SARM1 RNA Interfering Agents

Abstract

Provided herein are SARM1 RNAi agents and compositions comprising the SARM1 RNAi agents. Also provided herein are methods of using the SARM1 RNAi agents or compositions comprising the SARM1 RNAi agents to reduce SARM1 expression, reduce axonal degeneration, and / or treat a SARM1-mediated neurological disorder in a subject.

Description

[Technical field]

[0001] Sequence Listing This application has been submitted with a Sequence Listing in ST.26XML format. The Sequence Listing is provided in file entitled "30243", created on January 13, 2023, and is 361 kilobytes in size. The Sequence Listing information in ST.26XML format is incorporated herein by reference in its entirety. [Background technology]

[0002] Axonal degeneration is a pathological feature of many neurological disorders, including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (Gerdts et al., Science, 2015, 348:453-457). Damaged or unhealthy axons are eliminated by an intrinsic self-destructive program known as Wallerian degeneration, which is an active process of retrograde degeneration of the distal ends of axons, while proximal axonal segments and cell bodies remain intact (Gerdts, J. et al., Neuron, 2016, 89, 449-460; Whitmore, A. et al., Cell Death Differ., 2003, 10, 260-261).

[0003] SARM1 (sterile alpha and TIR motif containing 1) is an NAD+ hydrolase that plays a key role in axon degeneration. It has been reported that knocking down or eliminating the expression of SARM1 leads to long-term protection of sensory neurons against injury-induced axon degeneration (Gerdts et al., J. Neurosci, 2013, 33, 13569-13580). WO 2021 / 108602 describes SARM1 antisense oligonucleotides.

[0004] 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).

[0005] There remains a need for therapeutic agents that can inhibit or modulate the expression of SARM1, for example, by utilizing RNAi, to treat SARM1-mediated neurological disorders. Summary of the Invention

[0006] Provided herein are SARM1 RNAi agents and compositions comprising the SARM1 RNAi agents. Also provided herein are methods of using the SARM1 RNAi agents or compositions comprising the SARM1 RNAi agents to reduce SARM1 expression, reduce axonal degeneration, and / or treat a SARM1-mediated neurological disorder in a subject.

[0007] In one aspect, provided herein is a SARM1 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; Optionally, the SARM1 RNAi agent is such that 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.

[0008] In some embodiments, the sense and antisense strands of the SARM1 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; Optionally, the SARM1 RNAi agent is such that 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.

[0009] In some embodiments, the sense and antisense strands of the SARM1 RNAi agents described herein are (a) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:1, and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:2; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:5, and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:6; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 9, and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 10; (f) having a pair of nucleic acid sequences selected from the group consisting of a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:11, and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:12.

[0010] The SARM1 RNAi agents described herein may include a modifying agent. Modifications may be made to one or more nucleotides of the sense strand and / or antisense strand, or to 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 nucleotide is a 2'-fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide, such as a 2'-O-C12-16 alkyl modified nucleotide. 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, the nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methyl 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, the nucleotides at positions other than positions 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the sense strand has three 2'-fluoro modified nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, the nucleotides at positions other than positions 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, 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. In some embodiments, the nucleotides at positions other than positions 2, 5, 7, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides.In some embodiments, 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. In some embodiments, the nucleotides at positions other than positions 2, 5, 8, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides at positions 2, 3, 7, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the nucleotides at positions other than positions 2, 3, 7, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has two 2'-fluoro modified nucleotides at positions 2 and 14 from the 5' end of the antisense strand. In some embodiments, the nucleotides at positions other than positions 2 and 14 of the antisense strand are 2'-O-methyl modified nucleotides.

[0011] 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'-vinyl phosphonate. In some embodiments, the first nucleotide from the 5' end of the antisense strand has a 5' phosphate. In some embodiments, the sense strand comprises an abasic portion or an inverted abasic portion.

