MAPT RNA interfering agents

Abstract

Provided herein are MAPT RNAi agents and compositions comprising MAPT RNAi agents. Also provided herein are methods of using MAPT RNAi agents or compositions comprising MAPT RNAi agents to reduce MAPT expression in a subject and / or to treat tauopathy.

Description

[Technical Field]

[0001] Sequence Listing This application has been submitted with a Sequence Listing in ST.26XML format. The Sequence Listing is provided as file entitled "30170," created on November 2, 2022, and is 835 kilobytes in size. The Sequence Listing information in ST.26XML format is incorporated herein by reference in its entirety. [Background technology]

[0002] The microtubule-associated protein tau is encoded by the MAPT gene located on chromosome 17. Tau protein interacts with tubulin to stabilize microtubules and promotes tubulin assembly into microtubules. MAPT transcripts are differentially expressed throughout the body, primarily in the central and peripheral nervous systems.

[0003] The MAPT gene consists of 16 exons. Alternative mRNA splicing generates multiple MAPT isoforms. At least six tau isoforms exist in the human brain, ranging in length from 352 to 441 amino acids. Alternative splicing of exon 2 and / or exon 3 results in the inclusion of zero, one, or two copies of the N-terminal acidic domain, referred to as 0N, 1N, or 2N tau, respectively. Tau isoforms containing exon 10, which encodes an additional microtubule-binding domain, have four microtubule-binding domains and are therefore referred to as "4R tau (4RTau)." Tau isoforms that do not contain exon 10 have three microtubule-binding domains and are therefore referred to as "3R tau (3R tau)."

[0004] Mutations in MAPT and hyperphosphorylation of tau protein can lead to the aggregation and deposition of tau in pathogenic neurofibrillary tangles, resulting in progressive neurodegenerative disorders such as Alzheimer's disease, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and other tauopathies.

[0005] RNA interference (RNAi) is a highly conserved regulatory mechanism in which RNA molecules are involved in sequence-specific gene suppression of gene expression by double-stranded RNA molecules (dsRNA) (Fire et al., Nature 391:806-811, 1998).

[0006] Currently, there are no FDA (U.S. Food and Drug Administration)-approved disease-modifying therapeutic agents specifically for reducing MAPT and treating tauopathies. Aducanumab, which targets amyloid beta protein (Aβ), is the only disease-modifying drug currently approved for treating Alzheimer's disease. Therefore, there remains a need for therapeutic agents that can inhibit or regulate the expression of the MAPT gene to treat tauopathies, for example, by utilizing RNAi. Summary of the Invention

[0007] Provided herein are MAPT RNAi agents and compositions comprising a MAPT RNAi agent. Also provided herein are methods of using a MAPT RNAi agent or a composition comprising a MAPT RNAi agent to reduce MAPT expression in a subject and / or to treat a tauopathy.

[0008] In one aspect, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (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 sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 14; (h) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (i) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 18; (j) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 20; (k) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 22; (l) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 24; (m) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 55, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (n) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 56, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (o) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 57, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 58; (p) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 59, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 58; (q) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 60, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 61; (r) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 62, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 61; (s) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 117, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 118; and (t) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 119, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16. a MAPT RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

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

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

[0011] The MAPT RNAi agents described herein may contain modifying agents. Modifications may be made to one or more nucleotides of the sense strand and / or antisense strand, or to the internucleotide linkages. In some embodiments, one or more nucleotides of the sense strand are modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, one or more nucleotides of the antisense strand are modified nucleotides. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotides are 2'-fluoro-modified nucleotides, 2'-Om-methyl-modified nucleotides, or 2'-O-alkyl-modified nucleotides, for example, 2'-O-C16 alkyl-modified nucleotides. In some embodiments, the sense strand has four 2'-fluoro-modified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methyl-modified nucleotides or 2'-O-C16 alkyl-modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro-modified nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand. In some embodiments, 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. In some embodiments, the sense strand has three 2'-fluoro-modified nucleotides, for example, at positions 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the antisense strand has five 2'-fluoro-modified nucleotides, for example, at positions 2, 5, 7, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the antisense strand has five 2'-fluoro-modified nucleotides, for example, at positions 2, 5, 8, 14, and 16 from the 5' end of the antisense strand.In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides, e.g., at positions 2, 3, 7, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the remaining nucleotides in the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the sense strand comprises an abasic moiety or an inverted abasic moiety.

[0012] In some embodiments, the first nucleotide from the 5' end of the antisense strand is a modified nucleotide having a phosphate analog, e.g., 5'-vinylphosphonate. In some embodiments, the sense strand comprises an abasic portion or an inverted abasic portion. In some embodiments, the sense strand and the antisense strand have one or more modified internucleotide linkages, e.g., phosphorothioate linkages. In some embodiments, the sense strand has four or five phosphorothioate linkages. In some embodiments, the antisense strand has four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has four phosphorothioate linkages.

[0013] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 63, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (n) a sense strand comprising a first nucleic acid sequence selected from any one of SEQ ID NO: 64, SEQ ID NOs: 66 to 69, SEQ ID NO: 71, SEQ ID NOs: 75 to 86, and SEQ ID NOs: 93 to 100, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 64, and an antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 70 and any one of SEQ ID NOs: 72 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 comprising a second nucleic acid sequence of SEQ ID NO: 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 comprising a second nucleic acid sequence of SEQ ID NO: 91; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 101, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 102; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 103, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 104; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 65 and any one of SEQ ID NOs: 106 to 108; (u) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65; (v) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (w) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 112; (x) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 114; and (y) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 116. The MAPT RNAi agent comprises a pair of nucleic acid sequences selected from the group consisting of:

[0014] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 63, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (n) a sense strand having a first nucleic acid sequence selected from any one of SEQ ID NO: 64, SEQ ID NOs: 66 to 69, SEQ ID NO: 71, SEQ ID NOs: 75 to 86, and SEQ ID NOs: 93 to 100, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 64, and an antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 70 and any one of SEQ ID NOs: 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 a second nucleic acid sequence of SEQ 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 a second nucleic acid sequence of SEQ ID NO: 91; (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 101, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 102; (s) a sense strand having a first nucleic acid sequence of SEQ ID NO: 103, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 104; (t) a sense strand having a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 65 and any one of SEQ ID NOs: 106 to 108; (u) a sense strand having a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (v) a sense strand having a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (w) a sense strand having a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 112; (x) a sense strand having a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 114, and (y) a sense strand having a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 116. The MAPT RNAi agent has a pair of nucleic acid sequences selected from the group consisting of:

[0015] In some embodiments, the sense strand of a MAPT RNAi agent has a delivery moiety. In some embodiments, the sense strand of a MAPT RNAi agent has a delivery moiety conjugated to the 5'-end or 3'-end of the sense strand. In some embodiments, the sense strand of a MAPT RNAi agent has a delivery moiety conjugated to a nucleotide of the sense strand. In some embodiments, the delivery moiety is α-tocopherol or palmitic acid. In some embodiments, the delivery moiety is conjugated to the 5'-end or 3'-end of the sense strand via a linker, e.g., a linker in Table 5.

[0016] In a further aspect, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery means for delivering the dsRNA to a cell, and L is a linking means for linking the dsRNA to the delivery means, or is optionally absent, and wherein the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 55, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 56, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 57, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 59, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (q) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 60, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 62, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 117, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 118; and (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 119, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16. a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0017] In some embodiments, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a dsRNA having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery means for delivering the dsRNA to a cell, and L is a linking means for linking the dsRNA to a delivery means, or is optionally absent, and the sense strand and the antisense strand are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 13, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 23, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 55, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (n) a sense strand having a first nucleic acid sequence of SEQ ID NO: 56, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 57, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (p) a sense strand having a first nucleic acid sequence of SEQ ID NO: 59, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (q) a sense strand having a first nucleic acid sequence of SEQ ID NO: 60, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 62, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (s) a sense strand having a first nucleic acid sequence of SEQ ID NO: 117 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 118; and (t) a sense strand having a first nucleic acid sequence of SEQ ID NO: 119, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16. having a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0018] In some embodiments, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a dsRNA having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery means for delivering the dsRNA to a cell, and L is a linking means for linking the dsRNA to a delivery means, or is optionally absent, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 65 and SEQ ID NOs: 106 to 108; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 112; (q) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 114; and (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 116. The nucleic acid sequence comprises a pair of nucleic acid sequences selected from the group consisting of:

[0019] In some embodiments, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a dsRNA having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery means for delivering the dsRNA to a cell, and L is a linking means for linking the dsRNA to a delivery means, or is optionally absent, and the sense strand and the antisense strand are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 65 and SEQ ID NOs: 106 to 108; (n) a sense strand having a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (p) a sense strand having a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 112; (q) a sense strand having a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 114, and (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 116. The nucleic acid sequence has a pair of nucleic acid sequences selected from the group consisting of:

[0020] In another aspect, provided herein is a pharmaceutical composition comprising the MAPT RNAi agent described herein and a pharmaceutically acceptable carrier. Also provided herein is a pharmaceutical composition comprising a means for reducing MAPT expression in a cell and a pharmaceutically acceptable carrier.

[0021] In another aspect, provided herein is a method of reducing MAPT expression in a patient in need thereof, comprising administering to the patient an effective amount of a MAPT RNAi agent or pharmaceutical composition described herein.

[0022] In another aspect, provided herein is a method of treating a tauopathy in a patient in need thereof, comprising administering to the patient an effective amount of a MAPT RNAi agent or pharmaceutical composition described herein.

[0023] Also provided herein are methods of reducing MAPT expression in a cell (e.g., a nerve cell (neuron)), which may include introducing a MAPT RNAi agent described herein into the cell and incubating the cell for a time sufficient to degrade MAPT mRNA, thereby reducing MAPT expression in the cell.

[0024] In another aspect, provided herein is a MAPT RNAi agent or a pharmaceutical composition comprising a MAPT RNAi agent for use in reducing MAPT expression. Also provided herein is a MAPT RNAi agent or a pharmaceutical composition comprising a MAPT RNAi agent for use in therapy. Also provided herein is a MAPT RNAi agent or a pharmaceutical composition comprising a MAPT RNAi agent for use in treating tauopathy. Also provided herein is the use of a MAPT RNAi agent in the manufacture of a medicament for treating tauopathy. DETAILED DESCRIPTION OF THE INVENTION

[0025] Provided herein are MAPT RNAi agents and compositions comprising a MAPT RNAi agent. Also provided herein are methods of using a MAPT RNAi agent or a composition comprising a MAPT RNAi agent to reduce MAPT expression in a subject and / or to treat a tauopathy.

