MAPT RNA interferant

Abstract

To treat tauopathy, we provide a therapeutic agent that can inhibit or regulate the expression of the MAPT gene. [Solution] MAPT RNAi agents and compositions comprising MAPT RNAi agents are provided herein. Methods of using MAPT RNAi agents or compositions comprising MAPT RNAi agents to reduce MAPT expression in a subject and / or to treat tauopathy are also provided herein.

Description

[Technical Field]

[0001] Sequence List This application is filed together with a sequence listing in ST.26XML format. The sequence listing is 202 Provided as a file titled "30170" created on November 2, 2020, The file is 835 kilobytes. The sequence listing information in ST.26XML format is referenced in its entirety. This specification is more fully incorporated here. [Background technology]

[0002] Microtubule-associated protein tau is transmitted by the MAPT gene located on chromosome 17. It is done. Tau protein interacts with tubulin to stabilize microtubules, and then to microtubules It promotes tubulin aggregation. MAPT transcripts are distributed throughout the body, primarily in the central nervous system. It is expressed differentially in the transcatheter and peripheral nervous systems.

[0003] The MAPT gene consists of 16 exons. Alternative mRNA splicing is a process that involves multiple exons. This gives rise to several MAPT isoforms. At least six tau isoforms are human. It is found in the brain and ranges in length from 352 to 441 amino acids. Exon 2 and / or Exon 3 Alternative splicing results in the inclusion of 0, 1, or 2 copies of the N-terminal acidic domain. However, these are referred to as 0N, 1N, or 2N tau, respectively. Additional microtubule-bound tau The tau isoform containing exon 10, which codes for the main, has four microtubule-bound domains. Because it contains tau, it is called "4R tau (4RTau)". Tau that does not contain exon-10 The isoform has three microtubule-binding domains, hence it is called "3R Tau (3R Tau ) is referred to as "

[0004] MAPT mutations and tau protein hyperphosphorylation are associated with pathogenic neurofibrillary tangles. It causes aggregation and deposition of tau, leading to Alzheimer's disease and frontotemporal dementia (frontotemporal dementia). mporal dementia (FTD), Progressive Supranuclear Palsy (P It can cause progressive neurodegenerative disorders such as SP (severe palsy) and other tauopathies.

[0005] RNA interference (RNAi) is when RNA molecules interfere with double-stranded RNA molecules (double-stranded RNA molecules). Involved in sequence-specific gene repression of gene expression by le-stranded RNA (dsRNA), It is a highly conserved regulatory mechanism (Fire et al., Nature 391:806-811) , 1998).

[0006] Currently, there are FDA (Food and Drug Administration) products specifically for reducing MAPT and treating tauopathy. There are no disease-modifying therapeutic agents approved by the Drug Administration. Amyloid-beta protein (Aβ) Aducanumab, which targets [specific target], is currently approved for the treatment of Alzheimer's disease. It is the only disease-modifying agent. Therefore, for example, by utilizing RNAi To treat tauopathy, therapeutic agents that can inhibit or modulate the expression of the MAPT gene are available. It is still needed. [Overview of the Initiative]

[0007] MAPT RNAi agents and compositions containing MAPT RNAi agents are provided herein. It is used to reduce MAPT expression in subjects and / or to treat tauopathy. A method using a MAPT RNAi agent or a composition containing a MAPT RNAi agent for this purpose. Also provided herein.

[0008] In one aspect, provided herein is an M APT RNAi agent, wherein the sense strand and the antisense strand form a double strand, and the sense strand and the antisense strand (a) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 1 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 2, (b) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 3 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 4, (c) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 5 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 6, (d) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 7 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8, (e) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10, (f) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12, (g) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 13 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 14 Antisense strand containing nucleic acid sequence, (h) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 15 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 16 Antisense strand containing nucleic acid sequence, (i) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 17 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 18 Antisense strand containing nucleic acid sequence, (j) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 19 The sense strand and a second sequence having at least 95% sequence identity with respect to Sequence ID No. 20 Antisense strand containing nucleic acid sequence, (k) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 21 The sense strand and a second sequence having at least 95% sequence identity with respect to Sequence ID No. 22 Antisense strand containing nucleic acid sequence, (l) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 23 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 24 Antisense strand containing nucleic acid sequence, (m) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 55 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 16 Antisense strand containing nucleic acid sequence, (n) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 56 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 16 Antisense strand containing nucleic acid sequence, (o) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 57 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 58 Antisense strand containing nucleic acid sequence, (p) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 59 The sense strand and a second sequence having at least 95% sequence identity with respect to sequence number 58 Antisense strand containing nucleic acid sequence, (q) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 60. The sense strand and a second having at least 95% sequence identity with respect to SEQ ID NO: 61 Antisense strand containing nucleic acid sequence, (r) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 62 The sense strand and a second having at least 95% sequence identity with respect to SEQ ID NO: 61 Antisense strand containing nucleic acid sequence, (s) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 117. A sense strand containing and having at least 95% sequence identity with respect to sequence number 118. An antisense strand containing two nucleic acid sequences, and (t) A first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 119. A sense strand containing, and a second having at least 95% sequence identity with respect to SEQ ID NO: 16. Antisense strand containing nucleic acid sequence A MAPT RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0009] In some embodiments, the sense strand of the MAPT RNAi agent described herein And the antisense chain is (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and the second nucleic acid sequence of SEQ ID NO: 2 Antisense chains including (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and the second nucleic acid sequence of SEQ ID NO: 4 Antisense chains including (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and the second nucleic acid sequence of SEQ ID NO: 6 Antisense chains including (d) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and the second nucleic acid sequence of SEQ ID NO: 8 Antisense chains including (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and a second nucleic acid sequence of SEQ ID NO: 10 Antisense chain containing columns, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 11, and the second nucleic acid sequence of SEQ ID NO: 12 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 13, and the second nucleic acid sequence of SEQ ID NO: 14 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 15, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 17, and the second nucleic acid sequence of SEQ ID NO: 18 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and the second nucleic acid sequence of SEQ ID NO: 20 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and the second nucleic acid sequence of SEQ ID NO: 22 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23, and the second nucleic acid sequence of SEQ ID NO: 24 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 56, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 57, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (p) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (q) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 60, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 62, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (s) sense strand containing the first nucleic acid sequence of SEQ ID NO: 117, and the second of SEQ ID NO: 118 Antisense strands containing nucleic acid sequences, and (t) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleus of SEQ ID NO: 16 Antisense chain containing acid sequence It includes a pair of nucleic acid sequences selected from the group consisting of the following.

[0010] In some embodiments, the sense strand of the MAPT RNAi agent described herein And the antisense chain is (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 1, and a second nucleic acid sequence of SEQ ID NO: 2 Antisense chain having columns, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 3, and a second nucleic acid sequence of SEQ ID NO: 4 Antisense chain having columns, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 5, and a second nucleic acid sequence of SEQ ID NO: 6 Antisense chain having columns, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 7, and a second nucleic acid sequence of SEQ ID NO: 8 Antisense chain having columns, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 9, and the second nucleic acid sequence of SEQ ID NO: 10 Antisense strand having an array, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 11, and a second nucleus of SEQ ID NO: 12 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 13, and a second nucleus of SEQ ID NO: 14 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 15, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 17, and a second nucleus of SEQ ID NO: 18 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 19, and a second nucleus of SEQ ID NO: 20 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 21, and a second nucleus of SEQ ID NO: 22 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 23, and a second nucleus of SEQ ID NO: 24 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (n) A sense strand having the first nucleic acid sequence of SEQ ID NO: 56, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 57, and a second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (p) Sense strand having the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (q) A sense strand having the first nucleic acid sequence of SEQ ID NO: 60, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 62, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (s) a sense strand having the first nucleic acid sequence of SEQ ID NO: 117, and the second nucleic acid sequence of SEQ ID NO: 118 An antisense strand having the nucleic acid sequence, and (t) A sense strand having the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing nucleic acid sequence It has a pair of nucleic acid sequences selected from the group consisting of the following.

[0011] The MAPT RNAi agents described herein may include modifiers. The modification is performed on the sense strand. and / or to one or more nucleotides of the antisense strand, or between nucleotides This can be done for linking. In some embodiments, one or more nuclei of the sense chain A rheotide is a modified nucleotide. In some embodiments, each nucleus of the sense strand A rheotide is a modified nucleotide. In some embodiments, the antisense strand One or more nucleotides are modified nucleotides. In some embodiments, Each nucleotide in the nucleotide chain is a modified nucleotide. In some embodiments, Modified nucleotides include 2'-fluoromodified nucleotides and 2'-Om-methyl modified nucleotides. Nucleotides, or 2'-O-alkyl-modified nucleotides, for example, 2'-O-C16A It is a nucleotide modified by lucyl. In some embodiments, the sense strand is the sense strand Four 2'-fluoromodified nucleotides are located at positions 7, 9, 10, and 11 from the 5' end. It has. In some embodiments, positions other than the 7th, 9th, 10th, and 11th positions of the sense chain The nucleotides are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl It is a modified nucleotide. In some embodiments, the antisense strand is an antisense nucleotide. Four 2'-fluoromodified nucleos are located at the 2, 6, 14, and 16 positions from the 5' end of the sucrose chain. It has cydo. In some embodiments, the antisense chain has 2, 6, 14, and Nucleotides at positions other than position 16 are 2'-O-methyl modified nucleotides or 2'-O -It is a C16 alkyl-modified nucleotide. In some embodiments, the sense strand is For example, three 2'-fluoromodifications are applied from the 5' end of the sense chain to the 9th, 10th, and 11th positions. It has a creotide. In some embodiments, the other nucleotides of the sense strand are , a 2'-O-methyl modified nucleotide. In some embodiments, anticer The s chain, for example, is located at positions 2, 5, 7, 14, and 16 from the 5' end of the antisense chain. It has five 2'-fluoromodified nucleotides. In some embodiments, anti The sense strand is, for example, the 2nd, 5th, 8th, 14th, and 16th positions from the 5' end of the antisense strand. It has five 2'-fluoromodified nucleotides. In some embodiments, The antisense chain is, for example, the 2nd, 3rd, 7th, 14th, and 1st positions from the 5' end of the antisense chain. It has five 2'-fluoromodified nucleotides at position 6. In some embodiments, The other nucleotides in the antisense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the sense chain has an abasic moiety or an inverted moiety. It contains a base portion (inverted abasic moiety).

[0012] In some embodiments, the first nucleotide from the 5' end of the antisense strand is It is a modified nucleotide having a phosphate analog, such as 5'-vinylphosphonate. In some embodiments, the sense chain includes a debased moiety or an inverted debased moiety. In several embodiments, the sense strand and the antisense strand are one or more modified nucleotides Interconnections, for example, having phosphorothioate chains. In some embodiments, The chain has four or five phosphorothioate chains. In some embodiments, The antisense chain has four or five phosphorothioate chains. Several implementations Morphologically, the sense strand has four phosphorothioate chains, and the antisense strand has four It has two phosphorothioate chains.

[0013] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain and the antisense chain are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25, and the second nucleic acid sequence of SEQ ID NO: 26 Antisense strand containing a sequence, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27, and the second nucleic acid sequence of SEQ ID NO: 28 Antisense strand containing a sequence, (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 29, and the second nucleic acid sequence of SEQ ID NO: 30 Antisense strand containing a sequence, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 31, and the second nucleic acid sequence of SEQ ID NO: 32 Antisense strand containing a sequence, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 33, and the second nucleic acid sequence of SEQ ID NO: 34 Antisense strand containing a sequence, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 35, and the second nucleic acid sequence of SEQ ID NO: 36 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 37, and the second nucleic acid sequence of SEQ ID NO: 38 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 39, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 41, and the second nucleic acid sequence of SEQ ID NO: 42 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 43, and the second nucleic acid sequence of SEQ ID NO: 44 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 45, and the second nucleic acid sequence of SEQ ID NO: 46 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 47, and the second nucleic acid sequence of SEQ ID NO: 48 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 63, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand containing a sequence, (n) Sequence ID 64, Sequence IDs 66-69, Sequence ID 71, Sequence IDs 75-86, Array A sense strand containing a first nucleic acid sequence selected from any one of numbers 93 to 100, and a distribution Antisense strand containing the second nucleic acid sequence at column number 65, (o) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 64, and SEQ ID NO: 70, SEQ ID NO: 7 An antisense strand containing a second nucleic acid sequence selected from 2 to 74, (p) A sense strand comprising a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89, and an antisense strand containing the second nucleic acid sequence of sequence number 88, (q) A sense strand comprising a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92, and an antisense strand containing the second nucleic acid sequence of sequence number 91, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 101, and the second of SEQ ID NO: 102 Antisense strand containing nucleic acid sequence, (s) sense strand containing the first nucleic acid sequence of SEQ ID NO: 103, and the second of SEQ ID NO: 104 Antisense strand containing nucleic acid sequence, (t) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 105, and SEQ ID NO: 65, SEQ ID NO: An antisense strand containing a second nucleic acid sequence selected from one of 10⁶ to 10⁸, (u) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleus of SEQ ID NO: 65 Antisense chain containing acid sequence, (v) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 110, and the second nucleus of SEQ ID NO: 40 Antisense chain containing acid sequence, (w) sense strand containing the first nucleic acid sequence of SEQ ID NO: 111, and the second of SEQ ID NO: 112 Antisense strand containing nucleic acid sequence, (x) sense strand containing the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 Antisense strands containing nucleic acid sequences, and (y) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand containing nucleic acid sequence A MAPT RNAi agent containing a pair of nucleic acid sequences selected from the group consisting of the following:

[0014] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain and the antisense chain are (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 25, and a second nucleus of SEQ ID NO: 26 Antisense chain having an acid sequence, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 27, and a second nucleus of SEQ ID NO: 28 Antisense chain having an acid sequence, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 29, and a second nucleus of SEQ ID NO: 30 Antisense chain having an acid sequence, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 31, and a second nucleus of SEQ ID NO: 32 Antisense chain having an acid sequence, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 33, and a second nucleus of SEQ ID NO: 34 Antisense chain having an acid sequence, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 35, and a second nucleus of SEQ ID NO: 36 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 37, and a second nucleus of SEQ ID NO: 38 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 39, and a second nucleus of SEQ ID NO: 40 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 41, and a second nucleus of SEQ ID NO: 42 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 43, and a second nucleus of SEQ ID NO: 44 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 45, and a second nucleus of SEQ ID NO: 46 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 47, and a second nucleus of SEQ ID NO: 48 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of SEQ ID NO: 63, and the second nucleus of SEQ ID NO: 40 Antisense chain having an acid sequence, (n) Sequence ID 64, Sequence IDs 66-69, Sequence ID 71, Sequence IDs 75-86, Array A sense strand having a first nucleic acid sequence selected from any one of numbers 93 to 100, and Antisense strand having the second nucleic acid sequence of Sequence ID No. 65, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 64, and SEQ ID NO: 70, SEQ ID NO: An antisense strand having a second nucleic acid sequence selected from one of 72 to 74, (p) A sense strand having a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89 , and an antisense strand having the second nucleic acid sequence of Sequence ID No. 88, (q) A sense strand having a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92 , and an antisense strand having the second nucleic acid sequence of sequence number 91, (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 101, and the second nucleic acid sequence of SEQ ID NO: 102 Antisense strand having the nucleic acid sequence, (s) a sense strand having the first nucleic acid sequence of SEQ ID NO: 103, and the second nucleic acid sequence of SEQ ID NO: 104 Antisense strand having the nucleic acid sequence, (t) A sense strand having the first nucleic acid sequence of SEQ ID NO: 105, and SEQ ID NO: 65, sequence number An antisense strand having a second nucleic acid sequence selected from one of sequences 106-108. , (u) A sense strand having the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleic acid sequence of SEQ ID NO: 65 Antisense strand having nucleic acid sequence, (v) A sense strand having the first nucleic acid sequence of SEQ ID NO: 110, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand having nucleic acid sequence, (w) sense strand having the first nucleic acid sequence of SEQ ID NO: 111, and the second nucleic acid sequence of SEQ ID NO: 112 Antisense strand having the nucleic acid sequence, (x) A sense strand having the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 An antisense strand having the nucleic acid sequence, and (y) A sense strand having the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand having the nucleic acid sequence A MAPT RNAi agent having a pair of nucleic acid sequences selected from the group consisting of the following:

[0015] In some embodiments, the sense strand of the MAPT RNAi agent has a delivery portion. In some embodiments, the sense strand of the MAPT RNAi agent is the 5' end of the sense strand. It has a delivery portion conjugated at the end or 3' end. Several embodiments In this case, the sense strand of the MAPT RNAi agent has a conjugate in the nucleotide of the sense strand. It has a delivery portion that is α-tocopherol. In some embodiments, the delivery portion is α-tocopherol It is ole or palmitic acid. In some embodiments, the delivery portion is a linker, e.g. For example, via the linker shown in Table 5, it is conjugated to the 5' or 3' end of the sense strand. ru.

[0016] In a further embodiment, provided herein is MAPT of formula (I):RLD It is an RNAi agent, where R is a double-stranded RNA (d) having a sense strand and an antisense strand. sRNA is a double-stranded RNA in which the sense strand and antisense strand form a double helix, where D is ds A delivery means for delivering RNA to cells, where L is the dsRNA linked to the delivery means. It is a connecting means for the purpose of connecting the sense chain and the anchor, or it may be absent if desired. Chisen chains are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and the second nucleic acid sequence of SEQ ID NO: 2 Antisense chains including (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and the second nucleic acid sequence of SEQ ID NO: 4 Antisense chains including (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and the second nucleic acid sequence of SEQ ID NO: 6 Antisense chains including (d) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and the second nucleic acid sequence of SEQ ID NO: 8 Antisense chains including (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and a second nucleic acid sequence of SEQ ID NO: 10 Antisense chain containing columns, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 11, and the second nucleic acid sequence of SEQ ID NO: 12 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 13, and the second nucleic acid sequence of SEQ ID NO: 14 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 15, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 17, and the second nucleic acid sequence of SEQ ID NO: 18 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and the second nucleic acid sequence of SEQ ID NO: 20 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and the second nucleic acid sequence of SEQ ID NO: 22 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23, and the second nucleic acid sequence of SEQ ID NO: 24 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 56, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 57, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (p) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (q) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 60, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 62, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (s) sense strand containing the first nucleic acid sequence of SEQ ID NO: 117, and the second of SEQ ID NO: 118 Antisense strands containing nucleic acid sequences, and (t) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleus of SEQ ID NO: 16 Antisense chain containing acid sequence A pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0017] In some embodiments, the following is provided herein: M of formula (I):RLD APT RNAi agent, where R is a dsRN having sense strand and antisense strand. A is the sense strand and antisense strand, forming a double helix, where D is the dsRNA. It is a delivery means for delivering to cells, and L is used to link the dsRNA to the delivery means. The means of connecting the sense chain and the antisense The chain is (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 1, and a second nucleic acid sequence of SEQ ID NO: 2 Antisense chain having columns, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 3, and a second nucleic acid sequence of SEQ ID NO: 4 Antisense chain having columns, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 5, and a second nucleic acid sequence of SEQ ID NO: 6 Antisense chain having columns, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 7, and a second nucleic acid sequence of SEQ ID NO: 8 Antisense chain having columns, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 9, and the second nucleic acid sequence of SEQ ID NO: 10 Antisense strand having an array, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 11, and a second nucleus of SEQ ID NO: 12 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 13, and a second nucleus of SEQ ID NO: 14 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 15, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 17, and a second nucleus of SEQ ID NO: 18 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 19, and a second nucleus of SEQ ID NO: 20 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 21, and a second nucleus of SEQ ID NO: 22 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 23, and a second nucleus of SEQ ID NO: 24 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (n) A sense strand having the first nucleic acid sequence of SEQ ID NO: 56, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 57, and a second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (p) Sense strand having the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (q) A sense strand having the first nucleic acid sequence of SEQ ID NO: 60, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 62, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (s) a sense strand having the first nucleic acid sequence of SEQ ID NO: 117, and the second nucleic acid sequence of SEQ ID NO: 118 An antisense strand having the nucleic acid sequence, and (t) A sense strand having the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing nucleic acid sequence A pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0018] In some embodiments, the following is provided herein: M of formula (I):RLD APT RNAi agent, where R is a dsRN having sense strand and antisense strand. A is the sense strand and antisense strand, forming a double helix, where D is the dsRNA. It is a delivery means for delivering to cells, and L is used to link the dsRNA to the delivery means. The means of connecting the sense chain and the antisense The chain is (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25, and the second nucleic acid sequence of SEQ ID NO: 26 Antisense strand containing a sequence, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27, and the second nucleic acid sequence of SEQ ID NO: 28 Antisense strand containing a sequence, (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 29, and the second nucleic acid sequence of SEQ ID NO: 30 Antisense strand containing a sequence, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 31, and the second nucleic acid sequence of SEQ ID NO: 32 Antisense strand containing a sequence, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 33, and the second nucleic acid sequence of SEQ ID NO: 34 Antisense strand containing a sequence, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 35, and the second nucleic acid sequence of SEQ ID NO: 36 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 37, and the second nucleic acid sequence of SEQ ID NO: 38 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 39, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 41, and the second nucleic acid sequence of SEQ ID NO: 42 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 43, and the second nucleic acid sequence of SEQ ID NO: 44 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 45, and the second nucleic acid sequence of SEQ ID NO: 46 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 47, and the second nucleic acid sequence of SEQ ID NO: 48 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 105, and SEQ ID NO: 65, SEQ ID NO: An antisense strand containing a second nucleic acid sequence selected from 10⁶ to 10⁸, (n) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleus of SEQ ID NO: 65 Antisense chain containing acid sequence, (o) sense strand containing the first nucleic acid sequence of SEQ ID NO: 110, and the second nucleus of SEQ ID NO: 40 Antisense chain containing acid sequence, (p) sense strand containing the first nucleic acid sequence of SEQ ID NO: 111, and the second of SEQ ID NO: 112 Antisense strand containing nucleic acid sequence, (q) sense strand containing the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 Antisense strands containing nucleic acid sequences, and (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand containing nucleic acid sequence It includes a pair of nucleic acid sequences selected from the group consisting of the following.