[0012] In some embodiments, the sense strand and the antisense strand have one or more modified internucleotide linkages, such as 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 SARM1 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: 13, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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: 27; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO:28, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO:29; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO:28, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO:31; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (l) 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: 33; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 35; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 37; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (q) 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: 39; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 41; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 43; (u) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (v) 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: 45; (w) 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: 46, and (x) a SARM1 RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of 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: 47.

[0014] In some embodiments, provided herein is a SARM1 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 (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 14; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 16; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 18; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 20; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 22; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 24; (g) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 27; (h) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 32; (l) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 33; (m) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 35; (n) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 36; (o) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 37; (p) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 38; (q) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 214; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 39; (r) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 41; (s) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 42; (t) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 43; (u) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 44; (v) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 45; (w) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 46; (x) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SARM1 RNAi agent having a pair of nucleic acid sequences selected from the group consisting of SARM1 RNAi agent having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:47.

[0015] In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to the 3' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to the 5' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to both the 5' and 3' ends of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to a nucleotide of the sense strand. In some embodiments, the delivery moiety is alpha-tocopherol, palmitic acid, or another moiety in Table 4. In some embodiments, the delivery moiety is conjugated to the 5' or 3' end of the sense strand via a linker, e.g., a linker in Table 5. In some embodiments, the SARM1 RNAi agent is not lipid conjugated. In some embodiments, the SARM1 RNAi agent does not have a delivery moiety.

[0016] In a further aspect, provided herein is a SARM1 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 (e.g., a delivery moiety) for delivering the dsRNA to a cell, and L is a linking vehicle (e.g., a linker) for linking the dsRNA to the delivery vehicle, or is optionally absent, 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; Optionally, 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.

[0017] In some embodiments, provided herein is a SARM1 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 vehicle (e.g., a delivery moiety) for delivering the dsRNA to a cell, and L is a linking vehicle (e.g., a linker) for linking the dsRNA to a delivery vehicle or is optionally absent, wherein the sense strand and the antisense strand are (a) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:1; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:2; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:3; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:4; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:5; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:6; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 7; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:8; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:9; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:11; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 12, Optionally, 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.

[0018] In some embodiments, provided herein is a SARM1 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 vehicle (e.g., a delivery moiety) for delivering the dsRNA to a cell, and L is a linking vehicle (e.g., a linker) for linking the dsRNA to a delivery vehicle or is optionally absent, wherein the sense strand and the antisense strand are (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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: 27; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (l) 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: 33; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 35; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 37; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (q) 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: 39; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 41; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 43; (u) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (v) 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: 45; (w) 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: 46; (x) 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:47.

[0019] In some embodiments, provided herein is a SARM1 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 vehicle (e.g., a delivery moiety) for delivering the dsRNA to a cell, and L is a linking vehicle (e.g., a linker) for linking the dsRNA to a delivery vehicle or is optionally absent, wherein the sense strand and the antisense strand are (a) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 14; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 16; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 18; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 20; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 22; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 24; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 27; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 29; (g) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 30; (h) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 31; (i) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 32; (j) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 33; (k) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 35; (l) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 36; (m) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 37; (n) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 38; (o) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 39; (p) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 41; (q) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 42; (r) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 43; (s) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 44; (t) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 45; (u) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 46; (v) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:47.

[0020] In another aspect, provided herein is a pharmaceutical composition comprising the SARM1 RNAi agent described herein and a pharma- ceutical acceptable carrier.Also provided herein is a pharmaceutical composition comprising a means for reducing SARM1 expression in a cell and a pharma- ceutical acceptable carrier.

[0021] In another aspect, provided herein is a method for reducing SARM1 expression in a patient in need thereof, comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition described herein.

[0022] In another aspect, provided herein is a method for reducing axonal degeneration in a patient in need thereof, comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition described herein.

[0023] In another aspect, provided herein is a method for treating a SARM1-mediated neurological disease in a patient in need thereof, comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition described herein.

[0024] Also provided herein are methods for reducing SARM1 expression in a cell (e.g., a nerve cell (neuron)), which may include introducing a SARM1 RNAi agent described herein into the cell and incubating the cell for a period of time sufficient to degrade SARM1 mRNA, thereby reducing SARM1 expression in the cell.

