTE), CSF p-tau 181 continued to decline in ISIS 814907-treated participants in the 60 mg monthly and 115 mg quarterly groups, with mean changes from baseline of -56% and -46%, respectively. Functional, cognitive, psychiatric, and neurological clinical outcomes were as expected for participants with mild AD over the treatment and post-treatment study periods. No clinically meaningful differences in these parameters were observed between placebo- and ISIS 814907-treated participants, regardless of dose. The mean change from baseline in ventricular volume (VV) as a percentage of total intracranial volume at 6 months post-baseline was greater in the 10 mg, 30 mg, 60 mg, and 115 mg ISIS 814907 groups (0.5%, 0.7%, 0.7%, and 0.6%, respectively) than the change observed in the placebo group (0.2%). No ventricular enlargement (VE) was observed on MRI of the qualitative neuroradiological safety review from participants in the ISIS 814907 or placebo groups. No clinical findings potentially related to VE were observed during the treatment or post-treatment periods. Total brain volume decreased slightly from baseline in all groups, with no difference between participants receiving placebo and those receiving ISIS814907.

[0314] CSF was obtained by lumbar puncture from patients receiving ISIS814907 or placebo and phosphorylated tau protein concentrations were measured using the Elecsys Phospho-Tau(181P) CSF Assay. The Elecsys Phospho-Tau(181P) CSF Assay is an in vitro diagnostic immunoassay for the quantitative determination of phosphorylated tau protein in human CSF. Intended uses include: 1. The Elecsys Phospho-Tau(181P) CSF Assay is intended to be used alone or in combination with the Elecsys β-Amyloid(1-42) CSF Assay as a ratio in adult subjects with mild cognitive impairment (MCI) as an aid to identify subjects at low and high risk of cognitive decline as defined by change in clinical score within two years. 2. The Elecsys Phospho-Tau (181P) CSF Assay is intended for use in combination with the Elecsys β-Amyloid (1-42) CSF Assay as a ratio in cognitively impaired adult subjects being evaluated for AD and other causes of cognitive impairment, where positive and negative CSF results will be concordant with positive and negative amyloid positron emission tomography (PET) scan results, respectively.

[0315] CSF was obtained by lumbar puncture from patients receiving ISIS 814907 or placebo and β-amyloid (1-42) protein concentrations were measured with the Elecsys β-Amyloid (1-42) CSF Assay. The Elecsys β-Amyloid (1-42) CSF is an in vitro diagnostic immunoassay for the quantitative determination of β-amyloid (1-42) protein concentrations in human cerebrospinal fluid (CSF). Intended uses include: 1. The Elecsys β-Amyloid (1-42) CSF Assay is intended for use in cognitively impaired adult subjects being evaluated for Alzheimer's Disease (AD) and other causes of cognitive impairment. A result above the cutoff is consistent with a negative amyloid positron emission tomography (PET) scan. A negative β-amyloid PET scan indicates sparse to no neuritic plaques, which is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition, and a negative scan result makes it unlikely that the patient's cognitive impairment is due to AD. 2. The Elecsys β-Amyloid (1-42) CSF Assay is intended for use in combination with the Elecsys Phospho-Tau (181P) CSF or Elecsys Total-Tau CSF Assays as a ratio in cognitively impaired adult subjects being evaluated for AD and other causes of cognitive impairment, where positive and negative CSF results will be concordant with positive and negative amyloid positron emission tomography (PET) scan results, respectively. 3. The Elecsys β-Amyloid (1-42) CSF Assay is intended to be used alone or in combination with the Elecsys Phospho-Tau (181P) CSF or Elecsys Total-Tau CSF Assays as a ratio in adult subjects with mild cognitive impairment (MCI) as an aid to identifying subjects at low and high risk of cognitive decline as defined by change in clinical score within two years. [Table 3]

[0316] In conclusion, the ASO ISIS814907 bound to its target, as evidenced by a significant, dose-dependent and sustained reduction in CSF t-tau concentrations, and had a tolerable safety profile in participants with AD. More generally, these data demonstrate antisense-mediated inhibition of protein synthesis in the CNS of participants with neurodegenerative disease.