[0019] In some embodiments, the following is provided herein: M of formula (I):RLD APT RNAi agent, where R is a dsRN having sense strand and antisense strand. A is the sense strand and antisense strand, forming a double helix, where D is the dsRNA. It is a delivery means for delivering to cells, and L is used to link the dsRNA to the delivery means. The means of connecting the sense chain and the antisense The chain is (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 25, and a second nucleus of SEQ ID NO: 26 Antisense chain having an acid sequence, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 27, and a second nucleus of SEQ ID NO: 28 Antisense chain having an acid sequence, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 29, and a second nucleus of SEQ ID NO: 30 Antisense chain having an acid sequence, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 31, and a second nucleus of SEQ ID NO: 32 Antisense chain having an acid sequence, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 33, and a second nucleus of SEQ ID NO: 34 Antisense chain having an acid sequence, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 35, and a second nucleus of SEQ ID NO: 36 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 37, and a second nucleus of SEQ ID NO: 38 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 39, and a second nucleus of SEQ ID NO: 40 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 41, and a second nucleus of SEQ ID NO: 42 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 43, and a second nucleus of SEQ ID NO: 44 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 45, and a second nucleus of SEQ ID NO: 46 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 47, and a second nucleus of SEQ ID NO: 48 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of Sequence ID No. 105, and Sequence ID No. 65, Sequence No. An antisense strand having a second nucleic acid sequence selected from numbers 106-108, (n) A sense strand having the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleic acid sequence of SEQ ID NO: 65 Antisense strand having nucleic acid sequence, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 110, and the second of SEQ ID NO: 40 Antisense strand having nucleic acid sequence, (p) A sense strand having the first nucleic acid sequence of SEQ ID NO: 111, and the second nucleic acid sequence of SEQ ID NO: 112 Antisense strand having the nucleic acid sequence, (q) A sense strand having the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 An antisense strand having the nucleic acid sequence, and (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand having the nucleic acid sequence It has a pair of nucleic acid sequences selected from the group consisting of the following.

[0020] In another embodiment, the MAPT RN described herein is provided herein. This is a pharmaceutical composition containing an Ai agent and a pharmaceutically acceptable carrier. It is used for MAP in cells. Pharmaceutical compositions comprising means for reducing T expression and pharmaceutically acceptable carriers are also available. Provided herein.

[0021] In another embodiment, provided herein is a MAP in patients who require it. This method reduces T expression, and such a method involves an effective amount of MA as described herein. This includes administering a PT RNAi agent or pharmaceutical composition to a patient.

[0022] In another embodiment, provided herein is a tauo in patients who require it. A method for treating pathology, such as the effective amount of MA described herein. This includes administering a PT RNAi agent or pharmaceutical composition to a patient.

[0023] Reduces MAPT expression in cells (e.g., nerve cells (neurons)). Methods are also provided herein, but such methods are MA described herein. Introducing PT RNAi agents into cells and allowing sufficient time for MAPT mRNA degradation. Incubate the cells and thereby reduce MAPT expression in the cells. It may include the fact that...

[0024] In another embodiment, provided herein is a method for use in reducing MAPT expression , MAPT RNAi agent or pharmaceutical composition containing MAPT RNAi agent. MAPT RNAi agents or pharmaceutical compositions containing MAPT RNAi agents for use in the same manner. Furthermore, provided herein, MAP for use in the treatment of tauopathy. Pharmaceutical compositions containing T RNAi agents or MAPT RNAi agents are also provided herein. Provided. MAPT RNAi agents in the manufacture of pharmaceuticals for the treatment of tauopathy. Use is also provided herein. [Modes for carrying out the invention]

[0025] MAPT RNAi agents and compositions containing MAPT RNAi agents are provided herein. It is used to reduce MAPT expression in subjects and / or to treat tauopathy. A method using a MAPT RNAi agent or a composition containing a MAPT RNAi agent for this purpose. Also provided herein.

[0026] In some embodiments, MAPT RNA having a sense strand and an antisense strand Agent i is provided herein, wherein the sense strand and antisense strand form a double helix. The chisen chain is complementary to the MAPT mRNA region. In further embodiments, The sense strand and antisense strand are each 15-30 nucleotides long, for example, 20- It is 25 nucleotides long. In some embodiments, the sense strand is 21 nucleotides long. MAPT RNAi agents having an antisense strand of 23 nucleotides are provided herein. Provided. In some embodiments, the sense strand and antisequence strand of the MAPT RNAi agent are provided. The lance chain has an overhang at either the 5' or 3' end (i.e., 5' overhang). They may have hangs or 3' overhangs. For example, sense strands and antisense strands. This is a 5' overhang or 3' overhang of 1-5 nucleotides or 1-3 nucleotides. It may have hangs. In some embodiments, the antisense chain has two nuclei Includes the 3' overhang of the ocide. In some embodiments, MAPT RNAi The sense chain sequences and antisense chain sequences of the agent are provided in Table 1.

[0027] This specification provides MAPT RNAi having sense strand and antisense strand. The agent wherein the sense chain and the antisense chain form a double helix, and the sense chain and The antisense chain in question (a) At least 90% (for example, about 90%, about 91%, about 92%) of the sequence number 1 Approximately 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 1 A sense strand containing a first nucleic acid sequence having sequence identity of 00%, and for sequence number 2 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%, about 9) It has sequence identity of 5%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The antisense strand containing the second nucleic acid sequence, (b) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 3 Approximately 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 1 A sense strand containing a first nucleic acid sequence having sequence identity of 00%, and for sequence number 4 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%, about 9) It has sequence identity of 5%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The antisense strand containing the second nucleic acid sequence, (c) At least 90% for SEQ ID NO: 5 (e.g., approximately 90%, approximately 91%, approximately 92%) Approximately 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 1 A sense strand containing a first nucleic acid sequence having sequence identity of 00%, and for sequence number 6 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%, about 9) It has sequence identity of 5%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The antisense strand containing the second nucleic acid sequence, (d) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 7 Approximately 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 1 A sense strand containing a first nucleic acid sequence having sequence identity of 00%, and for sequence number 8 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%, about 9) It has sequence identity of 5%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The antisense strand containing the second nucleic acid sequence, (e) At least 90% for sequence number 9 (e.g., approximately 90%, approximately 91%, approximately 92%) Approximately 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 1 A sense strand containing a first nucleic acid sequence having sequence identity of 00%, and for sequence number 10 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%, about It has sequence identity of 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The antisense strand containing the second nucleic acid sequence, (f) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 11. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and corresponding to Sequence ID No. 12 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (g) At least 90% (e.g., about 90%, about 91%, about 92%) of the number of SEQ ID NO: 13 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 14 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (h) At least 90% (e.g., about 90%, about 91%, about 92%) for SEQ ID NO: 15 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 16 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (i) At least 90% (for example, about 90%, about 91%, about 92%) of the sequence number 17. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and corresponding to Sequence ID No. 18 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (j) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 19. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 20 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (k) At least 90% for sequence number 21 (e.g., about 90%, about 91%, about 92%) %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 22 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (l) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 23. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 24 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (m) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 55. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 16 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (n) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 56. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 16 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (o) At least 90% (e.g., about 90%, about 91%, about 92%) for SEQ ID NO: 57 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 58 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (p) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 59. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 58 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (q) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 60. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 61 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (r) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 62. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 61 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (s) At least 90% for sequence number 117 (e.g., about 90%, about 91%, about 9) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 118 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) The sequence is identical in the following proportions: %, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). An antisense strand containing a second nucleic acid sequence having a property, (t) At least 90% for sequence number 119 (e.g., about 90%, about 91%, about 90%) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and sequence number 16 In contrast, at least 90% (for example, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% Antisense strand containing a second nucleic acid sequence having A MAPT RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0028] In some embodiments, MAPT RNA having a sense strand and an antisense strand Agent i is provided herein, wherein the sense strand and antisense strand form a double strand, and the sense strand is , at least 95% for SEQ ID NO: 1 (for example, approximately 95%, approximately 96%, approximately 97%, approximately 9) It contains a first nucleic acid sequence having sequence identity of 8%, approximately 99%, or approximately 100%, and anti The sense strand should be at least 95% (e.g., approximately 95%, approximately 96%, approximately 9%) relative to SEQ ID NO: 2. It contains a second nucleic acid sequence with sequence identity of 7%, approximately 98%, approximately 99%, or approximately 100%. Furthermore, one or more nucleotides of the sense strand and antisense strand are independently modified nucleos It is a nucleotide, and optionally, one or more nucleotide ligations between the sense strand and the antisense strand. This is a modified nucleotide linkage. In some embodiments, the sense strand and anti MAPT RNAi agents having a sense strand are provided herein, and the sense strand and anti-sense strand The sense strand forms a double helix, and the sense strand is at least 95% (for example, approximately) of the value of SEQ ID NO: 3. It has sequence identity of 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The first nucleic acid sequence is included, and the antisense strand is at least 95% ( For example, arrays of approximately 95%, 96%, 97%, 98%, 99%, or 100%. A second nucleic acid sequence having identity, comprising one or more nucleotides of the sense strand and antisense strand. Otide is an independently modified nucleotide, and optionally, a sense strand and antisense strand. A junction between one or more nucleotides in a chain is a modified nucleotide junction. Several implementations In terms of form, MAPT RNAi agents having a sense strand and an antisense strand are described herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand corresponds to Sequence ID No. 5 and at least 95% (for example, about 95%, about 96%, about 97%, about 98%, about 99%) The antisense strand comprises a first nucleic acid sequence having sequence identity of approximately 100%, and the sequence For number 6, at least 95% (for example, approximately 95%, approximately 96%, approximately 97%, approximately 98%) It includes a second nucleic acid sequence having approximately 99% or approximately 100% sequence identity, and the sense strand and One or more nucleotides in the antisense strand are independently modified nucleotides, and desired As a result, one or more nucleotide junctions of the sense strand and antisense strand are modified nucleotides. It is a dot-to-dot connection. In some embodiments, the M has a sense chain and an antisense chain. APT RNAi agents are provided herein, in which the sense strand and antisense strand form a double helix. Furthermore, the sense chain is at least 95% (for example, about 95%, about 96%) relative to sequence number 7. A first nucleic acid sequence having approximately 97%, 98%, 99%, or 100% sequence identity. The antisense strand includes at least 95% (e.g., approximately 95%) relative to SEQ ID NO: 8. Second with sequence identity of approximately 96%, 97%, 98%, 99%, or 100% The nucleic acid sequence includes one or more nucleotides of the sense strand and antisense strand independently , modified nucleotides, and optionally one or more nucleotides of the sense strand and antisense strand Rheotide ligation is modified nucleotide ligation. In some embodiments, MAPT RNAi agents having a sense chain and an antisense chain are provided herein. The antisense strand forms a double helix, and the sense strand has at least 95 units relative to SEQ ID NO: 9. % (for example, approximately 95%, 96%, 97%, 98%, 99%, or 100%) It contains a first nucleic acid sequence having sequence identity, and the antisense strand is less than sequence number 10. At least 95% (for example, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately It contains a second nucleic acid sequence having 100% sequence identity, and the sense strand and antisense strand One or more nucleotides are independently modified nucleotides, and optionally, sense strands. And one or more internucleotide junctions of the antisense strand are modified internucleotide junctions. In some embodiments, MAPT RNA having a sense strand and an antisense strand Agent i is provided herein, wherein the sense strand and antisense strand form a double strand, and the sense strand is , at least 95% for SEQ ID NO: 11 (for example, about 95%, about 96%, about 97%, about It contains a first nucleic acid sequence having sequence identity of 98%, approximately 99%, or approximately 100%, and The chisen chain is at least 95% (e.g., approximately 95%, approximately 96%) relative to SEQ ID NO: 12. A second nucleic acid sequence having approximately 97%, 98%, 99%, or 100% sequence identity. The sense strand and antisense strand each contain one or more nucleotides, and independently, modified nucleotides A rheotide, and optionally between one or more nucleotides of the sense strand and antisense strand. The ligation is a modified nucleotide ligation. In some embodiments, the sense strand and MAPT RNAi agents having an antisense strand are provided herein, and the sense strand and antisense strand are provided herein. The sense strand forms a double helix, and the sense strand is at least 95% (for example) of SEQ ID NO: 13 (For example, approximately 95%, 96%, 97%, 98%, 99%, or 100%) identical sequences. The antisense strand comprises a first nucleic acid sequence having a specific property, and the antisense strand is at least relative to SEQ ID NO: 14. 95% (for example, approximately 95%, 96%, 97%, 98%, 99%, or 100%) It includes a second nucleic acid sequence having sequence identity with ), and one or more sense strands and antisense strands. The nucleotides are independently modified nucleotides, and optionally, the sense strand and an One or more nucleotide junctions in a cysnes chain are modified nucleotide junctions. In the embodiment, a MAPT RNAi agent having a sense strand and an antisense strand is the present invention Provided in the details, the sense strand and antisense strand form a double helix, and the sense strand is sequence number At least 95% of 15 (for example, about 95%, about 96%, about 97%, about 98%, about It comprises a first nucleic acid sequence having 99% or approximately 100% sequence identity, and an antisense strand This is at least 95% (for example, about 95%, about 96%, about 97%) for SEQ ID NO: 16. It contains a second nucleic acid sequence having approximately 98%, approximately 99%, or approximately 100% sequence identity, One or more nucleotides of the sense strand and antisense strand are independently modified nucleotides. Yes, and if desired, one or more nucleotide junctions of the sense strand and antisense strand can be modified. It is an internucleotide linkage. In some embodiments, a sense strand and an antisense strand. A MAPT RNAi agent having two sense strands and antisense strands is provided herein. The main strand is formed, and the sense strand is at least 95% (e.g., approximately 95%) relative to SEQ ID NO: 17. The sequence identity of the second (approximately 96%, 97%, 98%, 99%, or 100%) The nucleic acid sequence contains 1, and the antisense strand is at least 95% (for example) of sequence number 18. (For example, approximately 95%, 96%, 97%, 98%, 99%, or 100%) identical sequences. It contains a second nucleic acid sequence having sex, and one or more nucleotides of the sense strand and antisense strand. The nucleotide is independently a modified nucleotide, and optionally, the sense strand and antisense strand are One or more nucleotide junctions are modified nucleotide junctions. Several embodiments In this specification, MAPT RNAi agents having sense strands and antisense strands are provided. The sense strand and antisense strand form a double helix, and the sense strand corresponds to sequence number 19. and at least 95% (for example, about 95%, about 96%, about 97%, about 98%, about 99%, and It contains a first nucleic acid sequence having approximately 100% sequence identity, and the antisense strand is sequence number At least 95% for No. 20 (for example, about 95%, about 96%, about 97%, about 98%) It includes a second nucleic acid sequence having approximately 99% or approximately 100% sequence identity, and the sense strand and One or more nucleotides in the antisense strand are independently modified nucleotides, and desired Therefore, the linkage between one or more nucleotides in the sense strand and antisense strand is a modified nucleo It is inter-tide linked. In some embodiments, it has a sense chain and an antisense chain. MAPT RNAi agents are provided herein, and the sense strand and antisense strand form a double helix. The sense chain is at least 95% (e.g., approximately 95%, approximately 96%) relative to SEQ ID NO: 21. A first nucleic acid having sequence identity of %, approximately 97%, approximately 98%, approximately 99%, or approximately 100% The sequence is included, and the antisense strand is at least 95% (e.g., about 9%) relative to SEQ ID NO: 22. It has sequence identity of 5%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). It contains a second nucleic acid sequence, and one or more nucleotides of the sense strand and antisense strand are independently In other words, it is a modified nucleotide, and optionally, one or more sense strands and antisense strands. The nucleotide junctions are modified nucleotide junctions. In some embodiments, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand form a double helix, and the sense strand is less than that of Sequence ID No. 23. All are 95% (for example, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 10%). The first nucleic acid sequence has 0% sequence identity, and the antisense strand is sequence number 24. In contrast, at least 95% (for example, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%) It comprises a second nucleic acid sequence having sequence identity of , or approximately 100%), and includes a sense strand and an anti-sense strand. One or more nucleotides in the nucleotide chain are independently modified nucleotides, and optionally, One or more nucleotide junctions in the sense strand and antisense strand are modified nucleotide junctions. In conclusion, in some embodiments, MAPT has sense strands and antisense strands. RNAi agents are provided herein, in which the sense strand and antisense strand form a double helix. The lance chain is at least 95% (e.g., approximately 95%, approximately 96%, approximately 9%) relative to SEQ ID NO: 55. It contains a first nucleic acid sequence having sequence identity of 7%, approximately 98%, approximately 99%, or approximately 100%. Furthermore, the antisense chain must be at least 95% (for example, about 95%) relative to SEQ ID NO: 16. a second nucleic acid sequence having a sequence identity of 96%, about 97%, about 98%, about 99%, or about 100%), and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more nucleotide linkages between the sense strand and the antisense strand are modified nucleotide linkages. In some embodiments, an MAPT RNAi agent having a sense strand and an antisense strand is provided herein, the sense strand and the antisense strand form a double strand, and the sense strand has at least 95 % (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 56 and comprises a first nucleic acid sequence, the antisense strand has at least 95 % (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and comprises a second nucleic acid sequence, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more nucleotide linkages between the sense strand and the antisense strand are modified nucleotide linkages. In some embodiments, an MAPT RNA i agent having a sense strand and an antisense strand is provided herein, the sense strand and the antisense strand form a double strand, and the sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 57 and comprises a first nucleic acid sequence, the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 58 and comprises a second nucleic acid sequence, and one or more nucleotide linkages between the sense strand and the antisense strand are modified nucleotide linkages . In some embodiments, an MAPT RNA i agent having a sense strand and an antisense strand is provided herein, the sense strand and the antisense strand form a double strand, and the sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 57 and comprises a first nucleic acid sequence, the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 58 and comprises a second nucleic acid sequence . The sense strand and antisense strand each contain one or more nucleotides, and independently, modified nucleotides A rheotide, and optionally between one or more nucleotides of the sense strand and antisense strand. The ligation is a modified nucleotide ligation. In some embodiments, the sense strand and MAPT RNAi agents having an antisense strand are provided herein, and the sense strand and antisense strand are provided herein. The sense strand forms a double helix, and the sense strand is at least 95% (for example) of sequence number 59. (For example, approximately 95%, 96%, 97%, 98%, 99%, or 100%) identical sequences. The first nucleic acid sequence having a property is included, and the antisense strand is at least relative to SEQ ID NO: 58. 95% (for example, approximately 95%, 96%, 97%, 98%, 99%, or 100%) It includes a second nucleic acid sequence having sequence identity with ), and one or more sense strands and antisense strands. The nucleotides are independently modified nucleotides, and optionally, the sense strand and an One or more nucleotide junctions in a cysnes chain are modified nucleotide junctions. How many? In that embodiment, a MAPT RNAi agent having a sense strand and an antisense strand is Provided in the specification, the sense strand and antisense strand form a double helix, and the sense strand is sequence number At least 95% for No. 60 (for example, about 95%, about 96%, about 97%, about 98%) It contains a first nucleic acid sequence having approximately 99% or approximately 100% sequence identity, and antisense The chain is at least 95% (e.g., approximately 95%, approximately 96%, approximately 97%) relative to SEQ ID NO: 61. It includes a second nucleic acid sequence having approximately 98%, 99%, or 100% sequence identity. One or more nucleotides in the sense strand and antisense strand are independently modified nucleotides. And, if desired, one or more nucleotide ligations between the sense strand and the antisense strand are This is a modified nucleotide linkage. In some embodiments, the sense strand and the anticephalic nucleotide are used. MAPT RNAi agents having sense strands and antisense strands are provided herein. It forms a double helix, and the sense strand is at least 95% (e.g., about 9%) relative to SEQ ID NO: 62. It has sequence identity of 5%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). The first nucleic acid sequence is included, and the antisense strand is at least 95% ( For example, arrays of approximately 95%, 96%, 97%, 98%, 99%, or 100%. A second nucleic acid sequence having identity, comprising one or more nucleotides of the sense strand and antisense strand. Otide is an independently modified nucleotide, and optionally, a sense strand and antisense strand. A junction between one or more nucleotides in a chain is a modified nucleotide junction. Several implementations In terms of form, MAPT RNAi agents having a sense strand and an antisense strand are described herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is SEQ ID NO: 117 At least 95% (for example, about 95%, about 96%, about 97%, about 98%, about 99%) The antisense strand comprises a first nucleic acid sequence having sequence identity of %, or approximately 100%), For SEQ ID NO: 118, at least 95% (for example, about 95%, about 96%, about 97%, about It contains a second nucleic acid sequence having 98%, approximately 99%, or approximately 100% sequence identity, One or more nucleotides of the nucleotide chain and antisense chain are independently modified nucleotides. Furthermore, if desired, one or more nucleotide junctions of the sense strand and antisense strand may be modified. It is an internucleotide linkage. In some embodiments, a sense strand and an antisense strand. MAPT RNAi agents having the same are provided herein, and the sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence. The antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The sense strand and the antisense strand form a double-stranded structure. The sense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119 and includes a first nucleic acid sequence, and the antisense strand has at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16 and includes a second nucleic acid sequence. One or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[0029] [Table 1] In some embodiments, the sense strand and the antisense strand of the MAPT RNAi agent described herein are: (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20; [[ID=ect]] (k) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24; Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 13, and the second nucleic acid sequence of SEQ ID NO: 14 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 15, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 17, and the second nucleic acid sequence of SEQ ID NO: 18 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and the second nucleic acid sequence of SEQ ID NO: 20 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and the second nucleic acid sequence of SEQ ID NO: 22 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23, and the second nucleic acid sequence of SEQ ID NO: 24 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 56, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 57, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (p) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (q) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 60, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 62, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (s) sense strand containing the first nucleic acid sequence of SEQ ID NO: 117, and the second of SEQ ID NO: 118 Antisense strands containing nucleic acid sequences, and (t) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleus of SEQ ID NO: 16 Antisense chain containing acid sequence A pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0030] In some embodiments, MAPT RNA having a sense strand and an antisense strand Agent i is provided herein, wherein the sense strand and antisense strand form a double strand, and the sense strand is The first nucleic acid sequence of SEQ ID NO: 1 is included, and the antisense strand is the second nucleic acid sequence of SEQ ID NO: 2 The sense strand and antisense strand each contain one or more nucleotides, and independently, modified nucleotides A rheotide, and optionally between one or more nucleotides of the sense strand and antisense strand. The ligation is a modified nucleotide ligation. In some embodiments, the sense strand and MAPT RNAi agents having an antisense strand are provided herein, and the sense strand and antisense strand are provided herein. The sense strand forms a double strand, and the sense strand contains the first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand. The sense strand contains the second nucleic acid sequence of Sequence ID No. 4, and one or more of the sense strand and antisense strand. The nucleotides are independently modified nucleotides, and optionally, the sense strand and an One or more nucleotide junctions in a cysnes chain are modified nucleotide junctions. How many? In that embodiment, a MAPT RNAi agent having a sense strand and an antisense strand is Provided in the specification, the sense strand and antisense strand form a double helix, and the sense strand is sequence number The first nucleic acid sequence of sequence number 5 is included, and the antisense strand contains the second nucleic acid sequence of sequence number 6. One or more nucleotides in the sense strand and antisense strand are independently modified nucleotides. And, if desired, one or more nucleotide ligations between the sense strand and the antisense strand are This is a modified nucleotide linkage. In some embodiments, the sense strand and the anticephalic nucleotide are used. MAPT RNAi agents having sense strands and antisense strands are provided herein. It forms a double strand, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand is , comprising the second nucleic acid sequence of Sequence ID No. 8, and one or more nucleotides of the sense strand and antisense strand Otide is an independently modified nucleotide, and optionally, a sense strand and antisense strand. A junction between one or more nucleotides in a chain is a modified nucleotide junction. Several implementations In terms of form, MAPT RNAi agents having a sense strand and an antisense strand are described herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 9 The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 10, and the sense strand contains the second nucleic acid sequence of sequence number 10. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand contains The second nucleic acid sequence at column number 12 contains one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 13 The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 14, and the sense strand is 1. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand contains The second nucleic acid sequence at column number 16, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 17 The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 18, and the sense strand is 1. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand contains The second nucleic acid sequence at column number 20, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 21 The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 22, and the sense strand is 2. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand contains The second nucleic acid sequence at column number 24 contains one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, with the sense strand being the third strand of SEQ ID NO: 55. The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 16, and the sense strand is 1. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 56, and the antisense strand contains The second nucleic acid sequence at column number 16, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, with the sense strand being the third strand of SEQ ID NO: 57. The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 58, and the sense strand is 1. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand contains The second nucleic acid sequence at column number 58 contains one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, with the sense strand being the third strand of SEQ ID NO: 57. The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 58, and the sense strand is 1. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of SEQ ID NO: 60, and the antisense strand contains The second nucleic acid sequence at column number 61 contains one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, with the sense strand being the third strand of SEQ ID NO: 62. The first nucleic acid sequence is 1, and the antisense strand contains the second nucleic acid sequence of sequence number 61, and the sense strand is 61. One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand contains the first nucleic acid sequence of sequence number 117, and the antisense strand is The second nucleic acid sequence of sequence number 118 is included, and one or more nucleic acids of the sense strand and antisense strand Rheotide is independently a modified nucleotide, and optionally has a sense strand and antisense strand. A linkage between one or more nucleotides in a chain is a modified nucleotide linkage. In the application form, MAPT RNAi agents having a sense strand and an antisense strand are specified herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is SEQ ID NO: 11 The first nucleic acid sequence is 9, and the antisense strand contains the second nucleic acid sequence of sequence number 16. One or more nucleotides in the sense strand and antisense strand are independently modified nucleotides. And, if desired, one or more nucleotide ligations between the sense strand and the antisense strand are This is a modified nucleotide linkage.