[0026] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex. The antisense strand is complementary to a region of MAPT mRNA. In further embodiments, the sense strand and the antisense strand are each 15-30 nucleotides in length, e.g., 20-25 nucleotides in length. In some embodiments, provided herein is a MAPT RNAi agent having a 21-nucleotide sense strand and a 23-nucleotide antisense strand. In some embodiments, the sense strand and the antisense strand of the MAPT RNAi agent may have an overhang (i.e., a 5' overhang or a 3' overhang) at either the 5' or 3' end. For example, the sense strand and the antisense strand may have a 5' or 3' overhang of 1-5 nucleotides or 1-3 nucleotides. In some embodiments, the antisense strand includes a 3' overhang of 2 nucleotides. In some embodiments, the sense strand and the antisense strand sequences of the MAPT RNAi agent are provided in Table 1.

[0027] Provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:1, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:2; (b) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:3, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:4; (c) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:5, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:6; (d) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:7, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:8; (e) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:9, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:10; (f) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 12; (g) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 14; (h) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16; (i) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 18; (j) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 20; (k) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 22; (l) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 24; (m) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 55, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16; (n) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 56, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16; (o) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 57, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 58; (p) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 59, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 58; (q) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 60, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 61; (r) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 62, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 61; (s) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 117, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 118; (t) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 119, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 16. a MAPT RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0028] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:1, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:2, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:3, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:4, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 6, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 8, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 10, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 12, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 14, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence having 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, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 18, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 20, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 22, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 24, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 55, and the antisense strand comprises a second nucleic acid sequence having 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, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having 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 the antisense strand comprises a second nucleic acid sequence having 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, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand comprises a first nucleic acid sequence having 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 the antisense strand comprises 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 a second nucleic acid sequence having a sequence identity of about 97%, about 98%, about 99%, or about 100%), wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 59, and the antisense strand comprises a second nucleic acid sequence having 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, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 60, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 61, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 62, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 61, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 117, and the antisense strand comprises a second nucleic acid sequence having at least 95% (e.g., about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 118, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence having 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 the antisense strand comprises a second nucleic acid sequence having 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, wherein 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 and antisense strands of the MAPT RNAi agents described herein are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 55, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 56, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 57, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 59, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (q) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 60, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 62, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 117, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 118; and (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 119, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16. a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0030] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 55 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 56 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 57 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 59 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 57 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 60 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 62 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 117 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 118, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119 and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16, wherein 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.

[0031] In some embodiments, the sense and antisense strands of the MAPT RNAi agents described herein are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 13, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 23, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 55, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (n) a sense strand having a first nucleic acid sequence of SEQ ID NO: 56, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 57, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (p) a sense strand having a first nucleic acid sequence of SEQ ID NO: 59, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (q) a sense strand having a first nucleic acid sequence of SEQ ID NO: 60, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 62, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (s) a sense strand having a first nucleic acid sequence of SEQ ID NO: 117 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 118; and (t) a sense strand having a first nucleic acid sequence of SEQ ID NO: 119, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16. having a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0032] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 1 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 2, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 3 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 4, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 5 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 6, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 7 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 8, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 9 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 10, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 11 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 12, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 14, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 17 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 18, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 19 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 20, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 22, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 24, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 56, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 58, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 58, wherein 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.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 60 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 61, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 62 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 61, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 118, wherein 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. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16, wherein 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.

[0033] In some embodiments, a MAPT RNAi agent described herein may comprise a sense strand comprising a sequence that has one, two, or three differences from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO: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, SEQ ID NO:117, SEQ ID NO: 119. In some embodiments, a MAPT RNAi agent described herein may comprise an antisense strand comprising a sequence that has one, two, or three differences from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:58, SEQ ID NO:61, SEQ ID NO:118.

[0034] The MAPT RNAi agent described herein may contain a modifying agent. The modification may be made to one or more nucleotides of the sense strand and / or antisense strand, or to the internucleotide linkage, which is the bond between two nucleotides in the sense strand or antisense strand. For example, some 2'-modifications of ribose or deoxyribose may increase RNA stability or DNA stability and half-life. Such 2'-modifications may be 2'-fluoro, 2'-O-methyl (i.e., 2'-methoxy), 2'-O-alkyl, such as 2'-O-C16 alkyl-modified nucleotides, or 2'-O-methoxyethyl (2'-O-MOE).

[0035] In some embodiments, one or more nucleotides in the sense strand and / or antisense strand are independently modified nucleotides, meaning that the sense strand and the antisense strand can have different modified nucleotides. In some embodiments, one or more nucleotides in the sense strand are modified nucleotides. In some embodiments, each nucleotide in the sense strand is a modified nucleotide. In some embodiments, one or more nucleotides in the antisense strand are modified nucleotides. In some embodiments, each nucleotide in the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a 2'-O-alkyl-modified nucleotide, for example, a 2'-O-C16 alkyl-modified nucleotide. In some embodiments, each nucleotide in the sense strand and the antisense strand is independently a modified nucleotide, for example, a 2'-fluoro-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a 2'-O-alkyl-modified nucleotide, for example, a 2'-O-C16 alkyl-modified nucleotide.

[0036] In some embodiments, the sense strand has four 2'-fluoro modified nucleotides, e.g., at positions 7, 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides or 2'-O-C16 alkyl modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro modified nucleotides, e.g., at positions 2, 6, 14, and 16 from the 5' end of the antisense strand. In some embodiments, 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.

[0037] In some embodiments, the sense strand has three 2'-fluoro modified nucleotides, for example, at positions 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, the other nucleotides in the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides, for example, at positions 2, 5, 7, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides, for example, at positions 2, 5, 8, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides, for example, at positions 2, 3, 7, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the other nucleotides in the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the sense strand comprises an abasic moiety or an inverted abasic moiety.

[0038] In some embodiments, the modified nucleotide is a 2'-O-alkyl-modified nucleotide, such as a 2'-O-C16 alkyl-modified nucleotide, which can function as a delivery moiety. In some embodiments, the 2'-O-alkyl-modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine. In some embodiments, 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine is a modified nucleotide in the sense strand.

[0039] In some embodiments, the first nucleotide from the 5' end of the antisense strand is a modified nucleotide having a phosphate analog, for example, 5'-vinylphosphonate (5'-VP).

[0040] In some embodiments, the sense strand comprises an abasic portion or an inverted abasic portion, eg, a portion shown in Table 3.

[0041] In some embodiments, the sense strand and the antisense strand have one or more modified internucleotide linkages. In some embodiments, the modified nucleotide linkages are phosphorothioate linkages. In some embodiments, the sense strand has four or five phosphorothioate linkages. In some embodiments, the antisense strand has four or five phosphorothioate linkages. In some embodiments, the sense strand and the antisense strand each have four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has four phosphorothioate linkages.

[0042] In a further aspect, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 26; (b) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 28; (c) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 30; (d) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 31, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 32; (e) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 33, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 34; (f) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 35, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 36; (g) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 37, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 38; (h) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 39, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 40; (i) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 41, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 42; (j) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 43, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 44; (k) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 45, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 46; (l) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 47, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 48; (m) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 63, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 40; (n) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to any one of SEQ ID NO: 64, SEQ ID NOs: 66 to 69, SEQ ID NO: 71, SEQ ID NOs: 75 to 86, and SEQ ID NOs: 93 to 100, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 65; (o) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 64, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 70, any one of SEQ ID NOs: 72 to 74; (p) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 87 or SEQ ID NO: 89, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 88; (q) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:90 or SEQ ID NO:92, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:91; (r) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 101, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 102; (s) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 103, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 104; (t) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 105, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to any one of SEQ ID NO: 65 and SEQ ID NOs: 106 to 108; (u) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 109, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 65; (v) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 110, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 40; (w) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:111, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:112; (x) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 113, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO: 114; and (y) a sense strand comprising a first nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:115, and an antisense strand comprising a second nucleic acid sequence having at least 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) sequence identity to SEQ ID NO:116. The MAPT RNAi agent comprises a pair of nucleic acid sequences selected from the group consisting of:

[0043] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 63, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (n) a sense strand comprising a first nucleic acid sequence selected from any one of SEQ ID NO: 64, SEQ ID NOs: 66 to 69, SEQ ID NO: 71, SEQ ID NOs: 75 to 86, and SEQ ID NOs: 93 to 100, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 64, and an antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 70 and any one of SEQ ID NOs: 72 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 comprising a second nucleic acid sequence of SEQ ID NO: 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 comprising a second nucleic acid sequence of SEQ ID NO: 91; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 101, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 102; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 103, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 104; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 65 and any one of SEQ ID NOs: 106 to 108; (u) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65; (v) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (w) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 112; (x) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 114; and (y) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 116. The MAPT RNAi agent comprises a pair of nucleic acid sequences selected from the group consisting of:

[0044] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 26. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 28. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 34. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 46. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 48.

[0045] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 63, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence selected from any one of SEQ ID NOs: 64, 66-69, 71, 75-86, and 93-100, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 64, and the antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 70, and any one of SEQ ID NOs: 72 to 74. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 88. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand comprises a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 91.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 102. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 104.

[0046] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 65, and any one of SEQ ID NOs: 106 to 108. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 112. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 113, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 114. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 116.

[0047] In some embodiments, a MAPT RNAi agent described herein may comprise a sense strand comprising a sequence that has one, two, or three differences from SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NOs:66-69, SEQ ID NO:71, SEQ ID NOs:75-87, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NOs:92-101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NOs:109-111, SEQ ID NO:113, SEQ ID NO:115. In some embodiments, a MAPT RNAi agent described herein may comprise an antisense strand comprising a sequence that has one, two, or three differences from SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:65, SEQ ID NO:70, SEQ ID NOs:72-74, SEQ ID NO:88, SEQ ID NO:91, SEQ ID NO:102, SEQ ID NO:104, SEQ ID NOs:106-108, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116.