[0317] Example 2: Phase 2, human clinical trials with ISIS 814907 for Alzheimer's Disease (AD) A randomized, double-blind, placebo-controlled Phase 2 clinical trial will be conducted in adult human subjects with mild cognitive impairment (MCI) due to AD and mild AD dementia. Both doses of ISIS 814907 will be delivered via intrathecal administration.

[0318] Example 3: Phase 3 human clinical trial with ISIS 814907 for Alzheimer's disease A randomized, double-blind, placebo-controlled Phase 3 clinical trial will be conducted to evaluate the efficacy and safety of intrathecally administered ISIS 814907 in adult human subjects with MCI due to AD or mild AD dementia.

[0319] Example 4: Phase 2, Human Clinical Trials with ISIS 814907 for Progressive Supranuclear Palsy (PSP) A randomized, double-blind, placebo-controlled Phase 2 clinical trial in adult human subjects with PSP will be conducted. All doses of ISIS 814907 will be delivered intrathecally.

[0320] Example 5: Phase 3 human clinical trial with ISIS 814907 for PSP A randomized, double-blind, placebo-controlled Phase 3 clinical trial will be conducted to evaluate the efficacy and safety of intrathecally administered ISIS 814907 in adult human subjects with PSP.

[0321] Example 6: Phase 2, human clinical trials with ISIS 814907 for frontotemporal dementia (FTD) A randomized, double-blind, placebo-controlled Phase 2 clinical trial in adult human subjects with FTD will be conducted. All doses of ISIS 814907 will be delivered intrathecally.

[0322] Example 7: Phase 3 human clinical trial with ISIS 814907 for FTD A randomized, double-blind, placebo-controlled Phase 3 clinical trial will be conducted to evaluate the efficacy and safety of intrathecally administered ISIS 814907 in adult human subjects with FTD.

[0323] Example 8: Phase 2 study of ISIS 814907 Adequacy of the study population The study population included participants aged 50-80 years with MCI due to AD (stage 3) and mild AD dementia (stage 4). 18 A review of published reports on AD (F-AV-1451) identified several factors associated with increased brain tau concentrations (e.g., amyloidosis, disease severity), a negative correlation with age in the amyloid-positive population, and the relationship between baseline tau concentrations, tau progression, and cognitive decline. Due to these complex interacting factors, considerable heterogeneity and a high degree of overlap between MCI and mild AD dementia with respect to tau PET and CDR-SB was evident from studies with similar study populations. ISIS814907 is expected to provide benefit to patients in these early symptomatic stages of AD due to the reduction of pathogenic tau expression at a stage where significant neurodegeneration has not yet been established. Thus, currently maintaining a roughly equal split of MCI / mild AD dementia participants for the study balances the goal of targeting early disease with the need to measure changes over time in both clinical measures and tau PET.

[0324] Rationale for Phase 2 Dose Selection The three doses of ISIS814907 evaluated in this Phase 2 study are 60 mg Q24W, 115 mg Q24W, and 115 mg Q12W administered intrathecally (IT). The doses were selected based on PK-PD modeling using exposure and biomarker data from previous studies and are supported by nonclinical toxicity and clinical safety data.

[0325] In a double-blind, multiple-ascending dose (MAD) study, 34 participants were treated with ISIS814907 at 10 mg, 30 mg, or 60 mg Q4W or 115 mg Q12W, IT for 12 weeks (from first dose to last dose), with data collected up to 24 weeks after last dose. Steady dose-dependent reductions in CSF total tau and phosphorylated tau were observed. The mean reductions in CSF total tau from baseline at day 141 (8 weeks after last dose) were 29.5% in the 10 mg Q4W cohort, 39.7% in the 30 mg Q4W cohort, 48.8% in the 60 mg Q4W cohort, and 41.9% in the 115 mg Q12W cohort. In the two highest dose cohorts where CSF samples were collected 24 weeks after the last dose in the MAD portion and participants were seamlessly transferred to the long-term extension (LTE), CSF total tau continued to decrease after the last dose, with reductions sustained for 24 weeks after the last dose (mean reduction: 56.2% in the 60 mg Q4W dose and 50.6% in the 115 mg Q12W dose). In the majority of participants (7 of 8) who received the lower doses of 10 mg and 30 mg in the MAD portion who ultimately entered the LTE, reductions in CSF tau remained evident for >12 months after their last dose in the MAD study. Mean percent changes from baseline in total tau and phosphorylated tau were comparable.