[0031] In some embodiments, the sense strand of the MAPT RNAi agent described herein And the antisense chain is (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 1, and a second nucleic acid sequence of SEQ ID NO: 2 Antisense chain having columns, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 3, and a second nucleic acid sequence of SEQ ID NO: 4 Antisense chain having columns, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 5, and a second nucleic acid sequence of SEQ ID NO: 6 Antisense chain having columns, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 7, and a second nucleic acid sequence of SEQ ID NO: 8 Antisense chain having columns, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 9, and the second nucleic acid sequence of SEQ ID NO: 10 Antisense strand having an array, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 11, and a second nucleus of SEQ ID NO: 12 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 13, and a second nucleus of SEQ ID NO: 14 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 15, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 17, and a second nucleus of SEQ ID NO: 18 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 19, and a second nucleus of SEQ ID NO: 20 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 21, and a second nucleus of SEQ ID NO: 22 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 23, and a second nucleus of SEQ ID NO: 24 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (n) A sense strand having the first nucleic acid sequence of SEQ ID NO: 56, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 57, and a second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (p) Sense strand having the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (q) A sense strand having the first nucleic acid sequence of SEQ ID NO: 60, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 62, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (s) a sense strand having the first nucleic acid sequence of SEQ ID NO: 117, and the second nucleic acid sequence of SEQ ID NO: 118 An antisense strand having the nucleic acid sequence, and (t) A sense strand having the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing nucleic acid sequence A pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0032] In some embodiments, MAPT RNA having a sense strand and an antisense strand Agent i is provided herein, wherein the sense strand and antisense strand form a double strand, and the sense strand is The first nucleic acid sequence is sequence number 1, and the antisense strand is sequence number 2. It has one or more nucleotides in the sense strand and antisense strand that are independently modified nucleotides. A rheotide, and optionally between one or more nucleotides of the sense strand and antisense strand. The ligation is a modified nucleotide ligation. In some embodiments, the sense strand and MAPT RNAi agents having an antisense strand are provided herein, and the sense strand and antisense strand are provided herein. The sense strand forms a double helix, and the sense strand has the first nucleic acid sequence of SEQ ID NO: 3, and the antisect The sense strand has the second nucleic acid sequence of Sequence ID No. 4, and one or more of the sense strand and antisense strand. The nucleotides are independently modified nucleotides, and optionally, the sense strand and an One or more nucleotide junctions in a cysnes chain are modified nucleotide junctions. How many? In that embodiment, a MAPT RNAi agent having a sense strand and an antisense strand is Provided in the specification, the sense strand and antisense strand form a double helix, and the sense strand is sequence number The first nucleic acid sequence is sequence number 5, and the antisense strand has the second nucleic acid sequence of sequence number 6. One or more nucleotides in the sense strand and antisense strand are independently modified nucleotides. And, if desired, one or more nucleotide ligations between the sense strand and the antisense strand are This is a modified nucleotide linkage. In some embodiments, the sense strand and the anticephalic nucleotide are used. MAPT RNAi agents having sense strands and antisense strands are provided herein. It forms a double strand, the sense strand has the first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand is , having the second nucleic acid sequence of Sequence ID No. 8, and one or more nucleotides of the sense strand and antisense strand Otide is an independently modified nucleotide, and optionally, a sense strand and antisense strand. A junction between one or more nucleotides in a chain is a modified nucleotide junction. Several implementations In terms of form, MAPT RNAi agents having a sense strand and an antisense strand are described herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 9 The nucleic acid sequence 1 is present, and the antisense strand has the nucleic acid sequence 2 of sequence number 10, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand is It has a second nucleic acid sequence at column number 12, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 13 The nucleic acid sequence 1 is present, and the antisense strand has the nucleic acid sequence 2 of sequence number 14, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand is It has a second nucleic acid sequence at column number 16, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 17 The nucleic acid sequence 1 is present, and the antisense strand has the nucleic acid sequence 2 of sequence number 18, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand is It has a second nucleic acid sequence at column number 20, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 21 The nucleic acid sequence 1 is present, and the antisense strand has the second nucleic acid sequence of sequence number 22, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand is It has a second nucleic acid sequence at column number 24, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, with the sense strand being the third strand of SEQ ID NO: 55. The nucleic acid sequence 1 is present, and the antisense strand has the nucleic acid sequence 2 of sequence number 16, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 56, and the antisense strand is It has a second nucleic acid sequence at column number 16, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, with the sense strand being the third strand of SEQ ID NO: 57. The nucleic acid sequence 1 is present, and the antisense strand has the nucleic acid sequence 2 of sequence number 58, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand is It has a second nucleic acid sequence at column number 58, and one or more nucleos in the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. Provided, the sense strand and antisense strand form a double helix, and the sense strand is the third of SEQ ID NO: 60 The nucleic acid sequence 1 is present, and the antisense strand has the nucleic acid sequence 2 of sequence number 61, and sense One or more nucleotides in the chain and antisense chain are independently modified nucleotides. If desired, one or more nucleotide junctions between the sense strand and the antisense strand may be modified. It is a creotide linkage. In some embodiments, the sense chain and antisense chain are A MAPT RNAi agent having two strands is provided herein, the sense strand and the antisense strand. The strands are formed, the sense strand has the first nucleic acid sequence of SEQ ID NO: 62, and the antisense strand is It has a second nucleic acid sequence at column number 61, and one or more nucleos of the sense strand and antisense strand. A nucleotide is independently a modified nucleotide, and optionally, a sense strand and an antisense strand. One or more nucleotide junctions are modified nucleotide junctions. Several implementations In this context, MAPT RNAi agents having sense strands and antisense strands are provided herein. The sense strand and antisense strand are provided, and the sense strand forms a double helix, and the sense strand is of Sequence ID No. 117. The first nucleic acid sequence is present, and the antisense strand has the second nucleic acid sequence of sequence number 118. One or more nucleotides of the sense strand and antisense strand are independently modified nucleotides. Yes, and if desired, one or more nucleotide junctions between the sense strand and antisense strand can be repaired. This is a ligation between decorative nucleotides. In some embodiments, sense strands and antisense strands are used. A MAPT RNAi agent having a strand is provided herein, wherein the sense strand and antisense strand are It forms a double strand, the sense strand having the first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand It has the second nucleic acid sequence of Sequence ID No. 16, and one or more of the sense strand and antisense strand Cleotides are independently modified nucleotides, and optionally, sense strands and antiseptal strands. One or more nucleotide links in a nucleotide chain are modified nucleotide links.

[0033] In some embodiments, the MAPT RNAi agents described herein are sequence number Sequence ID 1, Sequence ID 3, Sequence ID 5, Sequence ID 7, Sequence ID 9, Sequence ID 11, Sequence ID 13 , SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 62, Array Number 117, sequence number 119, and sequence number 119 are sequences containing one, two, or three differences. It may include a lance chain. In some embodiments, MAPT R described herein NAi agents include SEQ ID NOs. 2, 4, 6, 8, 10, and sequence number Number 12, Sequence ID 14, Sequence ID 16, Sequence ID 18, Sequence ID 20, Sequence ID 22, Distribution Column number 24, sequence number 58, sequence number 61, and sequence number 118 refer to one, two, or three instances. It may include an antisense strand containing a sequence having the following differences.

[0034] The MAPT RNAi agents described herein may include modifiers. The modification is performed on the sense strand. and / or to one or more nucleotides of the antisense strand, or the sense strand or In contrast to internucleotide junctions, which are the bonds between two nucleotides in an antisense strand, This can be done. For example, some 2'-modifications of ribose or deoxyribose can be RN A stability or DNA stability and half-life may be increased. Such 2'-modifications are 2' -Fluoro, 2'-O-methyl (i.e., 2'-methoxy), 2'-O-alkyl, e.g. For example, 2'-O-C16 alkyl-modified nucleotide, or 2'-O-methoxyethyl (2 It could be '-O-MOE'.

[0035] In some embodiments, one or more nuclei of the sense chain and / or antisense chain Otides are independently modified nucleotides, which consist of a sense strand and an antisense strand. This means that it may have different modified nucleotides. One or more nucleotides in the nucleotide chain are modified nucleotides. In some embodiments... In some embodiments, each nucleotide in the sense strand is a modified nucleotide. And one or more nucleotides in the antisense strand are modified nucleotides. In this embodiment, each nucleotide in the antisense chain is a modified nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoromodified nucleotide, 2 '-O-methyl modified nucleotides, or 2'-O-alkyl modified nucleotides, for example, It is a 2'-O-C16 alkyl-modified nucleotide. In some embodiments, Each nucleotide in the nucleotide chain and antisense chain can independently be a modified nucleotide, for example, 2 '-Fluoro-modified nucleotide, 2'-O-methyl-modified nucleotide, or 2'-O-A These are alkyl-modified nucleotides, for example, 2'-O-C16 alkyl-modified nucleotides.

[0036] In some embodiments, the sense strand is, for example, from the 5' end of the sense strand to position 7, 9 It has four 2'-fluoromodified nucleotides at positions 10, 11, and 11. In the application form, nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand These are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides. In some embodiments, the antisense chain is, for example, 5 of the antisense chain. It has four 2'-fluoromodified nucleotides at the 2nd, 6th, 14th, and 16th positions from the end. In some embodiments, positions other than the 2nd, 6th, 14th, and 16th positions of the antisense chain. The nucleotide at this position is a 2'-O-methyl modified nucleotide or a 2'-O-C16 nucleotide. It is a kill-modified nucleotide.

[0037] In some embodiments, the sense strand is, for example, from the 5' end of the sense strand to position 9, It has three 2'-fluoromodified nucleotides at positions 0 and 11. Several embodiments In this case, the other nucleotides of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense chain is 2 from the 5' end of the antisense chain. It has five 2'-fluoromodified nucleotides at positions 1, 5, 7, 14, and 16. In some embodiments, the antisense chain is, for example, the 5' end of the antisense chain. It has five 2'-fluoromodified nucleotides at positions 2, 5, 8, 14, and 16. In some embodiments, the antisense chain is, for example, the 5' end of the antisense chain. Five 2'-fluoromodified nucleotides are located at positions 2, 3, 7, 14, and 16 from the end. It has. In some embodiments, the other nucleotides of the antisense strand are 2' It is an O-methyl-modified nucleotide. In some embodiments, the sense strand is desalted. It includes a base portion or an inverse debase portion.

[0038] In some embodiments, the modified nucleotide is a 2'-O-alkyl modified nucleo A nucleotide, for example, a 2'-O-C16 alkyl-modified nucleotide, is the delivery portion. It can function as a 2'-O-alkyl-modified nucleotide. In some embodiments, These are 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, and 2'-O-hexadecyluridine. It is xadecylguanine, or 2'-O-hexadecyladenosine. Several implementation forms In this state, 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2' -O-hexadecylguanine, or 2'-O-hexadecyladenosine, is present in the sense chain. It is a modified nucleotide.

[0039] In some embodiments, the first nucleotide from the 5' end of the antisense strand is Modified nucleos having phosphate analogs, e.g., 5'-vinylphosphonate (5'-VP). It's Chido.

[0040] In some embodiments, the sense strand may be a debase-debase-or inverse debase-or This includes the portion shown in Table 3.

[0041] In some embodiments, the sense strand and the antisense strand are one or more modified nuclei It has ostide linkages. In some embodiments, the modified nucleotide chain is phospho It is a rhyoate chain. In some embodiments, the sense chain consists of four or five rhyoates. It has a scholothioate chain. In some embodiments, the antisense chain has four or having five phosphorothioate chains. In some embodiments, sense chain and Each antisense chain has four or five phosphorothioate chains. In several embodiments, the sense chain has four phosphorothioate chains, and the antiseptic chain has four phosphorothioate chains. The lance chain has four phosphorothioate chains.