[0025] In another aspect, provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in reducing SARM1 expression. In another aspect, provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in reducing axonal degeneration. Also provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in treatment. Also provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in treating a neurological disease mediated by SARM1. Also provided herein is the use of a SARM1 RNAi agent in the manufacture of a medicament for reducing axonal degeneration. Also provided herein is the use of a SARM1 RNAi agent in the manufacture of a medicament for treating a neurological disease mediated by SARM1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Provided herein are SARM1 RNAi agents and compositions comprising the SARM1 RNAi agents. Also provided herein are methods of using the SARM1 RNAi agents or compositions comprising the SARM1 RNAi agents to reduce SARM1 expression, reduce axonal degeneration, and / or treat a SARM1-mediated neurological disorder in a subject.

[0027] In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, the sense strand and the antisense strand forming a duplex. The antisense strand is complementary to a region of SARM1 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 SARM1 RNAi agent having a sense strand of 21 nucleotides and an antisense strand of 23 nucleotides. In some embodiments, the sense strand and the antisense strand of the SARM1 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 and antisense strand sequences of a SARM1 RNAi agent are provided in Table 1.

[0028] Provided herein is a SARM1 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% sequence identity to SEQ ID NO:1; and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:2; (b) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:3; and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:4; (c) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:5; and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:6; (d) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:7; and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:8; (e) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:9; and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 10; (f) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO:11; and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 12, Optionally, the SARM1 RNAi agent is such that 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] Provided herein is a SARM1 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; 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; 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; Optionally, the SARM1 RNAi agent is such that 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.

[0030] In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:1, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:2, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:3, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:4, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:5, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:6, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:7, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO:8, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[0031] Table 1. Unmodified nucleic acid sequences of SARM1 RNAi agents [Table 1] *Nucleotides 2-23 of the antisense strand are complementary to human SARM1 mRNA.

[0032] In some embodiments, the sense and antisense strands of the SARM1 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; Optionally, 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, provided herein is a SARM1 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, 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 SARM1 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, 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 SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[0034] In some embodiments, the sense and antisense strands of the SARM1 RNAi agents described herein are (a) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:1; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:2; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:3; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:4; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:5; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:6; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 7; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:8; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:9; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:11; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 12, Optionally, 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.

[0035] In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. In some embodiments, provided herein is a SARM1 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, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[0036] The SARM1 RNAi agent described herein may include a modifying agent. Modifications 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, or 2'-O-methoxyethyl (2'-O-MOE).

[0037] In some embodiments, one or more nucleotides of the sense strand and / or the 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 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 nucleotide is a 2'-fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide, e.g., 2'-OC 12~16 In some embodiments, each nucleotide of the sense strand and the antisense strand is independently a modified nucleotide, such as a 2'-fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide, such as a 2'-OC 12~16 It is an alkyl-modified nucleotide.

[0038] 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, the nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2'-O-methyl 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, the nucleotides at positions other than positions 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the sense strand has three 2'-fluoro modified nucleotides, e.g., at positions 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, the nucleotides at positions other than positions 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, 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. In some embodiments, the nucleotides at positions other than positions 2, 5, 7, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, 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. In some embodiments, the nucleotides at positions other than positions 2, 5, 8, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides at positions 2, 3, 7, 14, and 16 from the 5' end of the antisense strand. In some embodiments, the nucleotides at positions other than 2, 3, 7, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has two 2'-fluoro modified nucleotides at positions 2 and 14 from the 5' end of the antisense strand. In some embodiments, the nucleotides at positions other than 2 and 14 of the antisense strand are 2'-O-methyl modified nucleotides.