[0326] To understand the relationship between different dose regimens and the resulting CSF tau reduction, and thus aid in the selection of dose regimens for the Phase 2 AD study, a population PK-PD model was created using data from the above studies. The model was constructed using available ISIS814907 concentrations and CSF total tau data. The model was then used to simulate the reduction in CSF tau over 72 weeks of treatment, predicting mean reductions in CSF tau from baseline at 76 weeks (the planned end of the study) of approximately 53%, 64%, and 76% with 60 mg Q24W, 115 mg Q24W, and 115 mg Q12W, respectively. In addition to tau reduction, the following considerations were taken into account in dose selection: The dose of 115 mg Q12W was selected as the maximum dose because it was the maximum dose tested in previous studies and Q12W is the most frequently IT dose considered for the AD patient population. Based on the no observed adverse effect level (NOAEL) in NHPs (35 mg Q4W, human equivalent dose (HED) = 350 mg) and maximum tolerated dose (MTD) (60 mg single dose, HED = 600 mg), respectively, 115 mg Q12W has a safety margin of 3-5.2-fold. The 115 mg Q24W dose allows for twice-yearly dosing trials, with the same safety margin as the 115 mg Q12W dose. The 60 mg Q24W dose provides additional data that may inform the minimal effective dose, which has a safety margin of 5.8-10 fold based on the NOAEL and MTD of ISIS 814907. The HED-based safety margin for the NHP NOAEL does not take into account dose frequency, and all proposed dosing regimens are less frequent than those in the NHP repeat-dose studies. The proposed dosing is expected to adequately characterize the relationships between dose, exposure, tau, and clinical outcomes.

[0327] Eligibility Criteria Key selection criteria: -Must meet all of the clinical criteria for MCI due to AD or mild AD dementia according to the National Institute on Aging at the National Institutes of Health and the Alzheimer's Association (NIA-AA) and, at Screening Visit 1, have the following: 1) Recurrent Neuropsychiatric Assessment Battery (RBANS) delayed memory index score of 85 or less, indicating objective evidence of memory impairment; 2) A CDR total score of 0.5 for MCI due to AD or 0.5 or 1 for mild AD dementia 3) MMSE score between 22 and 30 4) CDR memory box score ≥ 0.5 - Evidence of amyloid pathology as measured by positive emission tomography (PET) or cerebrospinal fluid (CSF) sampling.

[0328] Overview of the study Approximately 735 participants will be randomized to receive placebo Q12W, ISIS814907 60 mg Q24W, ISIS814907 115 mg Q24W, or ISIS814907 115 mg Q12W. Treatment group: Placebo Q12W ISIS814907 60mg Q24W ISIS814907 115mg Q24W ISIS814907 115mg Q12W

[0329] Participants will receive study treatment by IT injection every 12 weeks starting on study day 1. Participants in the ISIS814907 60mg Q24W and ISIS814907 115mg Q24W groups will receive ISIS814907 at weeks 1, 24, 48, and 72, and placebo at weeks 12, 36, and 60. Participants in the placebo group will receive placebo at each dosing visit. Participants in the ISIS814907 115mg Q12W group will receive ISIS814907 115mg at each dosing visit. CSF and blood will be collected from all participants for analysis of ISIS814907 PK and related biomarkers. Participants in the tau PET substudy will have tau concentrations in specific brain regions measured by tau PET imaging assessed. [Table 4]

[0330] Primary outcome measures: Dose-response in change from baseline to week 76 in CDR-SB [Time frame: baseline to week 76] The Clinical Dementia Rating (CDR) scale is a clinician-rated dementia staging system that tracks the progression of cognitive impairment in six categories: memory, orientation, judgment and problem solving, community activities, household and hobbies, and personal care. Each category is scored on a 5-point scale: none = 0, suspect = 0.5, mild = 1, moderate = 2, and severe = 3. The overall CDR score is established by clinical scoring criteria, with values ​​of 0 (no dementia), 0.5, (suspected dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). The CDR-SB is obtained by adding the ratings in each of the six categories, ranging from 0 to 18 with higher scores indicating greater impairment.