[0048] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 63, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (n) a sense strand having a first nucleic acid sequence selected from any one of SEQ ID NO: 64, SEQ ID NOs: 66 to 69, SEQ ID NO: 71, SEQ ID NOs: 75 to 86, and SEQ ID NOs: 93 to 100, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 64, and an antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 70 and any one of SEQ ID NOs: 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 a second nucleic acid sequence of SEQ 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 a second nucleic acid sequence of SEQ ID NO: 91; (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 101, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 102; (s) a sense strand having a first nucleic acid sequence of SEQ ID NO: 103, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 104; (t) a sense strand having a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 65 and any one of SEQ ID NOs: 106 to 108; (u) a sense strand having a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (v) a sense strand having a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (w) a sense strand having a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 112; (x) a sense strand having a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 114, and (y) a sense strand having a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 116. The MAPT RNAi agent has a pair of nucleic acid sequences selected from the group consisting of:

[0049] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 26. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 28. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 30. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 32. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 34. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 36.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 38. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 42. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 44. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 46. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 48.

[0050] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 63, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence selected from any one of SEQ ID NOs: 64, 66-69, 71, 75-86, and 93-100, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 65. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 64, and the antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 70, and any one of SEQ ID NOs: 72 to 74. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 88. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand has a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 91.In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 102. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 104.

[0051] In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 65, and any one of SEQ ID NOs: 106 to 108. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 65. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 40. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 112. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 113, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 114. In some embodiments, provided herein is a MAPT RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand having a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 116.

[0052] [Table 2-1]

[0053] [Table 2-2]

[0054] [Table 2-3]

[0055] [Table 2-4] Abbreviations - "m" indicates 2'-OMe, "f" indicates 2'-fluoro, * " indicates a phosphorothioate linkage, "VP" indicates 5'-vinylphosphonate, "Uhd" indicates 2'-O-hexadecyluridine, "Chd" indicates 2'-O-hexadecylcytidine, "Ahd" indicates 2'-O-hexadecyladenosine, "iAb" indicates an inverted abasic moiety, "n" indicates an abasic moiety, "S" indicates the sense strand, and "AS" indicates the antisense strand.

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

[0057] In some embodiments, the sense strand of a MAPT RNAi agent comprises a delivery moiety. In some embodiments, the sense strand of a MAPT RNAi agent comprises a delivery moiety conjugated to the 5' or 3' end of the sense strand. In some embodiments, the sense strand of a MAPT RNAi agent comprises a delivery moiety conjugated to a nucleotide of the sense strand. The delivery moiety may facilitate entry of the RNAi agent into a cell. In some embodiments, the delivery moiety is α-tocopherol or palmitic acid (see Table 4). In some embodiments, the delivery moiety is a well-known delivery moiety for delivering RNAi agents into cells, such as those described in Hu et al., Signal Transduction and Targeted Therapy (2020) 5:101. Placement of a delivery moiety on the RNAi agent is necessary to overcome potential inefficient loading of AGO2 (Argonaute-2) or other obstacles to RNA-Induced Silencing Complex (RISC) complex activity.

[0058] In some embodiments, the delivery moiety is conjugated to the 5' or 3' end of the sense strand via a linker. In some embodiments, the linker is selected from Linker 1, Linker 2, Linker 3, or Linker 4 in Table 5. Other suitable linkers are well known in the art. Exemplary linker-delivery moiety pairs are shown in Table 6. In some embodiments, the MAPT RNAi agent has a linker-delivery moiety pair in Table 6.

[0059] In some embodiments, the delivery moiety is conjugated to a nucleotide of the sense strand. In this case, the delivery moiety is a modified nucleotide located in the sense strand. In some embodiments, the modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine (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 aspect, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery means for delivering the dsRNA to a cell, and L is a linking means for linking the dsRNA to the delivery means, or is optionally absent, and wherein the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 55, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 56, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 57, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 59, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (q) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 60, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 62, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 117, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 118; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 119, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16. a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0066] In some embodiments, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery vehicle for delivering the dsRNA to a cell, and L is a linking vehicle for linking the dsRNA to a delivery vehicle, or is optionally absent, and wherein the sense strand and the antisense strand are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 13, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 23, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 55, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (n) a sense strand having a first nucleic acid sequence of SEQ ID NO: 56, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 57, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (p) a sense strand having a first nucleic acid sequence of SEQ ID NO: 59, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (q) a sense strand having a first nucleic acid sequence of SEQ ID NO: 60, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 62, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (s) a sense strand having a first nucleic acid sequence of SEQ ID NO: 117 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 118; and (t) a sense strand having a first nucleic acid sequence of SEQ ID NO: 119, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 16. having a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides in the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages in the sense strand and the antisense strand are modified internucleotide linkages.

[0067] In some embodiments, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery vehicle for delivering the dsRNA to a cell, and L is a linking vehicle for linking the dsRNA to a delivery vehicle, or is optionally absent, and wherein the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand comprising a second nucleic acid sequence selected from SEQ ID NO: 65 and SEQ ID NOs: 106 to 108; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 40; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 112; (q) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 114; and (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 116. The nucleic acid sequence comprises a pair of nucleic acid sequences selected from the group consisting of:

[0068] In some embodiments, provided herein is a MAPT RNAi agent of formula (I): RLD, wherein R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein D is a delivery vehicle for delivering the dsRNA to a cell, and L is a linking vehicle for linking the dsRNA to a delivery vehicle, or is optionally absent, and wherein the sense strand and the antisense strand are (a) a sense strand having a first nucleic acid sequence of SEQ ID NO: 25, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 26; (b) a sense strand having a first nucleic acid sequence of SEQ ID NO: 27, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 28; (c) a sense strand having a first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 30; (d) a sense strand having a first nucleic acid sequence of SEQ ID NO: 31, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 32; (e) a sense strand having a first nucleic acid sequence of SEQ ID NO: 33, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 34; (f) a sense strand having a first nucleic acid sequence of SEQ ID NO: 35, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 36; (g) a sense strand having a first nucleic acid sequence of SEQ ID NO: 37, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 38; (h) a sense strand having a first nucleic acid sequence of SEQ ID NO: 39, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (i) a sense strand having a first nucleic acid sequence of SEQ ID NO: 41, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 42; (j) a sense strand having a first nucleic acid sequence of SEQ ID NO: 43, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 44; (k) a sense strand having a first nucleic acid sequence of SEQ ID NO: 45, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 46; (l) a sense strand having a first nucleic acid sequence of SEQ ID NO: 47, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 48; (m) a sense strand having a first nucleic acid sequence of SEQ ID NO: 105, and an antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 65 and SEQ ID NOs: 106 to 108; (n) a sense strand having a first nucleic acid sequence of SEQ ID NO: 109, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (o) a sense strand having a first nucleic acid sequence of SEQ ID NO: 110, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (p) a sense strand having a first nucleic acid sequence of SEQ ID NO: 111, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 112; (q) a sense strand having a first nucleic acid sequence of SEQ ID NO: 113 and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 114, and (r) a sense strand having a first nucleic acid sequence of SEQ ID NO: 115, and an antisense strand having a second nucleic acid sequence of SEQ ID NO: 116. The nucleic acid sequence has a pair of nucleic acid sequences selected from the group consisting of:

[0069] In some embodiments, the delivery means is conjugated to the sense strand. In some embodiments, the delivery means is conjugated to the 5' or 3' end of the sense strand. In some embodiments, the delivery means is conjugated to a nucleotide of the sense strand. In some embodiments, the delivery means is palmitic acid or alpha tocopherol. In some embodiments, the linking means is selected from the group consisting of Linker 1, Linker 2, Linker 3, and Linker 4 in Table 5.

[0070] The sense and antisense strands of MAPT RNAi agents can be synthesized using any nucleic acid polymerization method known in the art, such as solid-phase synthesis using phosphoramidite chemistry methodology (e.g., Current Protocols in Nucleic Acid Chemistry, Beaucage, SL et al. (Eds.), John Wiley & Sons, Inc., New York, NY, USA), H-phosphonate methods, phosphotriester chemistry, or enzymatic synthesis. Automated synthesizers, such as the MerMade™ 12 from LGC Biosearch Technologies, or the 12-well plate synthesizer from BioAutomation or Applied Biosystems, can be used. Other synthesizers, such as those from Biosystems, can be used. Phosphorothioate linkages can be introduced using sulfurizing reagents such as phenylacetyl disulfide or DDTT (((dimethylaminomethylidene)amino)-3H-1,2,4-dithiazoline-3-thione). The use of similar techniques and commercially available modified amidites and controlled-pore glass (CPG) products to synthesize modified and conjugated oligonucleotides is well known.

[0071] Purification methods can be used to remove unwanted impurities from the final oligonucleotide product. Commonly used purification techniques for single-stranded oligonucleotides include reverse-phase ion pair high performance liquid chromatography (RP-IP-HPLC), capillary gel electrophoresis (CGE), anion exchange HPLC (AX-HPLC), and size exclusion chromatography (SEC). After purification, oligonucleotides can be analyzed by mass spectrometry and quantified by spectrophotometry at a wavelength of 260 nm. Then, sense strand and antisense strand can be annealed to form a double strand.

[0072] In another aspect, provided herein is a pharmaceutical composition comprising the MAPT RNAi agent described herein and a pharmaceutically acceptable carrier. Also provided herein is a pharmaceutical composition comprising a means for reducing MAPT expression in cells and a pharmaceutically acceptable carrier. Such pharmaceutical compositions may also comprise one or more pharmaceutically acceptable excipients, diluents, or carriers. Pharmaceutical compositions can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 23rd edition (2020), A. Loyd et al., Academic Press).

[0073] In a further aspect, provided herein is a method for reducing MAPT expression in a cell (e.g., a neuronal cell), which may include introducing a MAPT RNAi agent described herein into the cell and incubating the cell for a time sufficient to degrade MAPT mRNA, thereby reducing MAPT expression in the cell. The MAPT RNAi agent may be introduced into a cell (e.g., a neuronal cell) using methods well known in the art, such as transfection, electroporation, microinjection, or cellular uptake via natural transport mechanisms.

[0074] In another aspect, the present disclosure provides a method for reducing MAPT expression in a patient in need thereof, comprising administering to the patient an effective amount of a MAPT RNAi agent or pharmaceutical composition described herein. MAPT aggregation can be caused by overexpression of MAPT protein or mutations affecting the protein structure, resulting in an increased tendency of MAPT protein to self-associate. Therefore, reducing MAPT expression levels can be beneficial for patients with tauopathy.