[0042] In a further embodiment, provided herein are a device having a sense chain and an antisense chain. A MAPT RNAi agent wherein the sense strand and the antisense strand form a double helix. And the sense chain and the antisense chain, (a) At least 90% (e.g., about 90%, about 91%, about 92%) of the number of SEQ ID NO: 25 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and corresponding to Sequence ID No. 26 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (b) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 27 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and corresponding to Sequence ID No. 28 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (c) At least 90% (e.g., about 90%, about 91%, about 92%) of the number of sequence numbers 29. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 30 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (d) At least 90% (e.g., about 90%, about 91%, about 92%) of the number of SEQ ID NO: 31 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 32 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (e) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 33. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 34 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (f) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 35. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 36 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (g) At least 90% (e.g., about 90%, about 91%, about 92%) of the number of sequence numbers 37. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 38 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (h) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 39. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 40 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (i) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 41. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 42 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (j) At least 90% (e.g., about 90%, about 91%, about 92%) of the sequence number 43. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 44 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (k) At least 90% for sequence number 45 (e.g., about 90%, about 91%, about 92%) %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 46 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (l) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 47. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 48 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (m) At least 90% (e.g., about 90%, about 91%, about 92%) for sequence number 63. %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and against Sequence ID No. 40 and at least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand containing a second nucleic acid sequence, (n) Sequence ID 64, Sequence IDs 66-69, Sequence ID 71, Sequence IDs 75-86, Array At least 90% for any one of the numbers 93-100 (for example, approximately 90%, approximately 91) %, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99% A sense strand containing a first nucleic acid sequence having sequence identity of %, or approximately 100%, and a sequence number At least 90% of the 65 (for example, about 90%, about 91%, about 92%, about 93%) Distribution of approximately 94%, 95%, 96%, 97%, 98%, 99%, or 100%) An antisense strand containing a second nucleic acid sequence having column identity, (o) At least 90% (e.g., about 90%, about 91%, about 92%) for SEQ ID NO: 64 %, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately A sense strand containing a first nucleic acid sequence having 100% sequence identity, and Sequence ID No. 70, For any one of the column numbers 72-74, at least 90% (for example, approximately 90%, approximately 91%) %, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99% An antisense strand containing a second nucleic acid sequence having sequence identity of %, or approximately 100%, (p) At least 90% (for example, about 90%) of the values ​​for SEQ ID NO: 87 or SEQ ID NO: 89 Approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, A sense strand containing a first nucleic acid sequence having approximately 99% or approximately 100% sequence identity, and For sequence number 88, at least 90% (for example, approximately 90%, approximately 91%, approximately 92%, approximately 90%) 3%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100% An antisense strand containing a second nucleic acid sequence having sequence identity with ) (q) At least 90% (for example, about 90%) of the sequence number 90 or sequence number 92. Approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, A sense strand containing a first nucleic acid sequence having approximately 99% or approximately 100% sequence identity, and For sequence number 91, at least 90% (for example, about 90%, about 91%, about 92%, about 90%) 3%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100% An antisense strand containing a second nucleic acid sequence having sequence identity with ) (r) At least 90% (for example, about 90%, about 91%, about 90%) for SEQ ID NO: 101 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 102 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) The sequence is identical in the following proportions: %, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). An antisense strand containing a second nucleic acid sequence having a property, (s) At least 90% for sequence number 103 (e.g., about 90%, about 91%, about 9) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 104 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) The sequence is identical in the following proportions: %, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). An antisense strand containing a second nucleic acid sequence having a property, (t) At least 90% for sequence number 105 (e.g., about 90%, about 91%, about 90%) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 65, For any one of sequence numbers 106-108, at least 90% (for example, approximately 90%) Approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, An antisense strand containing a second nucleic acid sequence with approximately 99% or 100% sequence identity. , (u) At least 90% for sequence number 109 (e.g., about 90%, about 91%, about 9) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and sequence number 65 In contrast, at least 90% (for example, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand comprising a second nucleic acid sequence having, (v) At least 90% (e.g., about 90%, about 91%, about 90%) of the sequence number 110. 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and sequence number 40 In contrast, at least 90% (for example, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%) Sequence identity of approximately 95%, 96%, 97%, 98%, 99%, or 100% An antisense strand comprising a second nucleic acid sequence having, (w) At least 90% for sequence number 111 (e.g., about 90%, about 91%, about 9) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 112 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) The sequence is identical in the following proportions: %, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). An antisense strand containing a second nucleic acid sequence having a property, (x) At least 90% for sequence number 113 (for example, about 90%, about 91%, about 9 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 114 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) The sequence is identical in the following proportions: %, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). An antisense strand containing a second nucleic acid sequence having a property, and (y) At least 90% for sequence number 115 (e.g., about 90%, about 91%, about 90%) 2%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or A sense strand containing a first nucleic acid sequence having approximately 100% sequence identity, and Sequence ID No. 116 At least 90% (for example, about 90%, about 91%, about 92%, about 93%, about 94%) The sequence is identical in the following proportions: %, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%). Antisense strand containing a second nucleic acid sequence having a property A MAPT RNAi agent containing a pair of nucleic acid sequences selected from the group consisting of the following:

[0043] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain and the antisense chain are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25, and the second nucleic acid sequence of SEQ ID NO: 26 Antisense strand containing a sequence, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27, and the second nucleic acid sequence of SEQ ID NO: 28 Antisense strand containing a sequence, (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 29, and the second nucleic acid sequence of SEQ ID NO: 30 Antisense strand containing a sequence, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 31, and the second nucleic acid sequence of SEQ ID NO: 32 Antisense strand containing a sequence, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 33, and the second nucleic acid sequence of SEQ ID NO: 34 Antisense strand containing a sequence, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 35, and the second nucleic acid sequence of SEQ ID NO: 36 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 37, and the second nucleic acid sequence of SEQ ID NO: 38 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 39, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 41, and the second nucleic acid sequence of SEQ ID NO: 42 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 43, and the second nucleic acid sequence of SEQ ID NO: 44 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 45, and the second nucleic acid sequence of SEQ ID NO: 46 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 47, and the second nucleic acid sequence of SEQ ID NO: 48 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 63, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand containing a sequence, (n) Sequence ID 64, Sequence IDs 66-69, Sequence ID 71, Sequence IDs 75-86, Array A sense strand containing a first nucleic acid sequence selected from any one of numbers 93 to 100, and a distribution Antisense strand containing the second nucleic acid sequence at column number 65, (o) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 64, and SEQ ID NO: 70, SEQ ID NO: 7 An antisense strand containing a second nucleic acid sequence selected from 2 to 74, (p) A sense strand comprising a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89, and an antisense strand containing the second nucleic acid sequence of sequence number 88, (q) A sense strand comprising a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92, and an antisense strand containing the second nucleic acid sequence of sequence number 91, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 101, and the second of SEQ ID NO: 102 Antisense strand containing nucleic acid sequence, (s) sense strand containing the first nucleic acid sequence of SEQ ID NO: 103, and the second of SEQ ID NO: 104 Antisense strand containing nucleic acid sequence, (t) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 105, and SEQ ID NO: 65, SEQ ID NO: An antisense strand containing a second nucleic acid sequence selected from one of 10⁶ to 10⁸, (u) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleus of SEQ ID NO: 65 Antisense chain containing acid sequence, (v) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 110, and the second nucleus of SEQ ID NO: 40 Antisense chain containing acid sequence, (w) sense strand containing the first nucleic acid sequence of SEQ ID NO: 111, and the second of SEQ ID NO: 112 Antisense strand containing nucleic acid sequence, (x) sense strand containing the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 Antisense strands containing nucleic acid sequences, and (y) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand containing nucleic acid sequence A MAPT RNAi agent containing a pair of nucleic acid sequences selected from the group consisting of the following:

[0044] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. The sense strand forms a chain, and the sense strand includes the first nucleic acid sequence of SEQ ID NO: 25, and the antisense The chain is a MAPT RNAi agent containing the second nucleic acid sequence of SEQ ID NO: 26. In embodiments, the following is provided herein: M having a sense chain and an antisense chain. APT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense strand contains the first nucleic acid sequence of Sequence ID No. 27, and the antisense strand contains the sequence number This is a MAPT RNAi agent containing the second nucleic acid sequence of No. 28. In some embodiments... Provided herein is a MAPT RN having a sense strand and an antisense strand. An AI agent wherein the sense chain and the antisense chain form a double helix, and the sense chain However, it includes the first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand is the second of SEQ ID NO: 30. This is a MAPT RNAi agent containing the nucleic acid sequence. In some embodiments, this specification The book provides MAPT RNAi agents having sense strands and antisense strands. The sense strand and the antisense strand form a double helix, and the sense strand is the sequence number The first nucleic acid sequence is 31, and the antisense strand comprises the second nucleic acid sequence of SEQ ID NO: 32 It includes MAPT RNAi agents. In some embodiments, provided herein The MAPT RNAi agent having a sense strand and an antisense strand, The sense chain and the antisense chain form a double helix, and the sense chain is the first of Sequence ID No. 33 A MAP comprising a nucleic acid sequence, wherein the antisense strand comprises the second nucleic acid sequence of SEQ ID NO: 34. It is a T RNAi agent. In some embodiments, the following is provided herein: A MAPT RNAi agent having a sense chain and an antisense chain, wherein the sense chain and the The antisense strand forms a double helix, and the sense strand contains the first nucleic acid sequence of SEQ ID NO: 35. Furthermore, the antisense strand contains the second nucleic acid sequence of SEQ ID NO: 36, MAPT RNAi It is a drug. In some embodiments, the sense chain and an A MAPT RNAi agent having a sense strand, wherein the sense strand and the antisense strand The strand forms a double helix, and the sense strand contains the first nucleic acid sequence of SEQ ID NO: 37, and the an The cysens strand is a MAPT RNAi agent containing the second nucleic acid sequence of SEQ ID NO: 38. In some embodiments, the sense chain and antisense chain are provided herein. MAPT RNAi agent having a sense strand and an antisense strand that are double-stranded The sense strand is formed and comprises the first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand is It is a MAPT RNAi agent containing the second nucleic acid sequence of SEQ ID NO: 40. Several implementations In form, the herein provides a MAP having a sense strand and an antisense strand. A T RNAi agent wherein the sense strand and the antisense strand form a double helix, The sense strand contains the first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand contains SEQ ID NO: 4 It is a MAPT RNAi agent containing the second nucleic acid sequence of 2. In some embodiments, Provided herein are MAPT RNAi having sense strand and antisense strand. The agent wherein the sense chain and the antisense chain form a double helix, and the sense chain is The first nucleic acid sequence of SEQ ID NO: 43 is included, and the antisense strand is the second nucleus of SEQ ID NO: 44 It is a MAPT RNAi agent containing an acid sequence. In some embodiments, as specified herein Provided is a MAPT RNAi agent having a sense strand and an antisense strand, The sense strand and the antisense strand form a double helix, and the sense strand is sequence number 45 The first nucleic acid sequence comprises the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 46. , MAPT RNAi agent. In some embodiments, provided herein This is a MAPT RNAi agent having a sense strand and an antisense strand, and the sense strand and the antisense strand forms a double strand, and the sense strand is the first nucleic acid of SEQ ID NO: 47 MAPT includes a sequence, and the antisense strand includes the second nucleic acid sequence of SEQ ID NO: 48. It is an RNAi agent.

[0045] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. The sense strand forms a chain, and the sense strand includes the first nucleic acid sequence of SEQ ID NO: 63, and the antisense The chain is a MAPT RNAi agent containing the second nucleic acid sequence of SEQ ID NO: 40. In embodiments, the following is provided herein: M having a sense chain and an antisense chain. APT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense chain in question is sequence numbers 64, 66-69, 71, 75-8. 6. comprising a first nucleic acid sequence selected from any one of sequence numbers 93 to 100, said The nucleic acid strand is a MAPT RNAi agent containing the second nucleic acid sequence of Sequence ID No. 65. In some embodiments, sense strands and antisense strands are provided herein. A MAPT RNAi agent having a double-stranded sense strand and antisense strand. The sense strand comprises the first nucleic acid sequence of Sequence ID No. 64, and the antisense strand However, a second nucleic acid sequence is selected from one of sequence numbers 70 and 72-74. It includes MAPT RNAi agents. In some embodiments, provided herein The MAPT RNAi agent having a sense strand and an antisense strand, The sense strand and the antisense strand form a double helix, and the sense strand is sequence number 87 or sequence number It comprises a first nucleic acid sequence selected from number 89, wherein the antisense strand is sequence number 88 This is a MAPT RNAi agent containing a second nucleic acid sequence. In some embodiments, this Provided in the specification is a MAPT RNAi agent having a sense strand and an antisense strand. The sense strand and the antisense strand form a double helix, and the sense strand is arranged The first nucleic acid sequence comprises a sequence selected from sequence number 90 or sequence number 92, wherein the antisense strand is It is a MAPT RNAi agent containing the second nucleic acid sequence of SEQ ID NO: 91. Several implementations In form, the herein provides a MAP having a sense strand and an antisense strand. A T RNAi agent wherein the sense strand and the antisense strand form a double helix, The sense strand contains the first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand contains SEQ ID NO: It is a MAPT RNAi agent containing the second nucleic acid sequence 102. In some embodiments... Provided herein is a MAPT RN having a sense strand and an antisense strand. An AI agent wherein the sense chain and the antisense chain form a double helix, and the sense chain However, it includes the first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand is of SEQ ID NO: 104 It is a MAPT RNAi agent containing a second nucleic acid sequence.

[0046] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain comprises the first nucleic acid sequence of Sequence ID No. 105, and the antisense The chain is a second nucleus selected from one of the following: SEQ ID NO: 65, SEQ ID NOs: 106-108. It is a MAPT RNAi agent containing an acid sequence. In some embodiments, as specified herein Provided is a MAPT RNAi agent having a sense strand and an antisense strand, The sense strand and the antisense strand form a double helix, and the sense strand is sequence number 10 The first nucleic acid sequence is 9, and the antisense strand contains the second nucleic acid sequence of SEQ ID NO: 65. It is a MAPT RNAi agent. In some embodiments, provided herein This is a MAPT RNAi agent having a sense strand and an antisense strand, and the sense The chain and the antisense chain form a double helix, and the sense chain is the first of Sequence ID No. 110 A MAP comprising a nucleic acid sequence, wherein the antisense strand comprises the second nucleic acid sequence of SEQ ID NO: 40. It is a T RNAi agent. In some embodiments, the following is provided herein: A MAPT RNAi agent having a sense chain and an antisense chain, wherein the sense chain and the The antisense strand forms a double helix, and the sense strand corresponds to the first nucleic acid sequence of SEQ ID NO: 111. Including, the antisense strand contains the second nucleic acid sequence of SEQ ID NO: 112, MAPT RN It is an AI agent. In some embodiments, the sense chain and are provided herein. A MAPT RNAi agent having an antisense strand, wherein the sense strand and the antisense strand The sense strand forms a double helix, and the sense strand contains the first nucleic acid sequence of SEQ ID NO: 113, The antisense strand contains the second nucleic acid sequence of Sequence ID No. 114 in a MAPT RNAi agent. Yes. In some embodiments, the following are provided herein: a sense chain and an antisense chain. MAPT RNAi agent having a sense strand, wherein the sense strand and the antisense strand are It forms a double strand, and the sense strand contains the first nucleic acid sequence of Sequence ID No. 115, and the anti The sense strand is a MAPT RNAi agent containing the second nucleic acid sequence of Sequence ID No. 116.

[0047] In some embodiments, the MAPT RNAi agents described herein are sequence number No. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, Distribution Column number 37, Sequence ID 39, Sequence ID 41, Sequence ID 43, Sequence ID 45, Sequence ID 47 , SEQ ID NOs. 63, 64, 66-69, 71, 75-8 7, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NOs: 92-101, SEQ ID NO: 103, SEQ ID NO: 1 05, Sequence IDs 109-111, Sequence ID 113, Sequence ID 115 are one, two, and It may include a sense strand containing an array, having three differences. In some embodiments, The MAPT RNAi agents described herein are sequence numbers 26, 28, and 2016. Number 30, Sequence ID 32, Sequence ID 34, Sequence ID 36, Sequence ID 38, Sequence ID 40, Distribution Column number 42, Sequence ID 44, Sequence ID 46, Sequence ID 48, Sequence ID 65, Sequence ID 70 , SEQ ID NOs. 72-74, SEQ ID NOs. 88, SEQ ID NOs. 91, SEQ ID NOs. 102, SEQ ID NOs. 104 Sequence IDs 106-108, 112, 114, and 116 are 1 It may include antisense strands containing sequences having one, two, or three differences.

[0048] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain and the antisense chain are (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 25, and a second nucleus of SEQ ID NO: 26 Antisense chain having an acid sequence, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 27, and a second nucleus of SEQ ID NO: 28 Antisense chain having an acid sequence, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 29, and a second nucleus of SEQ ID NO: 30 Antisense chain having an acid sequence, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 31, and a second nucleus of SEQ ID NO: 32 Antisense chain having an acid sequence, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 33, and a second nucleus of SEQ ID NO: 34 Antisense chain having an acid sequence, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 35, and a second nucleus of SEQ ID NO: 36 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 37, and a second nucleus of SEQ ID NO: 38 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 39, and a second nucleus of SEQ ID NO: 40 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 41, and a second nucleus of SEQ ID NO: 42 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 43, and a second nucleus of SEQ ID NO: 44 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 45, and a second nucleus of SEQ ID NO: 46 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 47, and a second nucleus of SEQ ID NO: 48 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of SEQ ID NO: 63, and the second nucleus of SEQ ID NO: 40 Antisense chain having an acid sequence, (n) Sequence ID 64, Sequence IDs 66-69, Sequence ID 71, Sequence IDs 75-86, Array A sense strand having a first nucleic acid sequence selected from any one of numbers 93 to 100, and Antisense strand having the second nucleic acid sequence of Sequence ID No. 65, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 64, and SEQ ID NO: 70, SEQ ID NO: An antisense strand having a second nucleic acid sequence selected from one of 72 to 74, (p) A sense strand having a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89 , and an antisense strand having the second nucleic acid sequence of Sequence ID No. 88, (q) A sense strand having a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92 , and an antisense strand having the second nucleic acid sequence of sequence number 91, (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 101, and the second nucleic acid sequence of SEQ ID NO: 102 Antisense strand having the nucleic acid sequence, (s) a sense strand having the first nucleic acid sequence of SEQ ID NO: 103, and the second nucleic acid sequence of SEQ ID NO: 104 Antisense strand having the nucleic acid sequence, (t) A sense strand having the first nucleic acid sequence of SEQ ID NO: 105, and SEQ ID NO: 65, sequence number An antisense strand having a second nucleic acid sequence selected from one of sequences 106-108. , (u) A sense strand having the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleic acid sequence of SEQ ID NO: 65 Antisense strand having nucleic acid sequence, (v) A sense strand having the first nucleic acid sequence of SEQ ID NO: 110, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand having nucleic acid sequence, (w) sense strand having the first nucleic acid sequence of SEQ ID NO: 111, and the second nucleic acid sequence of SEQ ID NO: 112 Antisense strand having the nucleic acid sequence, (x) A sense strand having the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 An antisense strand having the nucleic acid sequence, and (y) A sense strand having the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand having the nucleic acid sequence A MAPT RNAi agent having a pair of nucleic acid sequences selected from the group consisting of the following:

[0049] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. The sense strand forms a chain, and the sense strand has the first nucleic acid sequence of Sequence ID No. 25, and the antisense The chain is a MAPT RNAi agent having the second nucleic acid sequence of SEQ ID NO: 26. In embodiments thereof, provided herein are those having a sense chain and an antisense chain A MAPT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense strand has the first nucleic acid sequence of Sequence ID No. 27, and the antisense strand has the sequence A MAPT RNAi agent having a second nucleic acid sequence number 28. Several embodiments In this specification, MAPT having sense strands and antisense strands is provided. RNAi agent wherein the sense strand and the antisense strand form a double helix, and the sense The nucleotide strand has the first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand has the sequence of SEQ ID NO: 30 It is a MAPT RNAi agent having a second nucleic acid sequence. In some embodiments, Provided herein are MAPT RNAi agents having a sense strand and an antisense strand. The sense strand and the antisense strand form a double helix, and the sense strand is arranged The first nucleic acid sequence is sequence number 31, and the antisense strand is the second nucleic acid sequence number 32. It is a MAPT RNAi agent having a sequence. In some embodiments, as specified herein Provided is a MAPT RNAi agent having a sense strand and an antisense strand, The sense strand and the antisense strand form a double helix, and the sense strand is sequence number 33 The first nucleic acid sequence is the sequence of the antisense strand, and the antisense strand has the second nucleic acid sequence of sequence number 34. It is a MAPT RNAi agent. In some embodiments, provided herein This is a MAPT RNAi agent having a sense strand and an antisense strand, and the sense The chain and the antisense chain form a double helix, and the sense chain is the first nucleus of Sequence ID No. 35 MAP having an acid sequence, wherein the antisense strand has the second nucleic acid sequence of SEQ ID NO: 36. It is a T RNAi agent. In some embodiments, the following is provided herein: A MAPT RNAi agent having a sense chain and an antisense chain, wherein the sense chain and the The antisense strand forms a double helix, and the sense strand has the first nucleic acid sequence of SEQ ID NO: 37. Furthermore, the antisense strand has the second nucleic acid sequence of SEQ ID NO: 38, MAPT RNA It is an i-agent. In some embodiments, the sense chain and a are provided herein. MAPT RNAi agent having an antisense strand, wherein the sense strand and the antisense strand The sense strand forms a double helix, and the sense strand has the first nucleic acid sequence of SEQ ID NO: 39, and the a The nucleic acid strand is a MAPT RNAi agent having the second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, the following are provided herein: sense chain and antisense A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain has the first nucleic acid sequence of SEQ ID NO: 41, and the antisense The chain is a MAPT RNAi agent having the second nucleic acid sequence of SEQ ID NO: 42. In embodiments thereof, provided herein are those having a sense chain and an antisense chain A MAPT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense strand has the first nucleic acid sequence of Sequence ID No. 43, and the antisense strand has the sequence A MAPT RNAi agent having a second nucleic acid sequence number 44. Several embodiments In this specification, MAPT having sense strands and antisense strands is provided. RNAi agent wherein the sense strand and the antisense strand form a double helix, and the sense The s-chain has the first nucleic acid sequence of SEQ ID NO: 45, and the antisense chain has the sequence of SEQ ID NO: 46 It is a MAPT RNAi agent having a second nucleic acid sequence. In some embodiments, Provided herein are MAPT RNAi agents having a sense strand and an antisense strand. The sense strand and the antisense strand form a double helix, and the sense strand is arranged The first nucleic acid sequence is sequence number 47, and the antisense strand is the second nucleic acid sequence number 48. It is a MAPT RNAi agent that has a specific sequence.