[0331] Secondary outcome measures: Change from baseline to week 76 in CDR-SB [Time frame: baseline to week 76] The CDR scale is a clinician-rated dementia staging system that tracks the progression of cognitive impairment in six categories (memory, orientation, judgment and problem solving, community activities, household and hobbies, and personal care). Each category is scored on a 5-point scale: none = 0, suspicious = 0.5, mild = 1, moderate = 2, and severe = 3. The overall CDR score is established by clinical scoring criteria, with values ​​of 0 (no dementia), 0.5, (suspected dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). The CDR-SB is obtained by adding the ratings in each of the six categories, ranging from 0 to 18, with higher scores indicating greater impairment. A positive change from baseline indicates clinical deterioration.

[0332] Change from baseline to week 76 in Alzheimer's Disease Cooperative Study of Mild Cognitive Impairment Activities of Daily Living (ADCS-ADL-MCI) [Timeframe: baseline to week 76] The ADCS-ADL-MCI consists of 17 instrumental items (e.g., shopping, preparing meals, using household appliances) and one basic item (dressing). The assessment reflects the caregiver's observations of the participant's actual functioning and provides an assessment of change in the participant's functional status over time. Total scores range from 0 to 53, with lower values ​​over time reflecting functional decline. A positive change from baseline indicates clinical improvement.

[0333] Change from baseline to week 76 in the Alzheimer's Disease Assessment Scale Cognitive Function subscale (ADAS-Cog13) [Time frame: baseline to week 76] The ADAS-Cog13 includes both cognitive tasks and clinical assessments of cognitive function. Items on the scale capture word recall, ability to follow commands, ability to correctly copy or draw pictures, naming, ability to interact with everyday objects, orientation, word recognition, memory, comprehension of spoken language, word finding, and language abilities, along with assessments of delayed word recall and concentration / distractibility. Total scores range from 0 to 85. Increasing scores over time indicate increasing cognitive impairment. A positive change from baseline indicates clinical deterioration.

[0334] Change from baseline to week 76 in the Minute Mental Status Examination (MMSE) [Time frame: baseline to week 76] The MMSE is a widely used, function-based test of global cognitive status. It consists of 11 tasks assessing orientation, word recall, attention and calculation, language ability, and visuospatial function. Scores from the 11 tests are combined to obtain a total score ranging from 0 to 30, with lower scores over time indicating increasing cognitive impairment. A positive change from baseline indicates clinical improvement.

[0335] Change from baseline to week 76 in the modified Integrated Alzheimer's Disease Rating Scale (iADRS) [Time frame: baseline to week 76] The iADRS is a composite scale, calculated as a linear combination of the ADAS-Cog13 total score and the Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living (ADCS-iADL) total score, measuring cognitive and daily functioning. The ADCS-iADL is calculated from a subset of questions from the ADCS-ADL. The ADCS-iADL ranges from 0 to 59, with higher scores reflecting better functioning. The ADAS-Cog13 includes cognitive tasks and clinical assessments of cognitive function. Items on the scale capture word recall, ability to follow commands, ability to correctly copy / draw, naming, ability to interact with everyday objects, orientation, word recognition, memory, speech comprehension, word finding, and language abilities, along with assessments of delayed word recall and concentration / distractibility. Scores range from 0 to 85, with higher scores reflecting cognitive impairment. iADRS scores range from 0 to 144, with higher scores indicating greater impairment. A positive change from baseline indicates clinical deterioration.

[0336] Change from baseline to week 76 in Alzheimer's Disease Composite Score (ADCOMS) [Time frame: baseline to week 76] The ADCOMS is a composite score composed of the ADAS-cog (4 items), MMSE (2 items) and CDR-SB (6 items). Total scores on the scale range from 0 to 1.97, with higher scores indicating greater disability. A positive change from baseline indicates clinical deterioration.