[0075] In another aspect, provided herein is a method of treating a tauopathy in a patient in need thereof, comprising administering to the patient an effective amount of a MAPT RNAi agent or pharmaceutical composition described herein. Exemplary tauopathies include, but are not limited to, Alzheimer's Disease (AD), frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant Primary Progressive Aphasia (nfvPPA), Parkinsonism, Pick's disease (PiD), Primary Progressive Aphasia-Semantic (PPA-S), Primary Progressive Aphasia-Logopenic (PPA-L), Multiple System Tauopathy with Presenile Dementia (MSD), and Presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt-Jakob diseaseCJD, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead toxic encephalopathy, Litiko-Bodig disease (Parkinson-Dementia Complex of Guam), meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C Neuropathic tauopathy includes neurodegenerative disorders such as encephalitis, encephalitis, cerebral amyloidosis, encephalopathy, encephalitis-associated tauopathy, encephalopathy-associated tau ...

[0076] The MAPT RNAi agent can be administered to the patient via intrathecal, intracerebroventricular, or intracisternal injection. In some embodiments, the MAPT RNAi agent is administered to the patient intrathecally via a catheter.

[0077] RNAi dosing regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.

[0078] Dosage values ​​can vary depending on the type and severity of the condition to be alleviated. It will be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0079] In another aspect, provided herein is a MAPT RNAi agent or a pharmaceutical composition comprising a MAPT RNAi agent for use in reducing MAPT expression. Also provided herein is a MAPT RNAi agent or a pharmaceutical composition comprising a MAPT RNAi agent for use in therapy. Also provided herein is a MAPT RNAi agent or a pharmaceutical composition comprising a MAPT RNAi agent for use in treating tauopathy. Also provided herein is the use of a MAPT RNAi agent in the manufacture of a medicament for treating tauopathy.

[0080] As used herein, the terms "a," "an," "the," and similar terms as used in the context of this disclosure (particularly in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise specified herein or clearly contradicted by context.

[0081] As used herein, the term "alkyl" means a saturated straight- or branched-chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C-C 20 Alkyl (C1-C 20 "Alkyl" means a radical having from 1 to 20 carbon atoms in a linear or branched arrangement.

[0082] As used herein, "antisense strand" refers to an oligonucleotide that is complementary to a region of a target sequence. Similarly, as used herein, "sense strand" refers to an oligonucleotide that is complementary to a region of the antisense strand.

[0083] As used herein, "complementary" refers to a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand) that allows the two nucleotides to base pair with each other. For example, when a purine nucleotide of one nucleic acid is complementary to a pyrimidine nucleotide of the opposing nucleic acid, they may base pair by forming hydrogen bonds with each other. Complementary nucleotides may base pair in a Watson-Crick manner or in any other manner that allows the formation of a stable duplex. Similarly, two nucleic acids may have regions of multiple nucleotides that are complementary to each other and form a region of complementarity, as described herein.

[0084] As used herein, a "delivery moiety" refers to a chemical moiety that facilitates entry of an oligonucleotide or RNAi agent into a cell. A delivery moiety can be a lipid, cholesterol, vitamin E, carbohydrate, amino sugar, polypeptide, or protein.

[0085] As used herein, "duplex," with respect to a nucleic acid or oligonucleotide, means the structure formed through complementary base pairing of two antiparallel sequences of nucleotides, whether formed by two separate nucleic acid strands or by a single folded strand (e.g., via a hairpin).

[0086] "Effective amount" refers to the amount (duration and means of administration) necessary to achieve the desired therapeutic result. The effective amount of an RNAi agent may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the RNAi agent to induce a desired response in the individual. An effective amount is also one in which any toxic or harmful effects of the RNAi agent are outweighed by the therapeutically beneficial effects.

[0087] The terms "have," "having," or "has," when referring to a sequence, mean consisting of or consisting essentially of.

[0088] The term "knockdown" or "expression knockdown" refers to the reduction of mRNA or protein expression of a gene following treatment with a reagent, eg, an RNAi agent.

[0089] As used herein, a "modified internucleotide linkage" refers to an internucleotide linkage having one or more chemical modifications compared to a reference internucleotide linkage having a phosphodiester bond. Typically, the modified internucleotide linkage confers one or more desirable properties to the nucleic acid in which the modified internucleotide linkage is present. For example, the modified nucleotide may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, biological activity, reduced immunogenicity, etc. In some embodiments, the modified internucleotide linkage is a phosphorothioate linkage.

[0090] As used herein, "modified nucleotide" refers to a nucleotide having one or more chemical modifications compared to a corresponding reference nucleotide selected from adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, uracil ribonucleotides, adenine deoxyribonucleotides, guanine deoxyribonucleotides, cytosine deoxyribonucleotides, and thymidine deoxyribonucleotides. The modified nucleotide may have one or more chemical modifications, for example, in its sugar, nucleobase, and / or phosphate group. Additionally, or alternatively, the modified nucleotide may have one or more chemical moieties conjugated to the corresponding reference nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a 2'-O-alkyl-modified nucleotide, e.g., a 2'-O-C16 alkyl-modified nucleotide. In some embodiments, the modified nucleotide has a phosphate analog, e.g., a 5'-vinyl phosphonate. In some embodiments, the modified nucleotide is an abasic moiety or an inverted abasic moiety, e.g., a moiety shown in Table 3.

[0091] As used herein, the term "tauopathy" refers to a disease associated with abnormal tau protein expression, secretion, phosphorylation, cleavage, and / or aggregation.

[0092] As used herein, "nucleotide" means an organic compound having a nucleoside (a nucleic acid base (e.g., adenine, cytosine, guanine, thymine, or uracil) and a pentose sugar (e.g., ribose or 2'-deoxyribose)) linked to a phosphate group, which can serve as a monomer unit of nucleic acid polymers (e.g., deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)).

[0093] As used herein, "oligonucleotide" means a polymer of linked nucleotides, each of which may or may not be modified. Oligonucleotides are typically less than about 100 nucleotides in length.

[0094] As used herein, "overhang" refers to an unpaired nucleotide(s) that protrude from the duplex structure of a double-stranded oligonucleotide. An overhang may include one or more unpaired nucleotides extending from the duplex region at the 5'-end or 3'-end of a double-stranded oligonucleotide. An overhang may be a 3'-overhang or a 5'-overhang on the antisense strand or the sense strand of a double-stranded oligonucleotide.

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

[0096] As used herein, "phosphate analog" refers to a chemical moiety that mimics the electrostatic and / or steric properties of a phosphate group. In some embodiments, the phosphate analog is located at the 5'-terminal nucleotide of an oligonucleotide in place of the 5'-phosphate, which is often susceptible to enzymatic removal. The 5' phosphate analog may include a phosphatase-resistant linkage. Examples of phosphate analogs include 5' methylene phosphonate (5'-MP) and 5'-(E)-vinyl phosphonate (5'-VP). In some embodiments, the phosphate analog is 5'-VP.

[0097] The term "% sequence identity" or "percent sequence identity" with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical to the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, using publicly available computer software programs, including those described in Current Protocols in Molecular Biology (Ausubel et al., eds., 1987, Supp. 30, section 7.7.18, Table 7.7.1), such as BLAST, BLAST-2, ALIGN, Clustal W2.0, Clustal X2.0, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. The percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, although the nucleic acid sequence fragment within the comparison window may contain additions or deletions (e.g., gaps or overhangs) compared to the reference sequence (which does not contain additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by calculating the number of positions where the same nucleotide, nucleoside, or nucleic acid base is present in both sequences to determine the number of matched positions, dividing the number of matched positions by the total number of positions within the comparison window, and multiplying the result by 100 to determine the percentage of sequence identity. The output is the percent identity of the subject sequence to the query sequence.

[0098] As used herein, "RNAi," "RNAi agent," "iRNA," "iRNA agent," and "RNA interference agent" refer to an agent that mediates sequence-specific degradation of target mRNA by RNA interference, for example, via the RNA-induced silencing complex (RISC) pathway. In some embodiments, the RNAi agent has a sense strand and an antisense strand, and the sense strand and the antisense strand form a duplex. In some embodiments, the sense strand has a delivery moiety, e.g., a delivery moiety conjugated to the 5' or 3' end of the sense strand or to a nucleotide of the sense strand.

[0099] As used herein, a "strand" refers to a single, contiguous sequence of nucleotides joined together by internucleotide linkages (e.g., phosphodiester or phosphorothioate linkages). A strand may have two free ends (e.g., a 5' end and a 3' end).

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

[0101] i. MAPT transcript variant 1 → tau protein isoform 1: NM_016835.5 (nucleotide sequence) → NP_058519.3 (amino acid sequence), ii. MAPT transcript variant 2 → tau protein isoform 2: NM_005910.6 (nucleotide sequence) → NP_005901.2 (amino acid sequence); iii. MAPT transcript variant 3 → tau protein isoform 3: NM_016834.5 (nucleotide sequence) → NP_058518.1 (amino acid sequence), iv. MAPT transcript variant 4 → tau protein isoform 4: NM_016841.5 (nucleotide sequence) → NP_058525.1 (amino acid sequence), v. MAPT transcript variant 5 → tau protein isoform 5: NM_001123067.4 (nucleotide sequence) → NP_001116539.1 (amino acid sequence), vi. MAPT transcript variant 6 → tau protein isoform 6: NM_001123066.4 (nucleotide sequence) → NP_001116538.2 (amino acid sequence), vii. MAPT transcript variant 7 → tau protein isoform 7: NM_001203251.2 (nucleotide sequence) → NP_001190180.1 (amino acid sequence); viii. MAPT transcript variant 8 → tau protein isoform 8: NM_001203252.2 (nucleotide sequence) → NP_001190181.1 (amino acid sequence); ix. MAPT transcript variant 9 → tau protein isoform 9: NM_001377265.1 (nucleotide sequence) → NP_001364194.1 (amino acid sequence), x. MAPT transcript variant 10 → tau protein isoform 10: NM_001377266.1 (nucleotide sequence) → NP_001364195.1 (amino acid sequence), xi. MAPT transcript variant 11 → tau protein isoform 11: NM_001377267.1 (nucleotide sequence) → NP_001364196.1 (amino acid sequence); xii. MAPT transcript variant 12 → tau protein isoform 4: NM_001377268.1 (nucleotide sequence) → NP_001364197.1 (amino acid sequence).

[0102] The nucleotide sequence of human MAPT transcript variant 6 (encoding 2N4R tau) can be found in NM_001123066.4.