[0050] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. The sense strand forms a chain, and the sense strand has the first nucleic acid sequence of SEQ ID NO: 63, and the antisense The chain is a MAPT RNAi agent having the second nucleic acid sequence of SEQ ID NO: 40. In embodiments thereof, provided herein are those having a sense chain and an antisense chain A MAPT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense chain in question is sequence number 64, sequence numbers 66-69, sequence number 71, sequence number 75- 86, having a first nucleic acid sequence selected from any one of sequence numbers 93 to 100, The antisense strand is a MAPT RNAi agent having the second nucleic acid sequence of Sequence ID No. 65. In some embodiments, the following are provided herein: sense chain and antisense chain. A MAPT RNAi agent having a sense strand, wherein the sense strand and the antisense strand are two This strand forms the sense strand having the first nucleic acid sequence of Sequence ID No. 64, and the antisense strand The chain is a second nucleic acid selected from one of the following: SEQ ID NOs. 70, SEQ ID NOs. 72-74. It is a MAPT RNAi agent having a row. In some embodiments, it is described herein The product provided is a MAPT RNAi agent having a sense strand and an antisense strand, The sense strand and the antisense strand form a double strand, and the sense strand is sequence number 87 or It has a first nucleic acid sequence selected from Sequence ID No. 89, and the antisense strand is Sequence ID No. It is a MAPT RNAi agent having a second nucleic acid sequence of 88. In some embodiments, Provided herein is a MAPT RN having a sense strand and an antisense strand. An AI agent wherein the sense chain and the antisense chain form a double helix, and the sense chain However, it has a first nucleic acid sequence selected from sequence number 90 or sequence number 92, and the anticell The nucleotide chain is a MAPT RNAi agent having the second nucleic acid sequence of SEQ ID NO: 91. In several embodiments, the present specification provides a sense chain and an antisense chain. A MAPT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense strand has the first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand is It is a MAPT RNAi agent that has the second nucleic acid sequence of SEQ ID NO: 102. In embodiments, the following is provided herein: M having a sense chain and an antisense chain. APT RNAi agent wherein the sense strand and the antisense strand form a double helix. The sense strand has the first nucleic acid sequence of Sequence ID No. 103, and the antisense strand has the sequence This is a MAPT RNAi agent that has the second nucleic acid sequence number 104.

[0051] In some embodiments, the following are provided herein: a sense chain and an antisense chain. A MAPT RNAi agent having two strands, wherein the sense strand and the antisense strand are two strands. A chain is formed, and the sense chain has the first nucleic acid sequence of Sequence ID No. 105, and the antisense The chain is a second nucleus selected from one of the following: SEQ ID NO: 65, SEQ ID NOs: 106-108. It is a MAPT RNAi agent having an acid sequence. In some embodiments, this specification Provided is a MAPT RNAi agent having a sense strand and an antisense strand. The sense strand and the antisense strand form a double helix, and the sense strand is SEQ ID NO: 1 It has a first nucleic acid sequence of 09, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 65 It is a MAPT RNAi agent. In some embodiments, provided herein The agent is a MAPT RNAi agent having a sense strand and an antisense strand, and the sense strand The sense strand and the antisense strand form a double helix, and the sense strand is the [number] of SEQ ID NO: 110 It has a nucleic acid sequence 1, and the antisense strand has a second nucleic acid sequence of sequence number 40, It is a MAPT RNAi agent. In some embodiments, the following are provided herein: A MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and The antisense strand forms a double helix, and the sense strand is the first nucleic acid of Sequence ID No. 111. A MAP having a sequence, wherein the antisense strand has the second nucleic acid sequence of SEQ ID NO: 112. It is a T RNAi agent. In some embodiments, the following is provided herein: A MAPT RNAi agent having a sense chain and an antisense chain, wherein the sense chain and the The antisense strand forms a double helix, and the sense strand corresponds to the first nucleic acid sequence of SEQ ID NO: 113. The antisense strand has the second nucleic acid sequence of SEQ ID NO: 114, MAPT R It is an NAi agent. In some embodiments, the sense chain and are provided herein. MAPT RNAi agent having an antisense strand, wherein the sense strand and the antisense strand The sense strand forms a double strand, and the sense strand has the first nucleic acid sequence of SEQ ID NO: 115. The antisense strand has the second nucleic acid sequence of SEQ ID NO: 116, MAPT RNAi It is a drug.

[0052] [Table 2-1]

[0053] [Table 2-2]

[0054] [Table 2-3]

[0055] [Table 2-4] Abbreviations - "m" stands for 2'-OMe, and "f" stands for 2'-fluoro, * "teeth, It shows a phosphorothioate chain, and "VP" indicates 5'-vinylphosphonate, and "Uh "d" indicates 2'-O-hexadecyluridine, and "Chd" indicates 2'-O-hexadecyluridine "Ahd" indicates lucitidine, and "iAb" indicates 2'-O-hexadecyladenosine. " indicates the inverse debasement region, "n" indicates the debasement region, and "S" means the sense strand. And "AS" stands for antisense chain.

[0056] [Table 3] "5'" and "3'" indicate the direction from 5' to 3' in the sequence.

[0057] In some embodiments, the sense strand of the MAPT RNAi agent has a delivery portion. In some embodiments, the sense strand of the MAPT RNAi agent is the 5' end of the sense strand. It has a delivery portion conjugated at the end or 3' end. In some embodiments, The sense strand of the MAPT RNAi agent is conjugated with nucleotides in the sense strand. It has a delivery portion. The delivery portion can facilitate the entry of RNAi agents into cells. In embodiments, the delivery portion is α-tocopherol or palmitic acid (see Table 4). (Referring to illumination). In some embodiments, the delivery portion delivers the RNAi agent to the cell. For example, the well-known delivery portion, Hu et al., Signal Transduction an d. The delivery section as described in Targeted Therapy (2020) 5:101. It takes minutes. The placement of the delivery portion on the RNAi agent is the potential of AGO2 (Argonaut-2). Inefficient loading, or RNA-Induced Silencing Complex Other impairments to the activity of the x, RISC) complex need to be overcome.

[0058] In some embodiments, the delivery portion is connected via a linker to the 5' end of the sense strand or It is conjugated at the 3' end. In some embodiments, the linker is as shown in Table 5. Selected from linker 1, linker 2, linker 3, or linker 4. Other suitable Linkers are well known in the art. Exemplary linker-delivery pairs are shown in Table 6. In some embodiments, MAPT RNAi agents are linked to the linker-delivery moiety shown in Table 6. It has.

[0059] In some embodiments, the delivery portion is conjugated to the nucleotides of the sense strand. In that case, the delivery portion is a modified nucleotide located on the sense strand. In the embodiment, the modified nucleotide is 2'-O-hexadecyluridine, 2'-O -Hexadecylcytidine, 2'-O-Hexadecylguanine, or 2'-O-Hexadecyl It is ruadenosine (Table 4).

[0060] [Table 4-1]

[0061] [Table 4-2]

[0062] [Table 5]

[0063] [Table 6-1]

[0064] [Table 6-2]

[0065] In a further embodiment, provided herein is MAPT of formula (I):RLD It is an RNAi agent, where R is a double-stranded RNA (d) having a sense strand and an antisense strand. sRNA is a double-stranded RNA in which the sense strand and antisense strand form a double helix, where D is ds A delivery means for delivering RNA to cells, where L is the dsRNA linked to the delivery means. It is a connecting means for the purpose of connecting the sense chain and the anchor, or it may be absent if desired. Chisen chains are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and the second nucleic acid sequence of SEQ ID NO: 2 Antisense chains including (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and the second nucleic acid sequence of SEQ ID NO: 4 Antisense chains including (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and the second nucleic acid sequence of SEQ ID NO: 6 Antisense chains including (d) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and the second nucleic acid sequence of SEQ ID NO: 8 Antisense chains including (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and a second nucleic acid sequence of SEQ ID NO: 10 Antisense chain containing columns, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 11, and the second nucleic acid sequence of SEQ ID NO: 12 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 13, and the second nucleic acid sequence of SEQ ID NO: 14 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 15, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 17, and the second nucleic acid sequence of SEQ ID NO: 18 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and the second nucleic acid sequence of SEQ ID NO: 20 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and the second nucleic acid sequence of SEQ ID NO: 22 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23, and the second nucleic acid sequence of SEQ ID NO: 24 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 56, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing a sequence, (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 57, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (p) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleic acid sequence of SEQ ID NO: 58 Antisense strand containing a sequence, (q) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 60, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 62, and the second nucleic acid sequence of SEQ ID NO: 61 Antisense strand containing a sequence, (s) sense strand containing the first nucleic acid sequence of SEQ ID NO: 117, and the second of SEQ ID NO: 118 Antisense strand containing nucleic acid sequence, (t) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleus of SEQ ID NO: 16 Antisense chain containing acid sequence A pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0066] In some embodiments, the following is provided herein: M of formula (I):RLD APT RNAi agent, where R is a double-stranded R having a sense strand and an antisense strand. It is NA(dsRNA), and the sense strand and antisense strand form a double helix, in the formula D L is a delivery means for delivering dsRNA to cells, and L is a delivery means for delivering said dsRNA. A connecting means for connecting to a step, or, if desired, not present, and the sense chain and The aforementioned antisense chain is (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 1, and a second nucleic acid sequence of SEQ ID NO: 2 Antisense chain having columns, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 3, and a second nucleic acid sequence of SEQ ID NO: 4 Antisense chain having columns, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 5, and a second nucleic acid sequence of SEQ ID NO: 6 Antisense chain having columns, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 7, and a second nucleic acid sequence of SEQ ID NO: 8 Antisense chain having columns, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 9, and the second nucleic acid sequence of SEQ ID NO: 10 Antisense strand having an array, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 11, and a second nucleus of SEQ ID NO: 12 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 13, and a second nucleus of SEQ ID NO: 14 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 15, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 17, and a second nucleus of SEQ ID NO: 18 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 19, and a second nucleus of SEQ ID NO: 20 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 21, and a second nucleus of SEQ ID NO: 22 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 23, and a second nucleus of SEQ ID NO: 24 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of SEQ ID NO: 55, and the second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (n) A sense strand having the first nucleic acid sequence of SEQ ID NO: 56, and a second nucleus of SEQ ID NO: 16 Antisense chain having an acid sequence, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 57, and a second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (p) Sense strand having the first nucleic acid sequence of SEQ ID NO: 59, and the second nucleus of SEQ ID NO: 58 Antisense chain having an acid sequence, (q) A sense strand having the first nucleic acid sequence of SEQ ID NO: 60, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 62, and a second nucleus of SEQ ID NO: 61 Antisense chain having an acid sequence, (s) a sense strand having the first nucleic acid sequence of SEQ ID NO: 117, and the second nucleic acid sequence of SEQ ID NO: 118 An antisense strand having the nucleic acid sequence, and (t) A sense strand having the first nucleic acid sequence of SEQ ID NO: 119, and the second nucleic acid sequence of SEQ ID NO: 16 Antisense strand containing nucleic acid sequence A pair of nucleic acid sequences selected from the group consisting of, If desired, one or more nucleotides of the sense strand and the antisense strand may be independently The modified nucleotide is, optionally, one of the sense strand and the antisense strand. Any nucleotide linkage of more than one type is a modified nucleotide linkage.

[0067] In some embodiments, the following is provided herein: M of formula (I):RLD APT RNAi agent, where R is a double-stranded R having a sense strand and an antisense strand. It is NA(dsRNA), and the sense strand and antisense strand form a double helix, in the formula D L is a delivery means for delivering dsRNA to cells, and L is a delivery means for delivering said dsRNA. A connecting means for connecting to a step, or, if desired, not present, and the sense chain and The aforementioned antisense chain is (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25, and the second nucleic acid sequence of SEQ ID NO: 26 Antisense strand containing a sequence, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27, and the second nucleic acid sequence of SEQ ID NO: 28 Antisense strand containing a sequence, (c) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 29, and the second nucleic acid sequence of SEQ ID NO: 30 Antisense strand containing a sequence, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 31, and the second nucleic acid sequence of SEQ ID NO: 32 Antisense strand containing a sequence, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 33, and the second nucleic acid sequence of SEQ ID NO: 34 Antisense strand containing a sequence, (f) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 35, and the second nucleic acid sequence of SEQ ID NO: 36 Antisense strand containing a sequence, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 37, and the second nucleic acid sequence of SEQ ID NO: 38 Antisense strand containing a sequence, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 39, and the second nucleic acid sequence of SEQ ID NO: 40 Antisense strand containing a sequence, (i) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 41, and the second nucleic acid sequence of SEQ ID NO: 42 Antisense strand containing a sequence, (j) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 43, and the second nucleic acid sequence of SEQ ID NO: 44 Antisense strand containing a sequence, (k) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 45, and the second nucleic acid sequence of SEQ ID NO: 46 Antisense strand containing a sequence, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 47, and the second nucleic acid sequence of SEQ ID NO: 48 Antisense strand containing a sequence, (m) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 105, and SEQ ID NO: 65, SEQ ID NO: An antisense strand containing a second nucleic acid sequence selected from 10⁶ to 10⁸, (n) Sense strand containing the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleus of SEQ ID NO: 65 Antisense chain containing acid sequence, (o) sense strand containing the first nucleic acid sequence of SEQ ID NO: 110, and the second nucleus of SEQ ID NO: 40 Antisense chain containing acid sequence, (p) sense strand containing the first nucleic acid sequence of SEQ ID NO: 111, and the second of SEQ ID NO: 112 Antisense strand containing nucleic acid sequence, (q) sense strand containing the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 Antisense strands containing nucleic acid sequences, and (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand containing nucleic acid sequence It includes a pair of nucleic acid sequences selected from the group consisting of the following.

[0068] In some embodiments, the following is provided herein: M of formula (I):RLD APT RNAi agent, where R is a double-stranded R having a sense strand and an antisense strand. It is NA(dsRNA), and the sense strand and antisense strand form a double helix, in the formula D L is a delivery means for delivering dsRNA to cells, and L is a delivery means for delivering said dsRNA. A connecting means for connecting to a step, or, if desired, not present, and the sense chain and The aforementioned antisense chain is (a) A sense strand having the first nucleic acid sequence of SEQ ID NO: 25, and a second nucleus of SEQ ID NO: 26 Antisense chain having an acid sequence, (b) A sense strand having the first nucleic acid sequence of SEQ ID NO: 27, and a second nucleus of SEQ ID NO: 28 Antisense chain having an acid sequence, (c) A sense strand having the first nucleic acid sequence of SEQ ID NO: 29, and a second nucleus of SEQ ID NO: 30 Antisense chain having an acid sequence, (d) A sense strand having the first nucleic acid sequence of SEQ ID NO: 31, and a second nucleus of SEQ ID NO: 32 Antisense chain having an acid sequence, (e) A sense strand having the first nucleic acid sequence of SEQ ID NO: 33, and a second nucleus of SEQ ID NO: 34 Antisense chain having an acid sequence, (f) A sense strand having the first nucleic acid sequence of SEQ ID NO: 35, and a second nucleus of SEQ ID NO: 36 Antisense chain having an acid sequence, (g) A sense strand having the first nucleic acid sequence of SEQ ID NO: 37, and a second nucleus of SEQ ID NO: 38 Antisense chain having an acid sequence, (h) A sense strand having the first nucleic acid sequence of SEQ ID NO: 39, and a second nucleus of SEQ ID NO: 40 Antisense chain having an acid sequence, (i) A sense strand having the first nucleic acid sequence of SEQ ID NO: 41, and a second nucleus of SEQ ID NO: 42 Antisense chain having an acid sequence, (j) A sense strand having the first nucleic acid sequence of SEQ ID NO: 43, and a second nucleus of SEQ ID NO: 44 Antisense chain having an acid sequence, (k) A sense strand having the first nucleic acid sequence of SEQ ID NO: 45, and a second nucleus of SEQ ID NO: 46 Antisense chain having an acid sequence, (l) A sense strand having the first nucleic acid sequence of SEQ ID NO: 47, and a second nucleus of SEQ ID NO: 48 Antisense chain having an acid sequence, (m) Sense strand having the first nucleic acid sequence of Sequence ID No. 105, and Sequence ID No. 65, Sequence No. An antisense strand having a second nucleic acid sequence selected from numbers 106-108, (n) A sense strand having the first nucleic acid sequence of SEQ ID NO: 109, and the second nucleic acid sequence of SEQ ID NO: 65 Antisense strand having nucleic acid sequence, (o) A sense strand having the first nucleic acid sequence of SEQ ID NO: 110, and the second of SEQ ID NO: 40 Antisense strand having nucleic acid sequence, (p) A sense strand having the first nucleic acid sequence of SEQ ID NO: 111, and the second nucleic acid sequence of SEQ ID NO: 112 Antisense strand having the nucleic acid sequence, (q) A sense strand having the first nucleic acid sequence of SEQ ID NO: 113, and the second nucleic acid sequence of SEQ ID NO: 114 An antisense strand having the nucleic acid sequence, and (r) A sense strand having the first nucleic acid sequence of SEQ ID NO: 115, and the second nucleic acid sequence of SEQ ID NO: 116 Antisense strand having the nucleic acid sequence It has a pair of nucleic acid sequences selected from the group consisting of the following.

[0069] In some embodiments, the delivery means is conjugated to a sense chain. In that embodiment, the delivery means conjugates the 5' or 3' end of the sense strand In some embodiments, the delivery means conjugates the nucleotides of the sense strand. It is gated. In some embodiments, the delivery means is palmitic acid or It is α-tocopherol. In some embodiments, the linking means is linker 1 shown in Table 5. The linker is selected from the group consisting of linker 2, linker 3, and linker 4.

[0070] The sense strand and antisense strand of the MAPT RNAi agent are any known in the art. Nucleic acid polymerization methods, for example, solid-phase synthesis using phosphoramidite chemical methodology (for example) Current Protocols in Nucleic Acid Chem Istry, Beaucage, SL et al. (Edrs.), John Wiley and John Wiley & Sons, Inc. (New York, New York) Using the state, US, H-phosphonate method, phosphotriester chemistry, or enzymatic synthesis It can be synthesized using an automated, commercially available synthesizer, such as the LGC Biosearch. M from Technologies Inc. (LGC Biosearch Technologies) erMade®12, or BioAutomation Inc. (on) or from Applied Biosystems, Inc. A synthesizer can be used. The phosphorothioate chain is phenylacetyl disulfide Alternatively, DDTT(((dimethylaminomethylidene)amino)-3H-1,2,4-dithiazo Modified oligonucleotides can be introduced using sulfidation reagents such as phosphorus-3-thione. And to synthesize conjugate oligonucleotides, similar techniques and commercially available modifications Use amidite and Controlled-Pore Glass (CPG) products. However, this is common knowledge.

[0071] Using a purification method, undesirable impurities are removed from the final oligonucleotide product. It is possible. A commonly used purification technique for single-stranded oligonucleotides is reversed phase. Ion-Pair High Performance Liquid Chromatography (Reverse-Phase Ion Pair High Performance Liquid Chromatography) Chromatography (RP-IP-HPLC), Capillary Gel Electrophoresis (Capillary G Electrophoresis (CGE), anion exchange HPLC (AX- HPLC, and Size Exclusion Chromatography (S EC is one example. After purification, the oligonucleotides are analyzed by mass spectrometry, and 260n It can be quantified by spectrophotometric method at a wavelength of m. Next, the sense chain and antisense chain are analyzed. They can be linked together to form a double helix.

[0072] In another embodiment, the MAPT RN described herein is provided herein. This is a pharmaceutical composition containing an Ai agent and a pharmaceutically acceptable carrier. It is used for MAP in cells. Pharmaceutical compositions comprising means for reducing T expression and pharmaceutically acceptable carriers are also available. Provided herein, such pharmaceutical compositions may also contain one or more pharmaceutically acceptable substances. It may contain excipients, diluents, or carriers. The pharmaceutical composition is well known in the art. It may be prepared by law (for example, Remington: The Science a nd Practice of Pharmacy,23rd edition(202 (Year 0), A. Loyd et al., Academic Press).

[0073] In a further embodiment, a method for reducing MAPT expression in cells (e.g., nerve cells) is described. As provided in the specification, such methods are MAPT RNAi agents described herein. The process involves introducing the substance into the cells and allowing sufficient time for MAPT mRNA degradation to occur within the cells. This may include incubating and thereby reducing MAPT expression in cells. MAPT RNAi agents are transmitted by methods well known in the art, such as transfection. Electroporation, microinjection , or using cellular uptake via natural transport mechanisms, cells (e.g., nerve cells) ) can be introduced into this.

[0074] In another embodiment, provided herein is a MAP in patients who require it. This method reduces T expression, and such a method involves an effective amount of MA as described herein. This includes administering a PT RNAi agent or pharmaceutical composition to a patient. MAPT aggregation is MAPT protein overexpression or mutations that affect the protein structure can trigger This can be triggered, leading to an increased tendency for MAPT proteins to self-associate. Therefore, Reducing MAPT expression levels is beneficial for patients with tauopathy. It is possible.