Claims

A composition for use in a method of doing so in a human subject in need of reducing tau RNA, reducing tau protein, or ameliorating a disease or disorder associated with tau protein, comprising the following chemical structure: 【Chemical 11】 a modified oligonucleotide according to (SEQ ID NO: 4), or a salt thereof, characterized in that a dose of said composition comprising said modified oligonucleotide is administered to said human subject, said composition comprising about 10 mg, about 30 mg, about 60 mg, or about 115 mg of said modified oligonucleotide, said composition. **Claim 2** The composition according to claim 1, wherein said modified oligonucleotide is a sodium salt or a potassium salt. A composition for use in a method of doing so in a human subject in need of reducing tau RNA, reducing tau protein, or ameliorating a disease or disorder associated with tau protein, comprising the following chemical structure: 【Chemical 12】 comprising a modified oligonucleotide according to (SEQ ID NO: 4), characterized in that a dose of said composition comprising said modified oligonucleotide is administered to said human subject, said composition comprising about 10 mg, about 30 mg, about 60 mg, or about 115 mg of said modified oligonucleotide, said composition. A composition for use in a method of doing so in a human subject in need of reducing tau RNA, reducing tau protein, or ameliorating a disease or disorder associated with tau protein, comprising a modified oligonucleotide, characterized in that a dose of said composition comprising said modified oligonucleotide is administered to said human subject, said composition comprising about 10 mg, about 30 mg, about 60 mg, or about 115 mg of said modified oligonucleotide, said modified oligonucleotide having the following chemical notation (5' to 3'): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (SEQ ID NO: 4), wherein A = adenine nucleobase, mC = 5-methylcytosine nucleobase, G = guanine nucleobase, T = thymine nucleobase, e = 2'-MOE sugar moiety, d = 2'-β-D-deoxyribosyl sugar moiety, s = phosphorothioate internucleoside linkage, and The composition, wherein o is a phosphodiester nucleoside internucleoside linkage. **Claim 5** The composition according to any one of claims 1 to 4, wherein the disease or disorder associated with the tau protein is a neurodegenerative disease or disorder. **Claim 6** The composition according to any one of claims 1, 3 and 4, wherein the disease or disorder associated with the tau protein is tauopathy. **Claim 7** The composition according to any one of claims 1, 3 and 4, wherein the disease or disorder associated with the tau protein is any one of Alzheimer's disease, frontotemporal dementia (FTD), frontotemporal dementia with Parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Pick's disease, argyrophilic grain dementia (AGD), globular glial tauopathy, epilepsy, or Dravet syndrome. **Claim 8** The composition according to any one of claims 1, 3 and 4, wherein the disease or disorder associated with the tau protein is Down syndrome, prion diseases (sCJD, vCJD, gCJD, GSS, FFI), diffuse neurofibrillary tangles with calcification, familial British dementia and familial Danish dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, myotonic dystrophy (DM1) and PROMM (DM2), age-related tau astrogliopathy, traumatic brain injury, chronic traumatic encephalopathy, IgLON5-related tauopathy, Guadeloupean parkinsonism, Guam parkinsonism-dementia complex, non-Guam type motor neuron disease with NFT, Guam amyotrophic lateral sclerosis, X-linked parkinsonism with spasticity, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, neurodegeneration with brain iron accumulation associated with PANK2 (NBIA), NBIA associated with PLA2G6, SLC9A6 mental retardation, or a disease or disorder associated with any gene mutation of LRRK2, PRKN, SNCA, TARDBP, or C9orf72. **Claim 9** The composition according to any one of claims 1, 3 and 4, wherein the disease is Alzheimer's disease (AD). [[ID=eleven]]**Claim 10** The composition according to claim 9, wherein the Alzheimer's disease is mild AD, mild cognitive impairment due to AD (MCI) or mild AD dementia. **Claim 11** The composition according to any one of claims 1, 3 and 4, wherein the disease is FTD.

12. The composition according to any one of claims 1, 3, and 4, wherein the human subject has a mutation in at least one gene selected from the group consisting of MAPT, APOE, APP, PSEN1, PSEN2, LRRK2, STX6, EIF2AK3, and MOBP.

13. The composition according to any one of claims 1, 3, and 4, wherein at least one symptom or feature of the disease or disorder associated with the tau protein is improved.

14. The composition according to claim 13, wherein the at least one symptom or feature includes memory loss, decline in cognitive function, loss of the ability to understand or speak, abnormal behavior, motor dysfunction, loss of cognitive function, neuropsychiatric behavioral dysfunction, general dysfunction, loss of motor function, cognitive impairment, neuropsychiatric dysfunction, daily living dysfunction, attention disorder, visual perception processing disorder, memory disorder, impairment of self-sufficiency, increased apathy, learning ability disorder, mental concentration disorder, disorder of understanding and speaking, disruptive behavior, depression, irritability, anger, mobility disorder, self-management disorder, pain, discomfort, anxiety, spasm, suicidal ideation, suicidal behavior, or an increase in the number and / or volume of neurofibrillary tangles.