[0103] JPEG0007785947000012.jpg193151

[0104] JPEG0007785947000013.jpg229151

[0105] JPEG0007785947000014.jpg25150 (sequence number 49).

[0106] The corresponding amino acid sequence of human tau protein isoform 6 can be found in NP_001116538.2:

[0107] JPEG0007785947000015.jpg53148 (sequence number 50).

[0108] The nucleotide sequence of human MAPT transcript variant 5 (encoding 1N4R tau) can be found at NM_001123067.4.

[0109] JPEG0007785947000016.jpg97150

[0110] JPEG0007785947000017.jpg229151

[0111] JPEG0007785947000018.jpg49150 (sequence number 51).

[0112] The corresponding amino acid sequence of human tau protein isoform 5 can be found in NP_001116539.1:

[0113] JPEG0007785947000019.jpg29148 (sequence number 52).

[0114] The nucleotide sequence of human MAPT transcript variant 4 (encoding 0N3R tau) can be found in NM_016841.5.

[0115] JPEG0007785947000020.jpg105150

[0116] JPEG0007785947000021.jpg229151

[0117] JPEG0007785947000022.jpg29150 (sequence number 53).

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

[0119] JPEG0007785947000023.jpg25148 (sequence number 54).

[0120] As used herein, "subject" means a mammal (including cats, dogs, mice, rats, chimpanzees, apes, monkeys, and humans). Preferably, the subject is a human.

[0121] As used herein, "treatment" or "treating" refers to any process that may slow, control, retard, or stop the progression of a disorder or disease disclosed herein, or ameliorate the symptoms of the disorder or disease, but does not necessarily indicate the complete elimination of all disorder or disease symptoms. Treatment includes the administration of a protein or nucleic acid or vector or composition for the treatment of a disease or condition in a patient, particularly a human. [Example]

[0122] Example 1. Synthesis of Linker-Delivery Moiety Pairs Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AEX" refers to anion exchange, "C / D" refers to cleavage and deprotection, "CPG" refers to controlled pore glass, "DCM" refers to dichloromethane, "DEA" refers to diethylamine, "DIEA" refers to N,N-diisopropylethylamine, "DMAP" refers to 4-dimethylaminopyridine, "DMF" refers to dimethylformamide, "DMSO" refers to dimethyl sulfoxide, and "DMTCl" refers to 4,4'-dimethoxytrityl chloride. chloride, "ES / MS" refers to electrospray mass spectrometry, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol and ethyl alcohol, "HBTU" refers to 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate, "HOBt" refers to 1-hydroxybenzotriazole, "IP-RP" refers to Ion-Pair Reverse Phase, "LCAA CPG" refers to long chain alkylamine controlled pore glass, and "LC / MS" refers to liquid chromatography-mass spectrometry."MeOH" refers to methanol and methyl alcohol, "MPA" refers to Mobile Phase A, "MPB" refers to Mobile Phase B, "MWCO" refers to Molecular Weight Cut-Off, "NMR" refers to Nuclear Magnetic Resonance, "PBS" refers to phosphate-buffered saline, "PEG" refers to polyethylene glycol, "PVDF" refers to polyvinylidene fluoride, "RP" refers to Reverse Phase, "RPM" refers to Revolutions Per Minute, and "siRNA" refers to small interfering ribonucleic acid. "TEA" refers to triethylamine, "THF" refers to tetrahydrofuran, "TLC" refers to thin layer chromatography, "TMP" refers to 2,2,6,6-tetramethylpiperidine, "UPLC" refers to ultra-performance liquid chromatography, and "UV" refers to ultraviolet light.

[0123] [ka]

[0124] Step A of Scheme 1 depicts the coupling of compounds (1) and (2) using a suitable base such as DMAP in a suitable solvent such as DCM to give compound (3). Step B depicts the coupling of compound (3) with 1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid in a solvent system such as water and THF in the presence of a base such as potassium carbonate to give compound (4).

[0125] [ka]

[0126] Step A of Scheme 2 shows the Mitsunobu reaction of compound (5) with tert-butyl 1-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate using triphenylphosphine and diisopropyl azodicarboxylate in a solvent such as THF to give compound (6). Step B shows the acidic deprotection of compound (6) using an acid such as HCl (hydrochloric acid) in a solvent such as 1,4-dioxane to give compound (7).

[0127] [ka]

[0128] Step A of Scheme 3 shows the protection of compound (8) using DMTCl with a suitable base such as DIEA in a solvent such as DCM to give compound (9). Step B shows the amide coupling of compound (9) with piperidin-4-ylmethanol using HBTU and HOBt with TMP in a solvent such as DCM to give compound (10). Step C shows the deprotection of compound (10) with 20% piperidine in DMF to give compound (11).

[0129] [ka]

[0130] Step A of Scheme 4 depicts the amide coupling between compound 11 and either compound 4 or compound 7 using standard coupling reagents such as HBTU and HOBt with a base such as DIEA in a solvent such as DMF to give compound 12. Those skilled in the art will recognize the various conditions that can be used to perform this amide coupling. Step B depicts the coupling of compound 12 with succinic anhydride using a base such as TEA and catalytic DMAP in a solvent such as DCM to give compound 13. Step C depicts the amide coupling of compound 13 to amino LCAA CPG using HBTU with a base such as DIEA in a solvent such as ACN, followed by a multi-step workup to give compound 14.

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

[0132] [ka]

[0133] Palmitic acid (2.00 g, 7.80 mmol) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.79 g, 9.36 mmol) and DMAP (0.19 g, 1.56 mmol) in DCM (31 mL). The mixture was stirred at ambient temperature for 5 minutes, and then 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 vacuo and purified by silica gel flash chromatography eluting with a gradient of 0-80% EtOAc in hexane to give the title compound 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]ethoxy]ethoxy]propanoic acid

[0135] [ka]

[0136] 1-Amino-3,6,9,12-tetraoxapentadecan-15-oic acid (0.14 mg, 0.53 mmol) was added to a solution of potassium carbonate (0.14 mg, 1.00 mmol) in THF (1 mL) and water (2 mL). 2,5-Dioxopyrrolidin-1-ylpalmitic acid (0.18 mg, 0.51 mmol) was added, and the reaction was stirred at ambient temperature for 18 hours. The reaction was quenched with water (30 mL), and the pH was adjusted to ∼3 with 1 N aqueous hydrochloric acid. A precipitate formed, which was collected by vacuum filtration to give the title compound as a white solid (0.19 mg, 74%). ES / MS m / z 504 (M+H).

[0137] Preparation 3 tert-Butyl 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoate

[0138] [ka]

[0139] (2R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-ol (3.00 mg, 6.90 mmol), tert-butyl 1-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate (2.50 mg, 7.60 mmol), and triphenylphosphine (2.00 mg, 7.60 mmol) were mixed in THF (28.0 mL), and diisopropyl azodicarboxylate (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, silica gel was added, and the mixture was concentrated in vacuo to give an off-white solid. The mixture was purified by silica gel flash chromatography eluting with 0-40% EtOAc / hexanes to give the title compound as an oil (3.33 g, 66%). 1 H NMR(CDCl3):3.84(s,4H),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),1.58-1.51(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]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoic acid

[0141] [ka]

[0142] Tert-butyl 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoate (3.33 mg, 4.53 mmol) was dissolved in 4 M HCl in dioxane (22.6 mL, 90.6 mmol) and stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to give the title compound as an off-white solid (3.08 g, 100%). ES / MS m / z 678.0 (MH).

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

[0144] [ka]

[0145] To a stirred solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-hydroxy-propanoic acid (40 g, 0.122 mol) in dry DCM (400 mL) at 0° C. under an inert atmosphere was added DIEA (64 mL, 0.366 mol). To this mixture was slowly added a solution of DMTCl (49.6 g, 0.146 mol) in DCM (200 mL). Warmed to ambient temperature and stirred for 16 h. After this time, the reaction mixture was diluted with water and extracted with DCM. The organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was washed with 10% EtOAc / hexanes and dried under vacuum to give the crude title compound as a light brown solid (62 g, crude). TLC: 5% MeOH / CHCl (R f :0.5)UV, 254nM.

[0146] Preparation 6 9H-Fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate

[0147] [ka]

[0148] To a stirred solution of (2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (62 mg, 0.103 mol) in DCM (750 mL) was slowly added HBTU (78.3 mg, 0.206 mol), HOBt (27.9 mg, 0.206 mol), and piperidin-4-ylmethanol (15.4 mg, 0.134 mol), followed by TMP (15 mL, 0.113 mol) under an inert atmosphere at 0 °C. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 4 h. After this time, the mixture was diluted with water and extracted with DCM. The organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with 20-40% EtOAc / hexanes and 1% MeOH / DCM to give the title compound (40 g, 52% over two steps). 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.

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

[0150] [ka]

[0151] A solution of 20% piperidine in DMF (400 mL) was slowly added to 9H-fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate (40 g, 0.055 mol) under an inert atmosphere at 0 °C. The mixture was allowed to warm to ambient temperature and stirred for 1 h. After this time, the mixture was diluted with water and extracted with EtOAc. The organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with 1-8% MeOH / DCM to afford the title compound as an off-white solid (13 g, 47%). ES / MS m / z 1009.5 (2M+H).

[0152] Preparation 8 N-[2-[2-[2-[2-[3-[[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]amino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethyl]hexadecanamide

[0153] [ka]

[0154] 3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (496 mg, 0.984 mmol), HOBt (146 mg, 1.08 mmol), HBTU (410 mg, 1.08 mmol), and DIEA (1.03 mL, 5.90 mmol) were mixed in DMF (9.84 mL) and stirred at ambient temperature for 10 minutes. (2S)-2-Amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one (546 mg, 1.08 mmol) was added to the mixture and stirred at ambient temperature for 16 hours. The mixture was partitioned between EtOAc and saturated aqueous sodium chloride. The layers were separated, and the organics were washed with saturated aqueous sodium chloride. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with 0-10% MeOH / DCM to give the title compound as an oil (327 mg, 34%). H NMR (DMSO-d6): 8.21 (d, J = 8.5 Hz, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.37-7.28 (m, 4H), 7.23-7.20 (m, 5H), 6.88 (d, J = 8.3 Hz, 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,24H),1.00-0.97(m,1H),0.88-0.82(m,5H).