[0075] In another embodiment, provided herein is a tauo in patients who require it. A method for treating pathology, such as the effective amount of MA described herein. This includes administering a PT RNAi agent or pharmaceutical composition to a patient. An example is tauopach. - This is not limited to Alzheimer's disease (A D) Frontotemporal dementia (FTD), linked to chromosome 17 and associated with parkinsonism in the frontal region. Temporal dementia (FTDP-17), frontotemporal lobar degeneration ion, FTLD), behavioral variant frontotemporal dementia (FTLD), behavioral variant frontotemporal dementia mentia, bvFTD), nonfluent variant primary progressive aphasia Progressive Aphasia (NFVPPA), Parkinson's Disease, Pick's Disease PiD), Primary Progressive Aphasia-Semantic (PPA-) S) Primary Progressive Aphasia-Logopenic (P PA-L), Multiple System Tauopathy with Premature Dementia (The presenile dementia, MSTD), neurofibrillary tangle, NF T) Dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic side Amyotrophic Lateral Sclerosis / Parkinsonism-Dementia Complex Syndrome sonism-Dementia Complex, ALS-PDC), Argyrophilic Grain Dementia (Argyrophilic Grain Dementia) Dementia (AGD), British-type amyloid angiopathy, cerebral amyloid angiopathy, Chronic Traumatic Encephalopathy (CTE), cerebral corticobasal nerve Corticobasal degeneration (CBD), Creutzfeldt-Jakob disease Zfeldt-Jakob Disease (CJD), Boxer's Dementia, Diffuse Neurofibrillary Tissue with Calcification calcification (idiopathic basal ganglia calcification, diffuse neurofibrillary tangles with calcification), Down syndrome, epilepsy, Gerstmann-Sträussler-Scheinker syndrome, Hallerfollicular syndrome Ruden-Spats disease, Huntington's disease, inclusion body myositis, lead-toxic brain disease, Ritiko-Bodig disease (Parkinsonian dementia complex syndrome in Guam), meningeal hemangioma, multiple system atrophy, myotonic dysplasia stroke, Niemann-Pick disease type C (NP-C), Non-Guanian motor neuron disease with neurofibrillary tangles, post-encephalitis sequelae parkinson's disease, Lyon protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle type senile Geriatric dementia, neurofibrillary senile dementia, argyrophilic granuloma, ganglioglioma, gangliocytoma, subacute subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis Primary age-related tauopathy (elderly tauopathy) , PART), Globular Glial Tauopathies (GGT), In some embodiments, tauopathy is associated with Alzheimer's disease (AD). It is either frontotemporal dementia (FTD) or progressive supranuclear palsy (PSP).

[0076] MAPT RNAi agents are administered to patients via intrathecal, intraventricular, or intracisional injection. Obtain. In some embodiments, MAPT RNAi agents are administered via a catheter to the patient. It is administered intrathecally to the patient.

[0077] RNAi drug regimens are designed to provide the optimal desired response (e.g., therapeutic response). The dosage may be adjusted. For example, a single bolus may be administered, or several divided doses may be given. It may be administered on an ad-hoc basis, or the dosage may be proportional, as indicated by the urgency of the treatment situation. It may decrease or increase.

[0078] The dosage may vary depending on the type and severity of the condition to be alleviated. For a given subject, the specific drug regimen is managed according to the individual needs and the administration of the composition. It should be further understood that this should be adjusted over time according to the professional judgment of the supervisor. It can be done.

[0079] In another embodiment, provided herein is a method for use in reducing MAPT expression , MAPT RNAi agent or pharmaceutical composition containing MAPT RNAi agent. MAPT RNAi agents or pharmaceutical compositions containing MAPT RNAi agents for use in the same manner. Furthermore, provided herein, MAP for use in the treatment of tauopathy. Pharmaceutical compositions containing T RNAi agents or MAPT RNAi agents are also provided herein. Provided. MAPT RNAi agents in the manufacture of pharmaceuticals for the treatment of tauopathy. Use is also provided herein.

[0080] When used herein, it is used in the context of this disclosure (particularly in the context of the claims). The terms "a," "an," "the," and similar terms are used unless otherwise specified herein. Unless otherwise, or unless the context clearly contradicts it, both singular and plural forms are used. Therefore, it should be interpreted as follows.

[0081] As used herein, the term "alkyl (alkyl)" means the number of carbon atoms indicated. This refers to a saturated linear or branched monovalent hydrocarbon group containing atoms. For example, "C1-C2 0 alkyl(C1-C 20 "Alkyl" refers to a group of 1 to 20 carbon atoms arranged in a linear or branched chain. It means to possess or to have a radical.

[0082] As used herein, “antisense strand” refers to a target sequence. This means oligonucleotides that are complementary to the region of [the specified region]. Similarly, as used herein The "sense strand" is an oligonucleotide complementary to the antisense strand region. It means Chido.

[0083] As used herein, “complementary” means two nucleotides. This allows them to form base pairs with each other (for example, on two opposing nucleic acids, or on a single It refers to the structural relationship between two nucleotides (on opposite regions of a single nucleic acid chain). If one nucleic acid has a purine nucleotide, it complements the pyrimidine nucleotide of the opposing nucleic acid. When they are targets, they may form base pairs by forming hydrogen bonds with each other. Complementary nucleotides are arranged in the Watson-Crick manner or in a stable duo. Base pairs can be formed in any other way that enables the formation of heavy chains. Similarly, two nuclei The acids, as described herein, are complementary to one another and form a region of complementarity, It may have a region of a certain number of nucleotides.

[0084] As used herein, “delivery portion” means oligonucleotides. This refers to the chemical portion that facilitates the entry of drugs or RNAi agents into cells. The delivery portion is lipids, collagen. It may be a sterol, vitamin E, carbohydrate, amino sugar, polypeptide, or protein. .

[0085] As used herein, "duplex" refers to nucleic acids or oligonucleotides. " is formed by two separate nucleic acid chains or by a single folded chain. Whether formed by (for example, via a hairpin), the two inverted planes of a nucleotide This refers to a structure formed through complementary base pairing of row sequences.

[0086] "Effective amount" is the amount (or duration) required to achieve the desired treatment outcome. This refers to the means of administration. The effective dose of RNAi agents depends on the individual's condition, age, sex and weight, as well as This can vary depending on factors such as the ability of the RNAi agent to induce the desired response in the individual. The effective dose also indicates that the therapeutically beneficial effect outweighs any toxic or adverse effects of the RNAi agent. It is an amount that exceeds the limit.

[0087] The terms "have," "having," or "has" When referring to an array, it means consisting of or essentially being made from.

[0088] "Knockdown" or "expression knockdown" The term refers to the reaction of mRNA or protein of a gene after treatment with a reagent, such as an RNAi agent. This refers to the current reduction.

[0089] As used herein, "modified internucleotide ligation" "Inkage)" refers to the comparison with the linkage between reference nucleotides having a phosphodiester bond. This refers to internucleotide links having one or more chemical modifications. Typically, modified nucleotides Rheotide ligations are one or more desirable properties in nucleic acids where modified nucleotide ligations exist. This confers properties such as thermal stability, resistance to degradation, and nuclease resistance. For example, modified nucleotides can confer properties such as thermal stability, resistance to degradation, and nuclease resistance. It may improve resistance, solubility, bioavailability, biological activity, and reduced immunogenicity. In several embodiments, the modified nucleotide linkage is a phosphorothioate chain.

[0090] As used herein, "modified nucleotide" means a Denine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, ura Silribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleate Rheotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide Selected from the range, having one or more chemical modifications compared to the corresponding reference nucleotide. This refers to nucleotides. Modified nucleotides are, for example, their sugars, nucleic acid bases, and / or The phosphate group may have one or more chemical modifications. In addition, or instead, the modified nucleus Otide has one or more chemical moieties conjugated to a corresponding reference nucleotide. This may also be the case. In some embodiments, the modified nucleotide is a 2'-fluoromodified nucleotide. Rheotide, 2'-O-methyl modified nucleotide, or 2'-O-alkyl modified nucleotide For example, a 2'-O-C16 alkyl-modified nucleotide. In some embodiments... In this case, the modified nucleotide has a phosphate analog, for example, 5'-vinylphosphonate. In some embodiments, the modified nucleotide is a debased moiety or an inverted debased moiety. For example, this is the portion shown in Table 3.

[0091] As used herein, the term "tauopathy" refers to an abnormality of the tauopathy This refers to diseases related to protein expression, secretion, phosphorylation, cleavage, and / or aggregation.

[0092] As used herein, "nucleotide" means a molecule linked to a phosphate group. Nucleosides (nucleic acid bases (e.g., adenine, cytosine, guanine, thymine or uranium)) It has silicic acid and pentose sugars (e.g., ribose or 2'-deoxyribose). It refers to a compound, which is a nucleic acid polymer (for example, deoxyribonucleic acid (deoxyribonucleic acid)). monomer units of ucleic acid (DNA) and ribonucleic acid (RNA) And it can have an effect.

[0093] As used herein, "oligonucleotide" means a combination of It means a polymer of combined nucleotides, each of which can be modified or They cannot be modified. Oligonucleotides are typically less than about 100 nucleotides in length. ru.

[0094] As used herein, "overhang" refers to a double-stranded oligonucleotide. This refers to unpaired nucleotides (one or more) that protrude from the double-strand structure of a rheotide. A bar hang extends from the 5' or 3' terminal of the double-stranded oligonucleotide. It may contain one or more unpaired nucleotides. The overhang is a double-strand oligonucleotide. 3' overhang or 5' overhang on the antisense or sense strand of a nucleotide It could be.

[0095] As used herein, the term "patient" refers to a human patient.

[0096] As used herein, "phosphate analog" refers to a static phosphate group. This refers to a chemical part that mimics electrical and / or stereochemical properties. In some embodiments, The phosphate analog is the 5' terminal nucleotide of the oligonucleotide instead of the 5'-phosphate. Located in this position, it is often susceptible to enzymatic removal. 5'-phosphates The analogues may include phosphatase resistance chains. An example of a phosphate analogue is 5'-methylene. Phosphonate (5'-MP) and 5'-(E)-vinylphosphonate (5'-VP) Examples include: In some embodiments, the phosphate analog is 5'-VP.

[0097] "Sequence identity % (% sequence identity)" or "Sequence identity P" for reference nucleic acid sequences. The term "percentage sequence identity" refers to the optimal alignment of sequences. Gaps or overhangs are introduced as needed to achieve the maximum sequence identity percentage. The nucleotide, nucleoside, or nucleic acid base in the reference nucleic acid sequence after insertion is identical. Defined as the percentage of nucleotides, nucleosides, or nucleic acid bases in a candidate sequence. Alignment for the purpose of determining nucleic acid sequence identity percentage is relevant to the technical field. In various ways within the scope of his skills, for example, publicly available computer software A program, for example, Current Protocols in Molecula r Biology (Ausubel et al., eds., 1987, Supp. 30, secti) Things like those listed on 7.7.18, Table 7.7.1), for example, BLAST, BLAST-2, ALIGN, Clustal W2.0, Clustal A computer containing X2.0 or Megal(DNASTAR) software. This can be achieved using a software program. Those skilled in the art will know that the total length of the sequences being compared is Including any algorithms required to achieve the maximum alignment across the board. This allows us to determine the appropriate parameters for measuring alignment. "Sequence identity (se The percentage of "quence identity)" is the two best-aligned values ​​across the comparison window. This can be determined by comparing the sequences, but the fragments of nucleic acid sequences within the comparison window This is a reference sequence (without additions or deletions) for the optimal alignment of the two sequences. Compared to the original, this may include additions or deletions (e.g., gaps or overhangs). A stage is a position where the same nucleotide, nucleoside, or nucleic acid base exists in both sequences. The number of positions is calculated, the number of matching positions is determined, and the number of matching positions is compared in the position in the comparison window. We divide by the total number of positions and multiply the result by 100 to find the percentage of sequence identity. Therefore, it can be calculated. The output is the percentage of identity between the subject sequence and the query sequence. ru.

[0098] As used herein, the terms "RNAi" and "RNAi agent" are used. "iRNA", "iRNA agent", and "RNA interfering agent (RNA "Interference agents" are, for example, involved in the RNA-induced silencing complex (RISC) pathway. This refers to drugs that mediate sequence-specific degradation of target mRNA through RNA interference. In some embodiments, the RNAi agent has a sense strand and an antisense strand, and The sense chain and the antisense chain form a double helix. In some embodiments, the sense chain is , the delivery portion, for example, the 5' or 3' end of the sense strand or the nucleotide of the sense strand It has a conjugated delivery portion.

[0099] As used herein, “strand” means a link between nucleotides (for example, nucleotides). Nucleotides linked together by a phosphorothioate chain or phosphorothioate chain A chain refers to a single, continuous sequence of fibers. A chain has two free ends (e.g., the 5' end and the 3' end). It may have an end.

[0100] As used herein, "MAPT" encodes the microtubule-associated protein tau. This refers to human MAPT mRNA transcripts. The nucleotide sequences of human MAPT transcription mutants and The amino acid sequences of the human tau protein isoforms can be found below.

[0101] i. MAPT transcription mutant 1 → tau protein isoform 1: NM_016835 .5 (nucleotide sequence) → NP_058519.3 (amino acid sequence), ii. MAPT transcription mutant 2 → tau protein isoform 2: NM_00591 0.6 (nucleotide sequence) → NP_005901.2 (amino acid sequence) iii. MAPT transcription mutant 3 → tau protein isoform 3: NM_0168 34.5 (nucleotide sequence) → NP_058518.1 (amino acid sequence) iv. MAPT transcription mutant 4 → tau protein isoform 4: NM_01684 1.5 (nucleotide sequence) → NP_058525.1 (amino acid sequence) v. MAPT transcription mutant 5 → tau protein isoform 5: NM_001123 067.4 (nucleotide sequence) → NP_001116539.1 (amino acid sequence) vi. MAPT transcription mutant 6 → tau protein isoform 6: NM_00112 3066.4 (nucleotide sequence) → NP_001116538.2 (amino acid sequence) vii. MAPT transcription variant 7 → tau protein isoform 7: NM_0012 03251.2 (nucleotide sequence) → NP_001190180.1 (amino acid sequence) , viii. MAPT transcription mutant 8 → tau protein isoform 8: NM_001 203252.2 (nucleotide sequence) → NP_001190181.1 (amino acid sequence) ), ix. MAPT transcription mutant 9 → tau protein isoform 9: NM_00137 7265.1 (nucleotide sequence) → NP_001364194.1 (amino acid sequence) x. MAPT transcription mutant 10 → tau protein isoform 10: NM_0013 77266.1 (nucleotide sequence) → NP_001364195.1 (amino acid sequence) , xi. MAPT transcription mutant 11 → tau protein isoform 11: NM_001 377267.1 (nucleotide sequence) → NP_001364196.1 (amino acid sequence) ), xii. MAPT transcription mutant 12 → tau protein isoform 4: NM_001 377268.1 (nucleotide sequence) → NP_001364197.1 (amino acid sequence) ).

[0102] The nucleotide sequence of human MAPT transcription mutant 6 (encoding 2N4R tau) is NM It can be found in _001123066.4.

[0103] JPEG2026053368000012.jpg193151

[0104] JPEG2026053368000013.jpg229151

[0105] JPEG2026053368000014.jpg25150 (SEQ ID NO: 49).

[0106] The corresponding amino acid sequence for human tau protein isoform 6 is NP_001116 It can be found in 538.2.

[0107] JPEG2026053368000015.jpg53148 (SEQ ID NO: 50).

[0108] The nucleotide sequence of human MAPT transcription mutant 5 (encoding 1N4R tau) is NM It can be found in _001123067.4.

[0109] JPEG2026053368000016.jpg97150

[0110] JPEG2026053368000017.jpg229151

[0111] JPEG2026053368000018.jpg49150 (Sequence ID 51).

[0112] The corresponding amino acid sequence for human tau protein isoform 5 is NP_001116 It can be found in 539.1.

[0113] JPEG2026053368000019.jpg29148 (Sequence ID 52).

[0114] The nucleotide sequence of human MAPT transcription mutant 4 (encoding 0N3R tau) is NM It can be found in _016841.5.

[0115] JPEG2026053368000020.jpg105150

[0116] JPEG2026053368000021.jpg229151

[0117] JPEG2026053368000022.jpg29150 (Sequence ID 53).

[0118] The corresponding amino acid sequence for human tau protein isoform 4 is NP_058525. .1: can be found.

[0119] JPEG2026053368000023.jpg25148 (Sequence ID 54).

[0120] As used herein, "subject" refers to a mammal (cat, dog, mau). This means (including rats, chimpanzees, apes, monkeys, and humans). Preferably, The subject of the test is a human.

[0121] As used herein, “treatment” or “treating” "This means slowing, controlling, delaying, or stopping the progression of any disorder or disease disclosed herein, or This refers to all processes that may lead to improvement in the symptoms of a disability or disease, but not necessarily all disabilities. Treatment does not indicate the complete elimination of symptoms of harm or disease. Treatment is not intended for the patient, especially in humans. The administration of proteins, nucleic acids, vectors, or compositions for the treatment of a disease or condition. nothing. [Examples]

[0122] Example 1. Synthesis of linker-delivery subpair pairs Certain abbreviations are defined as follows: "ACN" stands for acetonitrile. "AEX" refers to anion exchange, and "C / D" refers to the cutoff. Cleavage and Deprotection refers to controlled pore glass (C It refers to controlled porous glass, and "DCM" stands for dichloromethane. "DEA" refers to diethylamine, and "DIEA" refers to N,N - refers to diisopropylethylamine (N,N-diisopropylethylamine), and "DMAP" is , refers to 4-dimethylaminopyridine, and "DMF" stands for Dime Dimethylformamide is the term used, while "DMSO" stands for dimethyl sulfoxy It refers to dimethyl sulfoxide, and "DMTCl" is 4,4'-dimethoxytritilk It refers to loride (4,4'-dimethoxytrityl chloride), and "ES / MS" is electrosplash This refers to electrospray mass spectrometry, and "ELISA" is ethyl acetate. "EtOH" refers to ethyl acetate, and "EtOH" refers to ethanol or ethyl alcohol (eth HBTU refers to 3-[bis(dimethylamino)methyl alcohol], and 3-[bis(dimethylamino)methyl alcohol]. [Liumyl]-3H-benzotriazole-1-oxidehexafluorophosphate (3-[b is(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate) And "HOBt" is 1-hydroxybenzotriazole "IP-RP" refers to Ion-Pair Reverse Phase, and "LCAA" refers to ion-pair reverse phase. "CPG" stands for long-chain alkylamine controlled pore glass. "LC / MS" refers to liquid chromatography-mass spectrometry (Liquid pore glass). Chromatography (Mass Spectrometry) is the term, and "MeOH" refers to methanol and methyl alcohol. "Methanol and methyl alcohol" refers to the mobile phase A (Mobile Phase A). "MPB" refers to Mobile Phase B, and "MWCO" refers to Mobile Phase B. It refers to molecular weight cut-off, and "NMR" is nuclear magnetic resonance (NMR) Nuclear Magnetic Resonance (PBS) refers to phosphate-buffered saline (phosphate-buffered saline). "PEG" refers to polyethylene glycol (polyethylene glycol). l) refers to polyvinylidene fluoride. "RP" refers to Reverse Phase, and "RPM" refers to the number of revolutions per minute (Revol siRNA stands for small interfering ribonucleic acid (SMEs), and siRNA is a small interfering ribonucleic acid. "Ribone" refers to ribonucleic acid, while "TEA" refers to triethylamine. "THF" refers to tetrahydrofuran, and "TLC" refers to thin Thin Layer Chromatography (TMP) is a term that refers to (2,2 This refers to ,6,6-tetramethylpiperidine (2,2,6,6-tetramethylpiperidine), and "UP "LC" stands for Ultra-Performance Liquid Chromatography. ) refers to ultraviolet rays.

[0123] [ka]

[0124] Step A of Scheme 1 uses a suitable base such as DMAP in a suitable solvent such as DCM. This demonstrates the coupling of compounds (1) and (2) to obtain compound (3). B is compound (3) in the presence of a base such as potassium carbonate, in a solvent system such as water and THF. (and 1-amino-3,6,9,12-tetraoxopentadecane-15-acid) in a cup This shows that compound (4) is obtained by ringing.

[0125] [ka]

[0126] Step A of Scheme 2 involves the mixing of triphenylphosphene and azodica in a solvent such as THF. Using diisopropyl rubonate, compound (5) and tert-butyl 1-hydroxy- 3,6,9,12-tetraoxapentadecane-15-oate is subjected to the Mitsunobu reaction to combine the compounds. This shows that substance (6) is obtained. Step B involves HCl( The method involves using an acid such as hydrochloric acid to acidically deprotect compound (6) and obtain compound (7). vinegar.