[0039] In some embodiments, the modified nucleotide is a 2'-O-alkyl modified nucleotide, e.g., 2'-OC 12~16 Alkyl modified nucleotides can function as delivery moieties. In some embodiments, the 2'-O-alkyl modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecycytidine, 2'-O-hexadecyguanine, or 2'-O-hexadecyladenosine. In some embodiments, 2'-O-hexadecyluridine, 2'-O-hexadecycytidine, 2'-O-hexadecyguanine, or 2'-O-hexadecyladenosine is the modified nucleotide in the sense strand.

[0040] 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 (5'-VP). In some embodiments, the first nucleotide from the 5' end of the antisense strand has a 5' phosphate.

[0041] In some embodiments, the sense strand comprises an abasic portion or an inverted abasic portion, such as those shown in Table 3.

[0042] 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.

[0043] In a further aspect, provided herein is a SARM1 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: 13; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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: 27; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (l) 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: 33; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 35; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 37; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (q) 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: 39; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 41; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 43; (u) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (v) 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: 45; (w) 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: 46; (x) 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:47.

[0044] In some embodiments, provided herein is a SARM1 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: 13, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 14. In some embodiments, provided herein is a SARM1 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: 15, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 16. In some embodiments, provided herein is a SARM1 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: 17, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 18. In some embodiments, provided herein is a SARM1 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: 19, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 20. In some embodiments, provided herein is a SARM1 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: 21, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 22. In some embodiments, provided herein is a SARM1 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: 23, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 24.In some embodiments, provided herein is a SARM1 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: 15, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 27. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 29. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 31. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32. In some embodiments, provided herein is a SARM1 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: 13, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 33.In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 35. In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36. In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 37. In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38. In some embodiments, provided herein is a SARM1 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: 21, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 39. In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 41.In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42. In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 43. In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44. In some embodiments, provided herein is a SARM1 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: 17, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 45. In some embodiments, provided herein is a SARM1 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: 19, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 46. In some embodiments, provided herein is a SARM1 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: 23, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 47.

[0045] In some embodiments, provided herein is a SARM1 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 (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 14; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 16; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 18; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 20; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 22; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 24; (g) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 27; (h) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; (l) and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 32; (m) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 33; (n) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 35; (o) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 36; (p) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 37; (q) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 38; (r) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 39; (s) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 41; (t) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 42; (u) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 43; (v) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 44; (v) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 45; (w) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 46; (x) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SARM1 RNAi agent having a pair of nucleic acid sequences selected from the group consisting of SARM1 RNAi agent having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:47.

[0046] In some embodiments, provided herein is a SARM1 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. In some embodiments, provided herein is a SARM1 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. In some embodiments, provided herein is a SARM1 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. In some embodiments, provided herein is a SARM1 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. In some embodiments, provided herein is a SARM1 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. In some embodiments, provided herein is a SARM1 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.In some embodiments, provided herein is a SARM1 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: 27. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 29. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 30. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 31. In some embodiments, provided herein is a SARM1 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: 28, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 32. In some embodiments, provided herein is a SARM1 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: 33.In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 35. In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 36. In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 37. In some embodiments, provided herein is a SARM1 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: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 38. In some embodiments, provided herein is a SARM1 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: 39. In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 41.In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 42. In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 43. In some embodiments, provided herein is a SARM1 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: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 44. In some embodiments, provided herein is a SARM1 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: 45. In some embodiments, provided herein is a SARM1 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: 46. In some embodiments, provided herein is a SARM1 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: 47.

[0047] Table 2: SARM1 RNAi agents with modifiers [Table 2-1]

[0048] (Continuation of Table 2) [Table 2-2] Abbreviations - "m" denotes 2'-OMe, "f" denotes 2'-fluoro, * " indicates phosphorothioate linkage, "VP" indicates 5'-vinyl phosphonate, "S" refers to the sense strand, and "AS" refers to the antisense strand, except that unless otherwise specified, the 5' position of the AS may contain a 5'-phosphate or a 5'-vinyl phosphonate.

[0049] Table 3. Abasic or inverted abasic (iAb) moieties [Table 3] "5'" and "3'" indicate the 5' to 3' direction of a sequence.