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

[0156] [ka]

[0157] N-[2-[2-[2-[2-[3-[[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]amino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethyl]hexadecanamide (320 mg, 0.323 mmol), DMAP (120 mg, 0.969 mmol), TEA (225 μL, 1.62 mmol), and succinic anhydride (64.7 mg, 0.646 mmol) in DCM (6.46 mL) were mixed, and the mixture was stirred at ambient temperature for 16 h. The mixture was directly purified by silica gel flash chromatography, eluting with 0% to 40% MeOH / DCM, to give the title compound as an oil (279 mg, 79%). 1 H 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),7.2 4-7.20(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),1.24(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-methoxy]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid

[0159] [ka]

[0160] 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (1.20 g, 1.80 mmol), HOBt (260 mg, 1.90 mmol), HBTU (740 mg, 1.90 mmol), and DIEA (1.80 mL, 11.0 mmol) were mixed in DMF (18.0 mL) and stirred at ambient temperature for 10 minutes. (2S)-2-Amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one (980 mg, 1.90 mmol) was added to the mixture and stirred at ambient temperature for 16 hours. The mixture was partitioned between EtOAc and saturated aqueous sodium chloride. The layers were separated, and the organics were washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography, eluting with 0–10% MeOH / DCM, to give 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]ethoxy]ethoxy]propenamide as a yellow oil.

[0161] 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]ethoxy]ethoxy]propenamide (1.45 g, 1.24 mmol), DMAP (456 mg, 3.73 mmol), TEA (867 μL, 6.22 mmol), and succinic anhydride (249 mg, 2.49 mmol) in DCM (24.9 ml) were mixed and stirred at ambient temperature for 16 hours. The resulting residue was concentrated in vacuo and purified by silica gel flash chromatography eluting with 0-40% MeOH / DCM to give the title compound as an oil (1.36 g, 60%): ES / MS m / z 1264.4 (M−H).

[0162] Preparation 11 [4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoyl]amino] on CPG

[0163] [ka]

[0164] 4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid (270 mg, 0.248 mmol) was dissolved in ACN (12.5 mL) and the solution was transferred to a fritted glass addition funnel. DIEA (150 μL, 0.860 mmol) and HBTU (190 mg, 0.500 mmol) were added to the solution, and the mixture was shaken at ambient temperature for 10 minutes. Native amino LCAA CPG 500 Å (1.92 g, 129 μmol / g) was added to the solution, and the mixture was shaken at 500 RPM for 16 hours at ambient temperature. The CPG was drained and dried under nitrogen for 5 minutes. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). The CPG was dried under nitrogen for 30 minutes and then resuspended in pyridine (15 mL). Acetic anhydride (3.30 mL, 35.0 mmol) and TEA (0.50 mL) were added, and the mixture was shaken at 500 RPM for 2 hours at ambient temperature. The CPG was drained and dried under nitrogen for 5 minutes. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). The CPG was dried under nitrogen for 45 minutes, and the ligand loading was determined at 505 nm to give the title compound (1.92 mg, 75.5 μmol / g).

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

[0166] [ka]

[0167] The title compound was prepared from 4-[[1-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid in a manner essentially similar to Preparation 11. The ligand loading was determined at 505 nm to give the title compound (4.01 g, 66.9 μmol / g).

[0168] Preparation 13 3-[[(2R,3R,4R,5R)-2-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-hexadecoxy-5-(2-hydroxy-4-oxo-pyrimidin-1-yl)THF-3-yl]oxy-(diisopropylamino)phosphanyl]oxypropanenitrile

[0169] [ka]

[0170] The title compound was prepared according to the protocol described in WO2019217459. 1 H 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,13H),3.50-3.34(m,2H),2.75-2.62(m,1H),2.55(t,J=6.0Hz,1H),1 .66-1.51(m,2H),1.40-1.14(m,35H),1.08(d,J=6.8Hz,3H),0.91(t,J=6.8Hz,3H). 31P NMR(CD3CN):149.6, 149.2.

[0171] Preparation 14 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecoxy-tetrahydrofuran-2-yl]purin-6-yl]benzamide

[0172] [ka]

[0173] The title compound was prepared according to the protocol described in WO2019217459. 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=7.6Hz,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,1H),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) δ151.19, 150.78.

[0174] Preparation 15 N-[1-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecoxy-tetrahydrofuran-2-yl]-2-oxo-pyrimidin-4-yl]acetamide

[0175] [ka]

[0176] The title compound was prepared according to the protocol described in WO2019217459. 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=7.5Hz,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,6H),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). 31 P NMR(CD3CN)δ151.10,150.19.

[0177] Preparation 16 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecoxy-tetrahydrofuran-2-yl]-6-oxo-1H-purin-2-yl]-2-methyl-propanamide

[0178] [ka]

[0179] The title compound was prepared according to the protocol described in WO2019217459. 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). 31 P NMR(CDCl3)δ150.20, 149.92.

[0180] Example 2. Synthesis of MAPT RNAi Agent The single strands (sense and antisense) of the RNA duplex were synthesized on a solid support via MerMade™ 12 (LGC Biosearch Technologies). The sequences of the sense and antisense strands are shown in Table 2. Oligonucleotides were synthesized via phosphoramidite chemistry at either a 5, 10, 25, or 50 μmol scale.

[0181] For the sense strand, the solid support type was Universal CPG: (3'-piperidinol-PEG-palmitic acid) and (3'-piperidinol-PEG-tocopherol) were synthesized in-house (see Example 1), while Universal UnyLinker (Chemgenes, catalog number AT273-27) and 3'Teg-Tocopherol (LGC Biosearch Technologies, catalog number BG7-1190) were purchased commercially. For all antisense strands, commercially available standard supports were utilized. Standard reagents were used for oligo synthesis (Table 7), where 0.1 M hydrogenated xanthan gum in pyridine was used as the sulfurizing reagent and 20% DEA in ACN was used as a post-synthesis auxiliary wash. All monomers (Table 8) were made up at 0.1 M in ACN and contained a molecular sieves trap bag.

[0182] The oligonucleotides were cleaved and deprotected (C / D) at 45°C for 20 hours. The sense strand was C / Ded from the CPG using ammonium hydroxide (28-30%, cold), while 3% DEA in ammonium hydroxide (28-30%, cold) was used for the antisense strand. C / D was determined to be complete by IP-RP LCMS when the resulting mass data confirmed sequence identity. Depending on the scale, the CPG was filtered through a 0.45 μm PVDF syringeless filter, a 0.22 μm PVDF Steriflip® vacuum filter, or a 0.22 μm PVDF Stericup® Quick Release filter. The CPG was backwashed / rinsed with either 30% ACN / RNase-free water or 30% EtOH / RNase-free water, then filtered through the same filtration device and combined with the first filtrate. This was repeated twice. The material was then divided equally between 50 mL Falcon tubes and filtered through a Genevac™ to remove organics. After concentration, the crude oligonucleotide was diluted with RNase-free water back to synthesis scale and filtered through either a 0.45 μm PVDF syringeless filter, a 0.22 μm PVDF Steriflip® vacuum filtration, or a 0.22 μm PVDF Stericup® Quick release.

[0183] Crude oligonucleotides were purified via an AKTA™ Pure purification system using either anion exchange (AEX) or reversed-phase (RP) Source 15Q-RP columns. For AEX, the column temperature was maintained at 65°C on an ES Industry Source™ 15Q column with MPA: 20 mM NaH2PO4, 15% ACN, pH 7.4, and MPB: 20 ​​mM NaH2PO4, 1 M NaBr, 15% ACN, pH 7.4. For RP, the column temperature was maintained at 65°C on a Source™ 15Q-RP column with MPA: 50 mM NaOAc with 10% ACN, and MPB: 50 mM NaOAc with 80% ACN. In all cases, fractions containing greater than 85% mass purity and containing no impurities >5% were combined.

[0184] The purified oligonucleotides were desalted using a 15 mL 3K MWCO centrifuge spin tube at 3500 x g for approximately 30 minutes. The oligonucleotides were rinsed with RNase-free water until the eluate reached a conductivity of <100 μg / cm. After desalting was complete, 2-3 mL of RNase-free water was added, followed by 10 cycles of aspiration. The retentate was transferred to a 50 mL Falcon tube, and this process was repeated until complete transfer of the oligos by measuring the concentration of the compound on the filter via nanodrop. The final oligonucleotides were then nanofiltered twice at 3500 x g for 2 minutes through a 15 mL 100K MWCO centrifuge spin tube. The final desalted oligonucleotides were analyzed for concentration (nanodrop at A260) and characterized by IP-RP LCMS for mass purity and UPLC for UV purity.

[0185] To prepare the duplex, equimolar amounts of the sense and antisense strands were combined and heated to 65°C for 10 minutes, then slowly cooled to ambient temperature over 40 minutes. The integrity of the duplex was confirmed by UPLC analysis and characterized by LCMS using IP-RP. All duplexes were nanofiltered, and endotoxin levels were then measured using a Charles River Endosafe® Cartridge Device to obtain the final conjugated RNAi compounds (Table 9). For in vivo analysis, an appropriate amount of duplex was lyophilized and then reconstituted in 1x PBS for rodent studies or CSF for non-human primate studies.

[0186] [Table 7]

[0187] [Table 8]

[0188] [Table 9-1]

[0189] [Table 9-2]

[0190] [Table 9-3]

[0191] [Table 9-4] "S" refers to the sense strand and "AS" refers to the antisense strand. * LDP1 is linked 3' to the sense strand. ** LDPs 4 to 7 are Uhd, Ahd, Chd, and Ghd, respectively, linked to nucleotides in the sense strand.

[0192] Example 3. Characterization of MAPT RNAi agents Selected MAPT RNAi agents were tested in vitro for MAPT inhibition in cultured cells, including SH-SY5Y cells, mouse cortical neurons (MCN), and / or human induced pluripotent stem cells (hiPSC). A subset of selected MAPT RNAi agents was tested in vivo in transgenic human tau mice.