[0127] [ka]

[0128] Step A of Scheme 3 involves DM in a solvent such as DCM along with a suitable base such as DIEA. This shows that compound (8) is protected using TCl to obtain compound (9). Step B is: Compound (9) and P Compound (10) is obtained by amide coupling with peridine-4-ylmethanol. This shows that compound (10) is deprotected with 20% piperidine in DMF to obtain compound (11). Step C shows how to obtain this.

[0129] [ka]

[0130] Step A of Scheme 4 involves HBTU and a base such as DIEA in a solvent such as DMF. Using standard coupling reagents such as HOBt, compound (11) and compound (4) Alternatively, compound (12) can be obtained by amide coupling with any of the compounds (7). This demonstrates the various conditions that may be used to carry out this amide coupling. Those skilled in the art will see the various conditions that may be used to carry out this amide coupling. They will recognize the matter. Step B involves a base such as TEA and a catalyst in a solvent such as DCM. Using DMAP, compound (12) and succinic anhydride are coupled to form compound ( Step C is performed in a solvent such as ACN with a base such as DIEA. Using HBTU, the amide capillary of compound (13) to aminoLCAA CPG Next, we show a multi-step workup for obtaining compound (14).

[0131] Preparation 1 2,5-Dioxopyrrolidine-1-ylpalmitic acid

[0132] [ka]

[0133] Palmitic acid (2.00 g, 7.80 mmol) is added to 1-(3) of DCM (31 mL). -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.79g, 9.36 The mixture was added to a solution of mmol) and DMAP (0.19 g, 1.56 mmol). Stir at ambient temperature for 5 minutes, then add N-hydroxysuccinimide (0.99 mg, 8. 58 mmol) was added and stirred at ambient temperature for 18 hours. The resulting crude material was concentrated in a vacuum. Shrink and elute silica gel flash chloride in hexane with a gradient of 0-80% toluene. The title compound was purified by matrixing and obtained as a white solid (2.65 g, 96%). 1 H NMR(DMSO-d6)δ2.81(s,4H), 2.66(t,2H),1. 62(m,2H), 1.25(br s,24H), 0.87(t,3H).

[0134] Preparation 2 3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]eth [Xy]ethoxy]propanoic acid

[0135] [ka]

[0136] 1-Amino-3,6,9,12-tetraoxapentadecane-15-acid (0.14 mg) (0.53 mmol) is mixed with potassium carbonate (0.1 mL) in THF (1 mL) and water (2 mL). It was added to a 4 mg (1.00 mmol) solution. 2,5-Dioxopyrrolidine-1-I Add rubal palmitic acid (0.18 mg, 0.51 mmol) and allow the reaction to rise at ambient temperature for 1 minute. The mixture was stirred for 8 hours. The reaction mixture was quenched with water (30 mL) and the pH was adjusted with 1 N hydrochloric acid solution. The solution was adjusted to ~3. A precipitate formed, which was collected by vacuum filtration, and the title compound was obtained. It was obtained as a white solid (0.19 mg, 74%). ES / MSm / z504(M+H).

[0137] Preparation 3 tert-butyl3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetra Methyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6- Iyl oxyethoxyethoxyethoxyethoxyethoxypropanoate

[0138] [ka]

[0139] (2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12 [Rimethyltridecyl]chroman-6-ol (3.00 mg, 6.90 mmol), te rt-butyl1-hydroxy-3,6,9,12-tetraoxapentadecane-15-o Ethol (2.50 mg, 7.60 mmol), and triphenylphosphine (2.00 mg) Mix (g, 7.60 mmol) in THF (28.0 mL) and diazodicarboxylic acid Sopropyl (1.50 mL, 7.60 mmol) was added dropwise over 5 minutes. The mixture was heated at 60°C for 16 hours. The mixture was cooled to ambient temperature, and silica gel was added. The mixture was concentrated in a vacuum to obtain an off-white solid. The mixture was then subjected to silica gel flash chromatography. The title compound was purified by Graphy, eluted with 0-40% alkylammonium hexane, and extracted as an oil. It was obtained as a substance (3.33g, 66%). 1 ¹H NMR (CDCl3): 3.84(s,4) H),3.77-3.71(m,13H),2.59(t,J=6.8Hz,2H),2 .52(t,J=6.6Hz,2H),2.20-2.20(m,3H),2.15-2 .12(m,3H),2.10(s,3H),1.87-1.73(m,2H),1.5 8-1.51(m,4H),1.47(s,9H),1.35-1.27(m,21H) ,0.90-0.86(m,12H).

[0140] Preparation 4 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[( 4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyeth Xy]ethoxy]ethoxy]ethoxy]propanoic acid

[0141] [ka]

[0142] In 4M HCl (22.6 mL, 90.6 mmol) in dioxane, tert- Tyl 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[ (4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxy Toxyethoxyethoxyethoxypropanoate (3.33 mg, 4.53 mg) The solution (ol) was dissolved and stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure, and the title compound was obtained. It was obtained as an off-white solid (3.08 g, 100%). ES / MS m / z 678 0.0 (MH).

[0143] Preparation 5 (2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H -Fluorene-9-ylmethoxycarbonylamino)propanoic acid

[0144] [ka]

[0145] Under an inert atmosphere, at 0°C, (2S)-2-(9H-Fur in dry DCM (400 mL) Oren-9-ylmethoxycarbonylamino)-3-hydroxy-propanoic acid (40g, Add DIEA (64 mL, 0.366 mol) to a stirred solution of 0.122 mol. This mixture contains 49.6 g of DMTCl (0.146 ml) in 200 mL of DCM. The solution of (l) was slowly added. The mixture was heated to ambient temperature and stirred for 16 hours. After this, the reaction was carried out. The mixture was diluted with water and extracted with DCM. The organic matter was dried on anhydrous sodium sulfate. The crude residue was filtered and concentrated in a vacuum. The crude residue was washed with 10% dimethyl hexane and vacuum. The compound was dried underwater to obtain a crude, light brown solid (62 g, crude). TLC : 5% MeOH / CH2Cl2(R f :0.5) UV, 254 nM.

[0146] Preparation 6 9H-Fluoren-9-ylmethyl N-[(1S)-1-[[Bis(4-methoxymethyl [(nyl)-phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperyl] [zyl]-2-oxo-ethyl]carbamate

[0147] [ka]

[0148] (2S)-3-[bis(4-methoxyphenyl)-phenyl in DCM (750 mL) [Lu-methoxy]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propane In a stirred solution of nic acid (62 mg, 0.103 mol), HBT was added under an inert atmosphere at 0°C. U (78.3mg, 0.206mol), HOBt (27.9mg, 0.206mol) , and piperidine-4-ylmethanol (15.4 mg, 0.134 mol), followed by T MP (15 mL, 0.113 mol) was slowly added. The resulting reaction mixture was then cooled. The mixture was returned to warm temperature and stirred for 4 hours. After this, the mixture was diluted with water and extracted with DCM. The organic matter was extracted. The residue was dried on anhydrous sodium sulfate, filtered, and concentrated in a vacuum. The resulting residue was 20- Silica gel flush that elutes with 40% ammonium / hexane and 1% MeOH / DCM The compound was purified by sulfonometry to obtain the title compound (40g, 52% in two steps). Ta. 1 H NMR (DMSO-d6) δ7.88 (br d, J=7.5Hz, 2H), 7.79-7.59(m, 3H), 7.45-7.12(m, 13H), 6.92-6. 76(m, 4H), 4.79-4.44(m, 2H), 4.32(br d, J=11. 4Hz, 2H), 4.20(br s, 2H), 3.71(s, 6H), 3.21(br s, 4H), 2.99-2.79(m, 1H), 2.69(br s, 2H), 1.8 1-1.43(m, 3H), 1.08-0.73(m, 2H).

[0149] Preparation 7 (2S)-2-amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy] -1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one

[0150] [ka]

[0151] A 20% piperidine solution in DMF (400 mL) is incubated at 0°C under an inert atmosphere for 9 H-Fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl )-phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperidyl Slowly add to ]-2-oxo-ethyl]carbamate (40g, 0.055mol) Add. The mixture was heated to ambient temperature and stirred for 1 hour. After this, the mixture was diluted with water and E Extraction was performed using tOAc. The organic matter was dried on anhydrous sodium sulfate, filtered, and concentrated in a vacuum. Shrinkage occurred. The obtained residue was eluted with 1-8% MeOH / DCM silica gel flash. The title compound was purified by chromatography and obtained as an off-white solid (13g, 47%). The result obtained was: ES / MS m / z 1009.5 (2M+H).

[0152] Preparation 8 N-[2-[2-[2-[2-[3-[[(1S)-1-[[Bis(4-Methoxyphenate) [(nyl)-phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperyl] [zyl]-2-oxo-ethyl]amino]-3-oxo-propoxy]ethoxy]ethoxy Ethoxyethyl hexadecanamide

[0153] [ka]

[0154] 3-[2-[2-[2-[2-(Hexadecanoylaminoglycanamide in DMF (9.84 mL) Ethoxy]Ethoxy]Ethoxy]Ethoxy]Propanoic acid (496mg, 0.984mg) ol), HOBt (146 mg, 1.08 mmol), HBTU (410 mg, 1.08 Mix mmol) and DIEA (1.03 mL, 5.90 mmol) and leave at ambient temperature for 1 Stirred for 0 minutes. (2S)-2-amino-3-[bis(4-methoxyphenyl)-pheni [ru-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl]propane-1-o 546 mg (1.08 mmol) was added to the mixture and stirred at ambient temperature for 16 hours. The mixture was partitioned between toluene and saturated sodium chloride aqueous solution. The layers were separated and the organic The material was washed with a saturated sodium chloride solution. The organic matter was dried on sodium sulfate and filtered. The residue was then concentrated in a vacuum. The obtained residue was eluted with 0-10% MeOH / DCM. The title compound was purified by Kagel flash chromatography and extracted into an oil (327 mg, 3 It was obtained as 4%. ¹H NMR (DMSO-d6) 8.21 (d, J=8.5Hz, 1 H),7.80(t,J=5.6Hz,1H),7.37-7.28(m,4H),7. 23-7.20(m,5H),6.88(d,J=8.3Hz,4H),5.06-5. 02(m,1H),4.51-4.49(m,1H),4.45-4.40(m,1H) ,3.97-3.93(m,1H),3.74(s,5H),3.63-3.56(m, 2H),3.49-3.48(m,4H),3.47-3.45(m,7H),3.40 -3.35(m,2H),3.30(s,1H),3.23-3.13(m,7H),2 .41-2.33(m,2H),2.04(t,J=7.4Hz,2H),1.74-1 .69(m,3H),1.51-1.44(m,2H),1.26-1.24(m,24 H),1.00-0.97(m,1H),0.88-0.82(m,5H).

[0155] Preparation 9 4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxyphenyl ]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy [C]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]meth [Xy]-4-oxo-butanoic acid

[0156] [ka]

[0157] In DCM (6.46 mL), N-[2-[2-[2-[2-[3-[[(1S)-1 -[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(Hy) [Droxymethyl)-1-piperidyl]-2-oxo-ethyl]amino]-3-oxo-p Lopoxyethoxyethoxyethoxyethyl hexadecanamide (320 mg, 0.323mmol), DMAP (120mg, 0.969mmol), TEA (225 μL, 1.62 mmol), and succinic anhydride (64.7 mg, 0.646 mmol) The mixture was mixed and stirred at ambient temperature for 16 hours. The mixture was then subjected to silica gel flash chromatography. The title compound was purified directly by tography, eluted with 0% to 40% MeOH / DCM, and then... It was obtained as an oily substance (279 mg, 79%). 1 1H NMR (DMSO-d6) 12.65 -12.64(m,1H),8.24-8.19(m,1H),7.80(t,J=5. 6Hz,1H),7.37-7.28(m,4H),7.24-7.20(m,5H), 6.88(d,J=8.6Hz,4H),5.05-5.01(m,1H),4.44- 4.40(m,1H),3.97-3.95(m,3H),3.74(s,6H),3. 61-3.56(m,2H),3.49-3.45(m,11H),3.38(t,J= 5.9Hz, 3H), 3.22-3.14 (m, 6H), 2.48-2.31 (m, 7H) ),2.04(t,J=7.4Hz,2H),1.90-1.87(m,5H),1.2 4(s,23H),0.98-0.96(m,1H),0.87-0.82(m,4H) .

[0158] Preparation 10 4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxyphenyl ]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl- 2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]o Xyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]- 4-Piperidyl]methoxy]-4-oxo-butanoic acid

[0159] [ka]

[0160] 3-[2-[2-[2-[2-[(2R)-2,5,7, in DMF (18.0 mL) 8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chloromethyl Man-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (1.2 0g, 1.80mmol), HOBt (260mg, 1.90mmol), HBTU(7 Mix 40 mg (1.90 mmol) and DIEA (1.80 mL, 11.0 mmol). The mixture was combined and stirred at ambient temperature for 10 minutes. (2S)-2-amino-3-[bis(4-methoxy] [phenyl)-phenyl-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl] Add propan-1-one (980 mg, 1.90 mmol) to the mixture and heat at ambient temperature. The mixture was stirred for 16 hours. The mixture was then partitioned between toluene and a saturated sodium chloride aqueous solution. The layers were separated and the organic matter was washed with saturated sodium chloride solution. The residue was dried on a surface, filtered, and concentrated in a vacuum. The resulting residue was then flash-cloned with silica gel. Purified by matrixing, eluted with 0-10% MeOH / DCM, and N-[(1S)] -1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4- (Hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]-3-[2-[2-[ 2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8 ,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]eth [Xy]ethoxy]propenamide was obtained as a yellow oily substance.

[0161] In DCM(24.9), N-[(1S)-1-[[bis(4-methoxyphenyl)- Phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperidyl]- 2-Oxo-ethyl]-3-[2-[2-[2-[2-[(2R)-2,5,7,8-ethyl] Tramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman 6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propenamide (1.45 g, 1.24 mmol), DMAP (456 mg, 3.73 mmol), TEA (867 Mix μL (6.22 mmol) and succinic anhydride (249 mg, 2.49 mmol). The mixture was then stirred at ambient temperature for 16 hours. The resulting residue was concentrated in a vacuum and then flushed with silica gel. The compound was purified by chromatography, eluted with 0-40% MeOH / DCM, and the title compound was extracted. It was obtained as an oily substance (1.36 g, 60%). ES / MS m / z 1264.4 (M- H).

[0162] Preparation 11 [4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl on CPG [Lu-methoxy]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)eth Xy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-pipette Lysyl Methoxy-4-Oxo-Butanoyl Amino

[0163] [ka]

[0164] 4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxyphenyl ]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy [C]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]meth [Xy]-4-oxo-butanoic acid (270 mg, 0.248 mmol) is administered to ACN (12. Dissolve in 5 mL of DIEA (150 μL, Add 0.860 mmol) and HBTU (190 mg, 0.500 mmol) to the solution. The mixture was shaken at ambient temperature for 10 minutes. Natural amino LCAA CPG 500 Å (1 Add 0.92g (129 μmol / g) to the solution and leave the mixture at ambient temperature for 16 hours at 500°C. The mixture was shaken with RPM. The CPG was drained and dried under nitrogen for 5 minutes. The CPG was then processed with DCM ( (50 mL), 10% MeOH / DCM (50 mL), then diethyl ether (50 mL) Washed with L). The CPG was dried under nitrogen for 30 minutes, and then in pyridine (15 mL) The solution was resuspended in acetic anhydride (3.30 mL, 35.0 mmol) and TEA (0.50 mL). The mixture was then shaken at 500 RPM for 2 hours at ambient temperature. The CPG was drained and nitrated. Dry underwater for 5 minutes. CPG was mixed with DCM (50 mL) and 10% MeOH / DCM ( Next, wash with diethyl ether (50 mL). CPG was sterilized under nitrogen for 4 minutes. After drying for 5 minutes, the ligand loading was determined at 505 nm, and the title compound (1.92 mg, 7 A concentration of 5.5 μmol / g was obtained.

[0165] Preparation 12 [4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl on CPG [ru-methoxy]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-the Tramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman 6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]pro [Panoyl]-4-piperidyl]methoxy]-4-oxo-butanoyl]amino]

[0166] [ka]

[0167] In a method essentially similar to preparation 11, 4-[[1-[(2S)-3-[bis(4-me Toxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-[(2 R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethicone Tridecyl chroman-6-yl oxyeth [Propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-buta The title compound was prepared from phosphoric acid. The ligand loading was determined at 505 nm, and the title compound ( 4.01 g, 66.9 μmol / g) was obtained.

[0168] Preparation 13 3-[[(2R,3R,4R,5R)-2-[[Bis(4-methoxyphenyl)-phen yl-methoxy]methyl]-4-hexadecoxy(hexadecoxy)-5-(2-hydroxy -4-oxo-pyrimidin-1-yl)THF-3-yl]oxy-(diisopropyl a mino)phosphanyl]oxypropanenitrile

[0169] [Chemical Structure]

[0170] The title compound was prepared according to the protocol described in International Publication No. 2019217459. prepared. 1 1H NMR (CD3CN): 7.86 - 7.73 (m, 1H), 7.51 - 7 .43 (m, 2H), 7.40 - 7.23 (m, 7H), 6.95 - 6.87 (m, 4H ), 5.90 - 5.84 (m, 1H), 5.29 - 5.21 (m, 1H), 4.54 - 4 .40 (m, 1H), 4.21 - 4.13 (m, 1H), 4.10 - 3.56 (m, 13 H), 3.50 - 3.34 (m, 2H), 2.75 - 2.62 (m, 1H), 2.55 ( t, J = 6.0 Hz, 1H), 1.66 - 1.51 (m, 2H), 1.40 - 1.14 ( m, 35H), 1.08 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 6.8 Hz , 3H). 31 31P NMR (CD3CN): 149.6, 149.2.

[0171] Preparation 14 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)- Phenyl-methoxymethyl]-4-[2-cyanoethoxy-(diisopropylamino) Phosphanyl]oxy-3-hexadecoxytetrahydrofuran-2-yl]purine 6-yl]benzamide

[0172] [ka]

[0173] The title compound was prepared according to the protocol described in International Publication No. 2019217459. It was made. 1 H-NMR(CD3CN)δ9.37(s,1H),8.57(d,J=9. 4Hz,1H),8.27(d,J=10.3Hz,1H),7.99(d,J=7.6 Hz,2H),7.61(d,J=7.4Hz,1H),7.52(t,J=7.6Hz ,2H),7.42(t,J=7.3Hz,2H),7.34-7.16(m,7H), 6.85-6.77(m,4H),6.1 1(dd,J=5.0,2.5Hz,1H) ,4.80(m,1H),4.69(m,1H),4.32(m,1H),3.97-3 .78(m,1H),3.74(d,J=3.1Hz,7H),3.64(m,4H), 3.56-3.40(m,2H),3.33(m,1H),2.73-2.59(m,1 H),2.50(t,J=6.0Hz,1H),1.52-1.45(m,2H),1. 33-1.12(m,37H),1.09(d,J=6.8Hz,3H),0.87(t (J=6.8Hz, 3H). 31 P NMR (CD3CN) δ 151.19, 150.7 8.

[0174] Preparation 15 N-[1-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)- Phenyl-methoxymethyl]-4-[2-cyanoethoxy-(diisopropylamino) Phosphanyl]oxy-3-hexadecoxytetrahydrofuran-2-yl]-2-ol [Xopyrimidine-4-yl]acetamide

[0175] [ka]

[0176] The title compound was prepared according to the protocol described in International Publication No. 2019217459. It was made. 1 H-NMR(CD3CN)9.15(s,1H),8.46(dd,J=7. 5Hz,1H),7.95(d,J=7.6Hz,2H),7.63(t,J=7.5H z,1H),7.57-7.41(m,5H),7.41-7.31(m,6H),7. 28(m,1H),7.04(d,J=15.8Hz,1H),6.90(t,J=7. 9Hz,4H),5.90(d,J=7.8Hz,1H),4.51(m,1H),4. 20(dd,J=10.6,8.1Hz,1H),4.04(dd,J=31.3,4. 6Hz,1H),3.91-3.81(m,2H),3.79(d,J=3.1Hz,6 H),3.74(m,2H),3.69-3.41(m,6H),2.67-2.59( m,1H),2.54-2.48(m,1H),1.58(m,2H),1.36(m, 2H),1.25(d,J=4.7Hz,26H),1.21-1.09(m,10H) ,1.04(d,J=6.8Hz,3H),0.87(t,J=6.8Hz,3H). 31P NMR(CD3CN)δ151.10,150.19.