15. The composition according to any one of claims 1, 3, and 4, wherein the composition comprises 10 mg of the modified oligonucleotide.

16. The composition according to any one of claims 1, 3, and 4, wherein the composition comprises 30 mg of the modified oligonucleotide.

17. The composition according to any one of claims 1, 3, and 4, wherein the composition comprises 60 mg of the modified oligonucleotide.

18. The composition according to any one of claims 1, 3, and 4, wherein the composition comprises 90 mg of the modified oligonucleotide.

19. The composition according to any one of claims 1, 3, and 4, wherein the composition comprises 115 mg of the modified oligonucleotide.

20. The composition according to any one of claims 1, 3, and 4, wherein the method comprises administering the composition once every four weeks.

21. The composition according to any one of claims 1, 3, and 4, wherein the method comprises administering the composition once every eight weeks.

22. The composition according to any one of claims 1, 3, and 4, wherein the method comprises administering the composition once every twelve weeks.

23. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every 16 weeks.

24. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every 20 weeks.

25. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every 24 weeks.

26. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every six months.

27. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once a month.

28. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every two months.

29. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every three months.

30. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once per quarter.

31. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every six months.

32. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once a year.

33. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition once every two years.

34. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition containing 10 mg of the modified oligonucleotide once every 4 weeks.

35. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition containing 30 mg of the modified oligonucleotide once every 4 weeks.

36. The composition according to any one of claims 1, 3 and 4, wherein the method comprises administering the dose of the composition containing 60 mg of the modified oligonucleotide once every 4 weeks. The composition according to any one of claims 1, 3, and 4, wherein the method comprises administering a dose of the composition comprising 115 mg of the modified oligonucleotide once every 12 weeks.

38. The composition according to any one of claims 1, 3, and 4, wherein the modified oligonucleotide is administered to the CNS of the human subject.

39. The composition according to any one of claims 1, 3, and 4, wherein the modified oligonucleotide is administered by intrathecal administration.

40. The composition according to any one of claims 1, 3, and 4, wherein the modified oligonucleotide is administered by intrathecal bolus administration.

41. The composition according to any one of claims 1, 3, and 4, wherein tau RNA is decreased.

42. The composition according to any one of claims 1, 3, and 4, wherein tau protein is decreased.

43. The composition according to any one of claims 1, 3, and 4, wherein the method comprises detecting the amount of tau RNA in a biological sample from the human subject.

44. The composition according to any one of claims 1, 3, and 4, wherein the method comprises detecting the amount of tau protein in a biological sample from the human subject.

45. The composition according to claim 43, wherein the biological sample comprises cerebrospinal fluid.

46. The composition according to claim 43, wherein the detection is performed before the administration.

47. The composition according to claim 43, wherein the detection is performed after the administration.

48. The composition according to claim 43, wherein the detection is performed before and after the administration.

49. The composition according to claim 43, wherein the method comprises adjusting the initial loading dose, the loading dose, the maintenance dose, or the therapeutically effective amount administered after detection of the amount of tau RNA, tau protein, or a combination thereof. **Claim 50**: The composition according to any one of claims 1, 3 and 4, wherein the method includes analyzing the brain activity, brain size, size of neurofibrillary inclusion bodies, volume of neurofibrillary inclusion bodies, total tau protein, phosphorylated tau protein, or amyloid beta protein amount or concentration of the subject, or a combination thereof, by performing magnetic resonance imaging (MRI), positron emission tomography (PET), electroencephalogram (EEG), or CSF analysis. **Claim 51** The composition according to claim 50, wherein the MRI, PET, EEG, or CSF analysis is performed before administration, after administration, or a combination thereof. **Claim 52**: The composition according to claim 44, wherein the biological sample includes cerebrospinal fluid. **Claim 53**: The composition according to claim 44, wherein the detection is performed before the administration. **Claim 54**: The composition according to claim 44, wherein the detection is performed after the administration. **Claim 55**: The composition according to claim 44, wherein the detection is performed before and after the administration. **Claim 56**: The composition according to claim 44, wherein the method includes adjusting the initial loading dose, the loading dose, the maintenance dose, or the therapeutically effective amount administered after detecting the amount of tau RNA, tau protein, or a combination thereof.

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