[0193] Materials and Methods SH-SY5Y Cell Culture and RNAi Treatment and Analysis: SH-SY5Y cells (ATCC CRL-2266) were derived from the SK-N-SH neuroblastoma cell line (Ross, RA, et al., 1983. J Natl Cancer Inst 71, 741-747). The basal medium consisted of a 1:1 mixture of ATCC-formulated Eagle's Minimum Essential Medium (Cat. No. 30-2003) and F12 medium. Complete growth medium was supplemented with 10% fetal bovine serum, 1x amino acids, 1x sodium bicarbonate, and 1x penicillin-streptomycin (Gibco), and cells were incubated at 37°C in a humidified atmosphere of 5% CO2. On day 1, SH-SY5Y cells were seeded onto 96-well fibronectin-coated tissue culture plates and allowed to attach overnight. On day 2, the complete medium was removed and replaced with RNAi agent in serum-free medium. Cells were incubated with RNAi agents for 72 hours and then gene expression was analyzed. Analysis of gene expression changes in RNAi-treated SH-SY5Y cells was performed using Cells-to-C according to the manufacturer's protocol (ThermoFisher A35377). T Predesigned gene expression assays (supplied as a 20x mixture) were selected from Applied Biosystems (Foster City, CA, USA). The efficiency of these assays (Thermo Fisher Hs00902194_m1 MAPT and Thermo Fisher Hs99999905_m1 GAPDH) was characterized using a dilution series of cDNA. RT-QPCR was performed in a MicroAmp Optical 384-well reaction plate using a QuantStudio 7 Flex system. Relative amounts of gene expression were determined using the delta-delta CT method, normalizing to the housekeeping gene GAPDH. IC50 values ​​were determined using a four-parameter logistic fit using GraphPad Prism v9.0.

[0194] Mouse primary cortical neuron (MCN) culture and RNAi treatment and analysis: Mouse primary cortical neurons were isolated from hTau C57BL6 transgenic mouse embryos expressing a human tau transgene at E18. Cells were seeded at a density of 40k cells / well in poly-D-lysine-coated 96-well plates and cultured for 7 days at 37°C in NbActiv1 (BrainBits LLC) containing 1% antibiotic / antimycotic (Corning) in a tissue culture incubator in a humidified chamber with 5% CO2. On day 7, half of the medium was removed from each well, and RNAi was added at a 2x concentration in culture medium with 2% FBS for treatment as CRCs. The cells were incubated for an additional 7, 14, or 21 days. Half of the medium was replaced with fresh culture medium every 7 days. At the end of the RNAi treatment, RT-qPCR was performed to quantify MAPT mRNA levels using the TaqMan Fast Advanced Cell-to-CT kit. Specifically, cells were lysed, cDNA was generated using a Mastercycler X50a (Eppendorf), and qPCR was performed using a QuantStudio 7 Flex Real-Time PCR System (Applied Biosystems). Human MAPT (Thermo Fisher, Hs00902194_m1) gene expression levels were normalized to β-actin (Thermo Fisher, Mm02619580_g1) using the respective probes.

[0195] Human induced pluripotent stem cell-derived neuron (hiPSC) culture, RNAi treatment, and analysis: Doxycycline-inducible neurogenin 2 (NGN2) human induced pluripotent stem cells (hiPSCs) were developed by Eli Lilly and Company's Bioneer. hiPSCs were induced with doxycycline for 3 days (DIV3) to initiate neuronal differentiation. They were seeded at 30 kJ / well onto 96-well PDL and laminin-coated plates and grown in Neuronal Differentiation Media (NDM) consisting of DMEM / F12 (Life Technologies, 11330-057), Neurobasal Medium (Gibco 15240062), antibiotics, supplements, growth factors, and doxycycline in an incubator (37°C / 5% CO). Cells were half-fed every 7 days and treated with RNAi on DIV21 by serially diluting the RNAi agent in NDM, aspirating 75 μL according to the dilution, and adding 75 μL of 2x RNAi concentration for a final 1x RNAi concentration. After treatment, cells were half-fed every 7 days by removing half of the medium and adding back fresh NDM. Cell lysates were collected on DIV35 (14 days later) or DIV42 (21 days later) and analyzed using TaqMan Fast Advanced Cells-to-C. T RT-qPCR was performed using a kit (Thermo Fisher, A35377) to determine mRNA knockdown using a MAPT probe (Thermo Fisher, Hs00902194_m1) as the gene of interest and an ACTb probe (Thermo Fisher, Hs99999903_m1) as the housekeeping gene.

[0196] In vivo characterization of selected RNAi agents in transgenic mice The efficacy of selected RNAi agents was also studied in hTau transgenic mice expressing human MAPT RNA but lacking mouse MAPT RNA (Andorfer et al., J Neurochem 2003, 86, 582-590). Six mice were intracerebroventricularly (ICV) injected with 100 μg of RNAi agent or PBS (phosphate-buffered saline) and sacrificed 14 days after injection. MAPT mRNA expression in the brain was measured and analyzed by quantitative PCR (qPCR).

[0197] result Table 10A summarizes the in vitro and in vivo activities of selected MAPT RNAi agents. As shown in Table 10A, the tested RNAi agents knock down MAPT expression in vitro and in vivo.

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

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

[0200] [Table 11-1]

[0201] [Table 11-2]

[0202] Example 4. Knockdown of MAPT mRNA in cynomolgus monkeys after a single administration of MAPT siRNA via intrathecal injection In vivo testing of MAPT RNAi Agent No. 31 (sense strand of SEQ ID NO: 63 and antisense strand of SEQ ID NO: 40) in cynomolgus monkeys (Macaca fascicularis) was performed to evaluate the efficacy of MAPT siRNA. To elucidate the efficacy of siRNA in target gene silencing, cynomolgus monkeys (n=4 / group) were implanted with an intrathecal catheter in the lumbar region. Monkeys were infused with either aCSF or MAPT RNAi Agent No. 31 (2.4 mg / ml in aCSF) over 15 minutes and perfused 78 days later. Tissues collected at necropsy included the spinal cord (lumbar spine) and brain (prefrontal cortex, motor cortex, parietal cortex, hippocampus, and thalamus). qPCR and ELISA were performed to determine MAPT mRNA and protein knockdown in central nervous system (CNS) regions, respectively. Tables 11 and 12 below show the MAPT mRNA and protein knockdown observed in all regions 78 days after a single administration of siRNA.

[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 The inventions described in the original claims of this application are set forth below. [1] A MAPT RNAi agent having a sense strand and an antisense strand, the sense strand and the antisense strand form a duplex, the sense strand and the antisense strand (a) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (b) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:1, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:2; (c) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:3, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:4; (d) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:5, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:6; (e) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 7, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8; (f) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; (g) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12; (h) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 13, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 14; (i) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 18; (j) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 19, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 20; (k) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 21, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 22; (l) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 23, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 24; (m) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 55, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (n) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 56, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (o) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 57, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 58; (p) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 59, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 58; (q) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 60, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 61; (r) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 62, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 61; (s) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 117, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 118; and (t) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 119, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16. a pair of nucleic acid sequences selected from the group consisting of: Optionally, one or more nucleotides of said sense strand and said antisense strand are independently modified nucleotides, and optionally one or more internucleotide linkages of said sense strand and said antisense strand are modified internucleotide linkages. [2] The sense strand and the antisense strand are (a) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (b) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 2; (c) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 4; (d) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 6; (e) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 8; (f) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 10; (g) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 12; (h) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14; (i) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 22; (l) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 24; (m) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (n) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 56, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16; (o) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (p) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 58; (q) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 60, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (r) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 62, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 61; (s) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 118; and (t) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16. The MAPT RNAi agent according to [1], comprising a pair of nucleic acid sequences selected from the group consisting of: [3] The sense strand and the antisense strand are (a) the sense strand having a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (b) the sense strand having a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 2; (c) the sense strand having a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 4; (d) the sense strand having a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 6; (e) the sense strand having a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 8; (f) the sense strand having a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 10; (g) the sense strand having a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 12; (h) the sense strand having a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 14; (i) the sense strand having a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand having a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand having a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 22; (l) the sense strand having a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 24; (m) the sense strand having a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (n) the sense strand having a first nucleic acid sequence of SEQ ID NO: 56, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16; (o) the sense strand having a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (p) the sense strand having a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 58; (q) the sense strand having a first nucleic acid sequence of SEQ ID NO: 60, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (r) the sense strand having a first nucleic acid sequence of SEQ ID NO: 62, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 61; (s) the sense strand having a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 118; and (t) the sense strand having a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 16. The MAPT RNAi agent according to [1] or [2], having a pair of nucleic acid sequences selected from the group consisting of: [4] The MAPT RNAi agent according to any one of [1] to [3], wherein one or more nucleotides of the sense strand are modified nucleotides. [5] The MAPT RNAi agent according to any one of [1] to [4], wherein each nucleotide of the sense strand is a modified nucleotide. [6] The MAPT RNAi agent according to any one of [1] to [5], wherein one or more nucleotides of the antisense strand are modified nucleotides. [7] The MAPT RNAi agent according to any one of [1] to [6], wherein each nucleotide of the antisense strand is a modified nucleotide. [8] The MAPT RNAi agent according to any one of [1] to [7], wherein the modified nucleotide is a 2'-fluoro-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a 2'-O-C16 alkyl-modified nucleotide. [9] The MAPT RNAi agent according to any one of [1] to [8], wherein the sense strand has four 2'-fluoro-modified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand.

[10] The MAPT RNAi agent according to [9], 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.

[11] The MAPT RNAi agent according to any one of [8] to

[10] , wherein the antisense strand has four 2'-fluoro-modified nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand.

[12] The MAPT RNAi agent according to

[11] , wherein 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.

[13] The MAPT RNAi agent according to any one of [1] to [8], wherein the sense strand has three 2'-fluoro-modified nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand.

[14] The MAPT RNAi agent according to

[13] , wherein the nucleotides at positions other than positions 9, 10, and 11 of the sense strand are 2'-O-methyl-modified nucleotides or 2'-O-C16 alkyl-modified nucleotides.

[15] The MAPT RNAi agent according to any one of [1] to [8],

[13] , and

[14] , wherein the antisense strand has five 2'-fluoro-modified nucleotides at positions 2, 5, 7, 14, and 16 from the 5' end of the antisense strand.

[16] The MAPT RNAi agent according to

[15] , wherein 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.

[17] The MAPT RNAi agent according to any one of [1] to [8],

[13] , and

[14] , wherein the antisense strand has five 2'-fluoro-modified nucleotides at positions 2, 5, 8, 14, and 16 from the 5' end of the antisense strand.

[18] The MAPT RNAi agent according to

[17] , wherein 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.

[19] The MAPT RNAi agent according to any one of [1] to

[18] , wherein the sense strand and the antisense strand have one or more modified internucleotide linkages.