[0177] Preparation 16 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)- Phenyl-methoxymethyl]-4-[2-cyanoethoxy-(diisopropylamino) Phosphanyl]oxy-3-hexadecoxytetrahydrofuran-2-yl]-6-ol Xo-1H-purine-2-yl]-2-methylpropanamide

[0178] [ka]

[0179] The title compound was prepared according to the protocol described in International Publication No. 2019217459. It was made. 1 H-NMR(CDCl3)δ12.01-11.96(m,1H),7.82-7. 78(m,1H),7.59-7.53(m,1H),7.47-7.42(m,1H) ,7.41-7.37(m,2H),7.34-7.29(m,2H),7.27-7. 22(m,3H),6.85-6.80(m,4H),5.99-5.82(m,1H) ,4.40-4.36(m,1H),4.17-4.11(m,1H),3.80-3. 77(m,6H),3.76-3.68(m,6H),3.22-3.17(m,1H) ,2.84-2.79(m,1H),1.60-1.54(m,4H),1.35-1. 30(m,6H),1.27(s,19H),1.24-1.15(m,13H),1. 06-1.03(m,5H),0.93-0.88(m,6H),0.74-0.70( m, 1H). 31P NMR(CDCl3)δ150.20, 149.92.

[0180] Example 2. Synthesis of MAPT RNAi agent The single strand (sense and antisense) of an RNA double helix, MerMade (trademark) 12 Synthesized on a solid support via LGC Biosearch Technologies The sequences of the sense and antisense strands are shown in Table 2. Oligonucleotides were divided into 5 and 1. Synthesized via phosphoramidite chemistry on a scale of 0, 25, or 50 μmol. Ta.

[0181] Regarding the sense chain, the type of solid support was Universal CPG: (3'- (Piperidinol-PEG-palmitic acid) and (3'-Piperidinol-PEG-Tocof Although the ferol was synthesized in-house (see Example 1), Universal UnyLinker (manufactured by Chemgenes, catalog number AT2) 73-27) and 3'Teg-Tocopherol (LGC Biosearch Te The Knology products (catalog number BG7-1190) were purchased as retail items. For the antisense chain, a commercially available standard support mA was used. Standard reagents were used in the oligo synthesis. (Table 7) Here, 0.1 M xanthan hydride in pyridine was used as the sulfidation reagent. Furthermore, 20% DEA in ACN was used as an auxiliary wash after synthesis. All monomers (Table 8) was made with 0.1M ACN and molecular sieve trap bags (mole It contained a cular sieves trap bag.

[0182] The oligonucleotide was cleaved and deprotected (C / D) at 45°C for 20 hours. The sense strand was C / D is obtained from CPG using ammonia hydroxide (28-30%, cold), while hydroxyl 3% DEA in 28-30% ammonium compound (cold) was used as the antisense chain. When the mass data obtained was used to confirm the identity of the sequence, the C / D ratio was determined by IP-RP LCMS. It has been determined that it is complete. Depending on the scale, a 0.45um PVDF syringeless filter is used. 0.22um PVDF Steriflip® vacuum filtration, or 0.22um PVDF Stericup® Quick release via CP G was filtered. CPG was removed with 30% ACN / RNase free water or 30% EtOH / R Backwash / rinse with either NASE free water, then filter through the same filtration device. Then, it was mixed with the first filtrate. This was repeated twice. Next, the material was put into a 50 mL container. The material was evenly divided into containers, and organic matter was removed via Genevac®. After concentration, dilute with RNase-free water and return to the synthesis scale, then add 0.45 μm PVDF silica Ventilation-free filter, 0.22μm PVDF Steriflip® vacuum filtration. , or 0.22μm PVDF Stericup® Quick release Crude oligonucleotides were filtered using either se or other methods.

[0183] Use a source 15Q-RP column that uses either anion exchange (AEX) or reversed phase (RP). Crude oligonucleotides are purified using the AKTA® Pure purification system. Prepared. For AEX, MPA: 20mM NaH2PO4, 15% ACN, pH 7.4, and MPB: 20 ​​mM NaH2PO4, 1 M NaBr, 15% ACN, p ES Industry Source, which has H7.4 and maintains a column temperature of 65°C. The column was e(trademark)15Q. For RP, it contained 50% ACN with MPA:10%. S The column used was ource(trademark) 15Q-RP. In all cases, the percentage exceeded 85%. A mixture was prepared containing fractions that met mass purity and did not contain more than 5% impurities.

[0184] The purified oligonucleotides were centrifuged using a 15 mL 3K MWCO spin tube. Then, desalting was performed at 3500xg for approximately 30 minutes. The conductivity of the eluate was <100 usei / cm². The oligonucleotides were rinsed with RNase-free water until the desalting was complete. After that, add 2-3 mL of RNase-free water, then aspirate 10 times and remove the retained material (ret Transfer the ainment to a 50 mL Falcon tube, and then transfer it via nanodrop. By measuring the concentration of the compound on the filter, the process was repeated until the oligonucleotides had completely moved. Next, the final oligonucleotide was incubated at 3500xg for 2 minutes in 15 mL of 100K MW. The final desalted oligonucleotide was subjected to two nanofiltrations via a CO centrifuge spin tube. The concentration (nanodrops in A260) was analyzed, and the mass purity was determined by IP-RP L CMS was used to characterize the UV purity, while ULC was used to characterize the UV purity.

[0185] To prepare the double chain, equimolar amounts of sense and antisense chains are combined and heated at 65°C. It was heated for 10 minutes, and then slowly cooled to ambient temperature over 40 minutes. The completeness was confirmed by UPLC analysis and characterized by LCMS using IP-RP. All double-stranded cells were nanofiltered, and then the endotoxin levels were measured by Charles Rive r Measured by Endosafe® Cartridge Device The final compound of the conjugate RNAi was obtained (Table 9). For in vivo analysis, appropriate The double-stranded material was freeze-dried and then used in 1×PBS for rodent studies and non-human primate studies. For further investigation, it was reconstituted in CSF.

[0186] [Table 7]

[0187] [Table 8]

[0188] [Table 9-1]

[0189] [Table 9-2]

[0190] [Table 9-3]

[0191] [Table 9-4] "S" stands for sense chain, and "AS" stands for antisense chain. * LDP1 is , it is chained to the 3' of the sense chain. ** LDP4-7 are, respectively, nucleos in the sense chain. These are Uhd, Ahd, Chd, and Ghd, which are linked to Chid.

[0192] Example 3. Characterization of MAPT RNAi agents Selected MAPT RNAi agents were used in SH-SY5Y cells and mouse cortical neurons (Mo use cortical neurons (MCNs), and / or human induced pluripotent stem cells. Regarding MAPT inhibition in cultured cells, including human iPS cells (hiPSCs), The tests were conducted in vitro. A subset of selected MAPT RNAi agents were used in gene transfer humans. The study was conducted in vivo in horse mice.

[0193] Materials and methods SH-SY5Y cell culture, RNAi treatment, and analysis: SH-SY5Y cells (ATCC) CRL-2266) was derived from the SK-N-SH neuroblastoma cell line (Ross, R. A., et al., 1983. J Natl Cancer Inst 71, 741-747. The basal culture medium is Eagle's Minimum Essential with ATCC. It consists of a 1:1 mixture of Medium (catalog number 30-2003) and F12 medium. The following was done: 10% fetal bovine serum, 1x amino acids, and 1x sodium bicarbonate were added to complete growth medium. Supplement the cells with 1x penicillin-streptomycin (Gibco) and 5% C The cells were incubated at 37°C in a humidified O2 atmosphere. On day 1, SH-SY5Y cells were selected. The cells were seeded onto a 96-well fibronectin-coated tissue culture plate and allowed to adhere overnight. On the second day... The complete medium was removed and replaced with the RNAi agent in serum-free medium. The cells were then mixed with the RNAi agent. After incubation for 72 hours, gene expression was analyzed. RNAi-treated SH-S Analysis of gene expression changes in Y5Y cells using the manufacturer's protocol (Thermo Fisher). According to ThermoFisher (A35377), Cells-to-CT tree Measurements were taken using a pre-designed gene development kit (supplied as a 20x mixture). The current assay is being developed by Applied Bio-Systems Inc. Selected from MS (Foster City, California, USA). These assays (Manufactured by Thermo Fisher, Hs00902194_m1 MAPT, and Thermo Fisher) The efficiency of the Shar Hs99999905_m1 GAPDH) in the cDNA dilution series It was used to characterize it. Using the QuantStudio 7 Flex system, Mi RT-QPCR was performed using a croAmp Optical 384-well reaction plate. . The delta-delta CT method normalizes for the housekeeping gene GAPDH (del The relative levels of gene expression were determined using the ta-delta CT method. Using GraphPad Prism v9.0, 4-parameter logistic analysis I decided on the IC50 for my Fit.

[0194] Mouse primary cortical neurons (MCNs) culture, RNAi treatment, and analysis: Mouse primary cortical Nerve cells expressing the human tau transgene at E18, htau C57BL6 gene transgene Cells were isolated from embryos. 40k cells were placed in a poly-D-lysine coated 96-well plate. Seeds are seeded at a density of / well and placed in a tissue culture incubator in a humidified chamber with 5% CO2. Within, NbActiv1 contains 1% antibiotic / antifungal agent (manufactured by Corning). The culture was incubated in BrainBits LLC at 37°C for 7 days. On the 7th day, half of the culture medium was used. Remove the 2x concentration of RNAi from each well and CR in culture medium with 2% FBS. Add as C for treatment, and leave with the cells for a further 7, 14, or 21 days. The culture medium was incubated. Half of the medium was replaced every 7 days using fresh culture medium. RNA At the end of the i-processing, RT-qPCR is performed, and TaqMan Fast Advanced MAPT mRNA levels were quantified using the ed Cell-to-CT kit. Specifically, the cells are lysed and then processed using a Mastercycler X50a (manufactured by Eppendorf). ) generate cDNA and QuantStudio 7 Flex Real-Time qPCR was performed using a PCR System (Applied Biosystems). Human MAPT (manufactured by Thermo Fisher, Hs00902194_m1) gene expression level Using each probe, β-actin (Thermo Fisher, Mm026) Normalized using 19580_g1).

[0195] Human induced pluripotent stem cell-derived nerve cells Neuron, hiPSC nerve cell culture, RNAi treatment, and analysis: Doxycycline-inducible Neurogenin 2 (NGN2) human induced pluripotent stem cells (hiPSCs) are Developed by Eli Lilly's Bioneer. hiPSC is administered over 3 days (DI). V3) Doxycycline induction is used to initiate neuronal differentiation, and 96-well PDL and LA Seeds were sown at 30k / well on Minin coated plates and placed in an incubator (37°C / DMEM / F12 (Life Technologies Inc.) (Manufactured by Gibco, 11330-057), Neurobasal medium (Gibco 1524006) 2) Neuronal cell differentiation consisting of antibiotics, supplements, growth factors, and doxycycline. The cells were grown in Neuronal Differentiation Media (NDM). The solution is supplied in two halves, and the RNAi agent is sequentially diluted with NDM in DIV21, 75 μg according to the dilution. Aspirate L, and add 75 μL of 2x RNAi concentration so that the final result is 1x RNAi. The cells were treated with RNAi. After treatment, half of the culture medium was removed and fresh NDM was added. By returning the cells, half of them were supplied every 7 days. The cell lysate was DIV35(1 Samples are collected 4 days later or DIV42 (21 days later) and processed using TaqMan Fast Advanced. ed cells-to-C T Use the kit (Thermo Fisher, A35377). Then RT-qPCR was performed, and the target gene was identified using a MAPT probe (Thermo Fisher). - Company (Hs00902194_m1) and ACTb gene as a housekeeping gene Using a Thermo Fisher (Hs99999903_m1) mRNA knockout I decided on a knockdown.

[0196] In vivo characterization of selected RNAi agents in genetically modified mice The efficacy of the selected RNAi agent also depends on whether the agent expresses human MAPT RNA or mouse MAPT RNA. This study was conducted in transgenic mice lacking T RNA and containing the h-tau gene (Andorfer et al.). (J Neurochem 2003, 86, 582-590). 6 mice, 1 Administer 00 μg of RNAi agent or PBS (phosphate-buffered saline) as an intracerebral (ICV) injection. The animals were euthanized 14 days after injection. MAPT mRNA expression in the brain was measured, and quantitative PCR was performed. The analysis was performed using (qPCR).

[0197] result Table 10A shows the in vitro and in vivo activities of the selected MAPT RNAi agents. To summarize, as shown in Table 10A, the RNAi agents tested were in vitro and in vivo. This knocks down MAPT expression.

[0198] [Table 10] * NE means that no effect was observed.

[0199] Additional RNAi agents with different modification patterns were also tested. Table 10B shows the different The in vitro and in vivo activities of additional MAPT RNAi agents with modification patterns show.

[0200] [Table 11-1]

[0201] [Table 11-2] * ND means "Not decided."

[0202] Example 4. Cynomolgus monkeys after a single dose of MAPT siRNA administered by intrathecal injection. Knockdown of MAPT mRNA MAPT RN in cynomolgus macaques (Macaca fascicularis) AI agent number 31 (sense strand of SEQ ID NO: 63 and antisense strand of SEQ ID NO: 40) A biopsy was conducted to evaluate the effectiveness of MAPT siRNA. To elucidate the effectiveness of siRNA in cynomolgus monkeys, n=4 / group were subjected to a study on cynomolgus monkeys. An indwelling catheter was implanted into the spinal cavity of the region. Monkeys were given aCSF or MAPT RNAi agents. Inject either of the following (2.4 mg / ml in aCSF): 31 over 15 minutes, and after 78 days Perfusion was performed. The tissues collected at the time of autopsy were the spinal cord (lumbar vertebrae) and the brain (prefrontal cortex, motor cortex, parietal vertebrae). It included the lobar cortex, hippocampus, and thalamus. MAPT in the central nervous system (CNS) region. To determine mRNA and protein knockdown, qPCR and ELI are used, respectively. SA was performed. Tables 11 and 12 below show all results 78 days after a single dose of siRNA. This shows MAPT mRNA and protein knockdown observed in the region.

[0203] [Table 12]

[0204] [Table 13]

[0205] [Table 14-1]

[0206] [Table 14-2]

[0207] [Table 14-3]

[0208] [Table 14-4]

[0209] [Table 14-5]

[0210] Table 14-6

[0211] Table 14-7

[0212] Table 14-8

[0213] Table 14-9

Claims

1. A MAPT RNAi agent having a sense strand and an antisense strand, The sense strand and the antisense strand form a double strand. The sense strand and the antisense strand each comprise a pair of nucleic acid sequences. The sense strand comprises the first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises the second nucleic acid sequence of SEQ ID NO:

18. MAPT RNAi agent.

2. The sense strand and the antisense strand each have a pair of nucleic acid sequences, The sense strand has the first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand has the second nucleic acid sequence of SEQ ID NO:

18. The MAPT RNAi agent according to claim 1.

3. The MAPT RNAi agent according to claim 1, wherein one or more nucleotides of the sense strand are modified nucleotides.

4. The MAPT RNAi agent according to claim 1, wherein each nucleotide of the sense strand is a modified nucleotide.

5. The MAPT RNAi agent according to claim 1, wherein one or more nucleotides of the antisense strand are modified nucleotides.

6. The MAPT RNAi agent according to claim 1, wherein each nucleotide of the antisense strand is a modified nucleotide.

7. The MAPT RNAi agent according to claim 1, wherein the modified nucleotide is a 2'-fluoromodified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-C16 alkyl modified nucleotide.

8. The MAPT RNAi agent according to claim 1, wherein the sense strand has four 2'-fluoromodified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand.

9. The MAPT RNAi agent according to claim 8, wherein the nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides.

10. The MAPT RNAi agent according to claim 7, wherein the antisense strand has four 2'-fluoromodified nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand.

11. The MAPT RNAi agent according to claim 10, wherein the nucleotides at positions other than 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides.

12. The MAPT RNAi agent according to claim 1, wherein the sense strand has three 2'-fluoromodified nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand.

13. The MAPT RNAi agent according to claim 12, wherein the nucleotides at positions other than 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides.

14. The MAPT RNAi agent according to claim 1, wherein the antisense strand has five 2'-fluoromodified nucleotides at positions 2, 5, 7, 14, and 16 from the 5' end of the antisense strand.

15. The MAPT RNAi agent according to claim 14, wherein the nucleotides at positions other than 2, 5, 7, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides.

16. The MAPT RNAi agent according to claim 1, wherein the antisense strand has five 2'-fluoromodified nucleotides at positions 2, 5, 8, 14, and 16 from the 5' end of the antisense strand.

17. The MAPT RNAi agent according to claim 16, wherein the nucleotides at positions other than 2, 5, 8, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides.

18. The MAPT RNAi agent according to claim 1, wherein the sense strand and the antisense strand have one or more modified nucleotide linkages.

19. The MAPT RNAi agent according to claim 18, wherein the modified nucleotide linkage is a phosphorothioate chain.

20. The MAPT RNAi agent according to claim 19, wherein the sense strand has four or five phosphorothioate chains.

21. The MAPT RNAi agent according to claim 19, wherein the antisense strand has four or five phosphorothioate chains.

22. The MAPT RNAi agent according to claim 1, wherein the first nucleotide from the 5' end of the antisense strand is a modified nucleotide which is a 5'-vinylphosphonate.

23. The MAPT RNAi agent according to claim 1, wherein the sense strand includes a debase portion or an inverted debase portion.

24. The MAPT RNAi agent according to claim 1, wherein the sense strand has a delivery portion conjugated to the 5' or 3' end of the sense strand.

25. The MAPT RNAi agent according to claim 1, wherein the sense strand has a delivery portion conjugated to the nucleotides of the sense strand.

26. The MAPT RNAi agent according to claim 24, wherein the delivery portion is conjugated to the 3' end of the sense strand.

27. ​​The sense chain and the antisense chain are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 42, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 101, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 102, A MAPT RNAi agent according to claim 1, comprising a pair of nucleic acid sequences selected from.

28. The sense chain and the antisense chain are (a) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 42, (b) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 101, and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 102, A MAPT RNAi agent according to claim 1, having a pair of nucleic acid sequences selected from.

29. A pharmaceutical composition comprising the MAPT RNAi agent described in Claim 1 and a pharmaceutically acceptable carrier.

30. A method for reducing MAPT expression in cells in vitro, The MAPT RNAi agent described in claim 1 is introduced into the cells, A method comprising incubating the cells for a period of time sufficient to degrade the MAPT mRNA, thereby reducing MAPT expression in the cells.

31. A MAPT RNAi agent according to claim 1, or a pharmaceutical composition according to claim 29, for use in treatment.

32. A MAPT RNAi agent according to claim 1, or a pharmaceutical composition according to claim 29, for use in reducing MAPT expression.

33. A MAPT RNAi agent according to claim 1, or a pharmaceutical composition according to claim 29, for use in the treatment of tauopathy.

34. The tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia linked to chromosome 17 and accompanied by parkinsonism (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), parkinson's disease, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA- L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinson's disease-dementia complex syndrome (ALS-PDC), argyrophilic grain dementia (AGD), British-type amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglia ganglion degeneration (CBD), Creutzfeldt-2019 Tojakob disease (CJD), boxer's dementia, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down syndrome, epilepsy, Gerstmann-Streussler-Scheinker disease, Harrellforden-Spatz disease, Huntington's disease, inclusion body myositis, lead-toxic brain disease, Litikordeg disease, meningeal hemangioma, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian disease with neurofibrillary tangles A MAPT RNAi agent or pharmaceutical composition according to claim 33, selected from neurokinetic diseases, post-encephalitis-associated parkinson's disease, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle-type senile dementia, neurofibrillary senile dementia, argyrophilic granulopathy, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (elderly tauopathy, PART), or globular glial tauopathy (GGT).

35. The MAPT RNAi agent or pharmaceutical composition according to claim 33, wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).

36. Use of the MAPT RNAi agent according to claim 1 in the manufacture of a pharmaceutical product for the treatment of tauopathy.

37. The tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), parkinson's disease, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA -L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinson's disease-dementia complex syndrome (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglia ganglion degeneration (CBD), Creutzfeldt-Kre Ruth-Jakob disease (CJD), boxer's dementia, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down syndrome, epilepsy, Gerstmann-Streussler-Scheinker disease, Harrellforden-Spatz disease, Huntington's disease, inclusion body myositis, lead-toxic brain disease, Litikord-Bodig disease, meningeal hemangioma, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guanian neurofibrillary tangles The use according to claim 36, selected from motor neuron disease, post-encephalitis parkinson's disease, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle-type senile dementia, neurofibrillary senile dementia, argyrophilic granulopathy, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (elderly tauopathy, PART), or glial tauopathy (GGT).

38. The use according to claim 36, wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).