[20] The MAPT RNAi agent according to

[19] , wherein the modified internucleotide linkage is a phosphorothioate linkage.

[21] The MAPT RNAi agent according to

[20] , wherein the sense strand has four or five phosphorothioate linkages.

[22] The MAPT RNAi agent according to

[20] or

[21] , wherein the antisense strand has four or five phosphorothioate linkages.

[23] The MAPT RNAi agent according to any one of [1] to

[22] , wherein the first nucleotide from the 5' end of the antisense strand is a modified nucleotide having a phosphate analogue.

[24] The MAPT RNAi agent according to

[23] , wherein the phosphate analog is 5'-vinylphosphonate.

[25] The MAPT RNAi agent according to any one of [1] to

[24] , wherein the sense strand comprises an abasic portion or an inverted abasic portion.

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

[27] The sense strand and the antisense strand are (a) the sense strand having a first nucleic acid sequence of SEQ ID NO: 63, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (b) the sense strand having a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 26; (c) the sense strand having a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 28; (d) the sense strand having a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 30; (e) the sense strand having a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 32; (f) the sense strand having a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 34; (g) the sense strand having a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 36; (h) the sense strand having a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 38; (i) the sense strand having a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (j) the sense strand having a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 42; (k) the sense strand having a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 44; (l) the sense strand having a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 46; (m) the sense strand having a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 48; (n) the sense strand having a first nucleic acid sequence selected from any one of SEQ ID NO: 64, SEQ ID NOs: 66 to 69, SEQ ID NO: 71, SEQ ID NOs: 75 to 86, and SEQ ID NOs: 93 to 100, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (o) the sense strand having a first nucleic acid sequence of SEQ ID NO: 64, and the antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 70 and any one of SEQ ID NOs: 72 to 74; (p) the sense strand having a first nucleic acid sequence selected from SEQ ID NO: 87 or SEQ ID NO: 89, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 88; (q) the sense strand having a first nucleic acid sequence selected from SEQ ID NO: 90 or SEQ ID NO: 92, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 91; (r) the sense strand having a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 102; (s) the sense strand having a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 104; (t) the sense strand having a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand having a second nucleic acid sequence selected from SEQ ID NO: 65 and any one of SEQ ID NOs: 106 to 108; (u) the sense strand having a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 65; (v) the sense strand having a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 40; (w) the sense strand having a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 112; (x) the sense strand having a first nucleic acid sequence of SEQ ID NO: 113 and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 114; and (y) the sense strand having a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 116. The MAPT RNAi agent according to

[26] , having a pair of nucleic acid sequences selected from the group consisting of:

[28] The MAPT RNAi agent according to any one of [1] to

[27] , wherein the sense strand has a delivery moiety conjugated to the 5' end or 3' end of the sense strand.

[29] The MAPT RNAi agent according to any one of [1] to

[28] , wherein the sense strand has a delivery moiety conjugated to a nucleotide of the sense strand.

[30] The MAPT RNAi agent according to

[28] , wherein the delivery moiety is conjugated to the 3' end of the sense strand, optionally via a linker.

[31] A pharmaceutical composition comprising the MAPT RNAi agent according to any one of [1] to

[30] and a pharmaceutically acceptable carrier.

[32] A method for reducing MAPT expression in a patient in need thereof, comprising administering to the patient an effective amount of the MAPT RNAi agent according to any one of [1] to

[30] or the pharmaceutical composition according to

[31] .

[33] A method for treating a tauopathy in a patient in need thereof, comprising administering to the patient an effective amount of the MAPT RNAi agent according to any one of [1] to

[30] or the pharmaceutical composition according to

[31] .

[34] The tauopathies are Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), Parkinsonism, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA-S), and primary logopenic progressive aphasia (PPA-S). L), multisystem tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Creutzfeldt-Jakob disease Chronic Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead toxic encephalopathy, Litiko-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian syndrome with neurofibrillary tangles The method according to

[33] , wherein the tauopathy is selected from the group consisting of encephalitic motor neuron disease, post-encephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle senile dementia, neurofibrillary senile dementia, argyrophilic grain disease, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (geriatric tauopathy, PART), and glial globular tauopathy (GGT).

[35] The method according to

[33] or

[34] , wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).

[36] The method according to any one of

[33] to

[35] , wherein the MAPT RNAi agent is administered to the patient via intrathecal, intracerebroventricular, or intracisternal injection.

[37] A method for reducing MAPT expression in a cell, comprising: Introducing the MAPT RNAi agent according to any one of [1] to

[30] into the cells; and incubating the cells for a time sufficient to degrade MAPT mRNA, thereby reducing MAPT expression in the cells.

[38] The MAPT RNAi agent according to any one of [1] to

[30] or the pharmaceutical composition according to

[31] , for use in treatment.

[39] The MAPT RNAi agent according to any one of [1] to

[30] or the pharmaceutical composition according to

[31] , for use in reducing MAPT expression.

[40] The MAPT RNAi agent according to any one of [1] to

[30] or the pharmaceutical composition according to

[31] , for use in the treatment of tauopathy.

[41] The tauopathy is not limited to Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), Parkinsonism, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA-L). ), multisystem tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Creutzfeldt-Jakob disease Cobb's disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down's syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead toxic encephalopathy, Litiko-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles

[40] The MAPT RNAi agent or pharmaceutical composition for use according to

[40] , wherein the MAPT RNAi agent or pharmaceutical composition is selected from neurofibromic tangle senile dementia, post-encephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle senile dementia, neurofibrillary senile dementia, argyrophilic grain disease, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (geriatric tauopathy, PART), or glioglobular tauopathy (GGT).

[42] The MAPT RNAi agent or pharmaceutical composition for use according to

[40] or

[41] , wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).

[43] Use of the MAPT RNAi agent according to any one of [1] to

[30] in the manufacture of a pharmaceutical for the treatment of tauopathy.

[44] The tauopathies are Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), Parkinsonism, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA -L), multisystem tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British amyloid angiopathy, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Creutzfeldt-Jakob disease Sclerotic Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead toxic encephalopathy, Litiko-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian syndrome with neurofibrillary tangles The use according to

[43] , wherein the patient is selected from the group consisting of encephalitic motor neuron disease, post-encephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle senile dementia, neurofibrillary senile dementia, argyrophilic grain disease, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (geriatric tauopathy, PART), and glioglobular tauopathy (GGT).

[45] The use according to

[43] or

[44] , wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).

Claims

1. A MAPT RNAi agent having a sense strand and an antisense strand, the sense strand and the antisense strand form a duplex, A MAPT RNAi agent comprising a pair of nucleic acid sequences, wherein the sense strand and the antisense strand comprise a first nucleic acid sequence of SEQ ID NO: 15, and an antisense strand comprises a second nucleic acid sequence of SEQ ID NO:

16.

2. 2. The MAPT RNAi agent of claim 1, wherein the sense strand and the antisense strand have a pair of nucleic acid sequences, the sense strand having a first nucleic acid sequence of SEQ ID NO: 15 and the antisense strand having a second nucleic acid sequence of SEQ ID NO:

16.

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

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

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

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

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

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

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

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

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

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

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

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

17. The MAPT RNAi agent of claim 16, wherein 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. 2. The MAPT RNAi agent of claim 1, wherein the sense strand and the antisense strand have one or more modified internucleotide linkages.

19. 20. The MAPT RNAi agent of claim 18, wherein the modified internucleotide linkage is a phosphorothioate linkage.

20. 20. The MAPT RNAi agent of claim 19, wherein the sense strand has four or five phosphorothioate linkages.

21. 20. The MAPT RNAi agent of claim 19, wherein the antisense strand has four or five phosphorothioate linkages.

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

23. 2. The MAPT RNAi agent of claim 1, wherein the sense strand comprises an abasic portion or an inverted abasic portion.

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

25. 2. The MAPT RNAi agent of claim 1, wherein the sense strand has a delivery moiety conjugated to a nucleotide of the sense strand.

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

27. 10. A pharmaceutical composition comprising the MAPT RNAi agent of claim 1 and a pharmaceutically acceptable carrier.

28. A method for reducing MAPT expression in a cell in vitro, comprising: introducing the MAPT RNAi agent of claim 1 into the cell; and incubating said cells for a time sufficient to degrade MAPT mRNA, thereby reducing MAPT expression in said cells.

29. 28. The MAPT RNAi agent of claim 1 or the pharmaceutical composition of claim 27 for use in therapy.

30. 28. The MAPT RNAi agent of claim 1 or the pharmaceutical composition of claim 27 for use in reducing MAPT expression.

31. 28. The MAPT RNAi agent of claim 1 or the pharmaceutical composition of claim 27 for use in the treatment of a tauopathy.

32. The tauopathy may be Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), Parkinsonism, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA-L), or the like. ), multisystem tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), amyloid angiopathy of the British type, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Creutzfeldt-Jakob disease Cobb's disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down's syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead toxic encephalopathy, Litiko-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron with neurofibrillary tangles 32. The MAPT RNAi agent or pharmaceutical composition for use according to claim 31, wherein the MAPT RNAi agent or pharmaceutical composition is selected from the group consisting of encephalitic parkinsonism, post-encephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle senile dementia, neurofibrillary senile dementia, argyrophilic grain disease, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (geriatric tauopathy, PART), and globular glial tauopathy (GGT).

33. 32. The MAPT RNAi agent or pharmaceutical composition for use according to claim 31 , wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).

34. 10. Use of the MAPT RNAi agent of claim 1 in the manufacture of a medicament for the treatment of a tauopathy.

35. The tauopathy may be Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), Parkinsonism, Pick's disease (PiD), primary semantic progressive aphasia (PPA-S), primary logopenic progressive aphasia (PPA -L), multisystem tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), amyloid angiopathy of the British type, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), Creutzfeldt-Jakob disease Grün-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification (idiopathic basal ganglia calcification), Down syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington's disease, inclusion body myositis, lead toxic encephalopathy, Litiko-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian with neurofibrillary tangles 35. The use of claim 34, wherein the disease is selected from motor neuron disease, post-encephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, neurofibrillary tangle senile dementia, neurofibrillary senile dementia, argyrophilic grain disease, ganglioglioma, gangliocytoma, subacute sclerosing panencephalitis, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (geriatric tauopathy, PART), or glioglobular tauopathy (GGT).

36. 35. The use of claim 34, wherein the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), or progressive supranuclear palsy (PSP).

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