[0050] In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to the 3' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to the 5' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery moiety conjugated to both the 5' end and the 3' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has 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, palmitic acid, or another moiety in Table 4. In some aspects, the delivery moiety is a delivery moiety known for delivering an RNAi agent into a cell. Placement of a delivery moiety on the RNAi agent must overcome potential inefficient loading of AGO2 (Argonaute-2) or other impediments to RNA-Induced Silencing Complex (RISC) conjugate activity. In some embodiments, the SARM1 RNAi agent is not a lipid conjugate. In some embodiments, the SARM1 RNAi agent does not have a delivery moiety.

[0051] 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 known in the art. Exemplary linker-delivery moiety pairs are shown in Table 6. In some embodiments, the SARM1 RNAi agent has a linker-delivery moiety pair in Table 6.

[0052] In some embodiments, the delivery moiety is conjugated to a nucleotide of the sense strand. In that case, the delivery moiety is a modified nucleotide (e.g., 2'-OC 12~16In some embodiments, the modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine (Table 4).

[0053] Table 4. Delivery part [Table 4-1]

[0054] (Continuation of Table 4) [Table 4-2]

[0055] (Continuation of Table 4) [Table 4-3]

[0056] [Table 5]

[0057] [Table 6-1]

[0058] [Table 6-2]

[0059] [Table 6-3]

[0060] In a further aspect, provided herein is a SARM1 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 (e.g., a delivery moiety) for delivering the dsRNA to a cell, and L is a linking means (e.g., a linker) 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; Optionally, 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.

[0061] In some embodiments, provided herein is a SARM1 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 (e.g., a delivery moiety) for delivering dsRNA to a cell, and L is a linking means (e.g., a linker) for linking the dsRNA to a delivery means, or is optionally absent, wherein the sense strand and the antisense strand are (a) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:1; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:2; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:3; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:4; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:5; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:6; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 7; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:8; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:9; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO:11; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 12, Optionally, 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.

[0062] In some embodiments, provided herein is a SARM1 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 (e.g., a delivery moiety) for delivering dsRNA to a cell, and L is a linking means (e.g., a linker) for linking the dsRNA to a delivery means, or is optionally absent, wherein the sense strand and the antisense strand are (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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: 27; (h) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 32; (l) 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: 33; (m) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 35; (n) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (o) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 37; (p) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (q) 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: 39; (r) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 41; (s) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (t) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 43; (u) a sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (v) 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: 45; (w) 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: 46; (x) 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:47.

[0063] In some embodiments, provided herein is a SARM1 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 (e.g., a delivery moiety) for delivering dsRNA to a cell, and L is a linking means (e.g., a linker) for linking the dsRNA to a delivery means, or is optionally absent, wherein the sense strand and the antisense strand are (a) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 14; (b) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 16; (c) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 18; (d) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 20; (e) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 22; (f) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 24; (g) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 15; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 27; (h) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 28; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 32; (l) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 13; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 33; (m) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 35; (n) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 36; (o) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 37; (p) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 34; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 38; (q) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 21; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 39; (r) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 41; (s) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 42; (t) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 43; (u) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 40; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 44; (v) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 17; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 45; (w) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 19; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO: 46; (x) a sense strand having (e.g., consisting of, or consisting essentially of) a first nucleic acid sequence of SEQ ID NO: 23; and an antisense strand having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SARM1 RNAi agent having a pair of nucleic acid sequences selected from the group consisting of SARM1 RNAi agent having (e.g., consisting of, or consisting essentially of) a second nucleic acid sequence of SEQ ID NO:47.

[0064] In some embodiments, the delivery means is conjugated to the 3' end of the sense strand. In some embodiments, the delivery means is conjugated to the 5' 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, α-tocopherol, or another moiety of Table 4. In some embodiments, the linking means is selected from the group consisting of Linker 1, Linker 2, Linker 3, and Linker 4 of Table 5.

[0065] The sense and antisense strands of the SARM1 RNAi agent can be synthesized using any nucleic acid polymerization method known in the art, such as solid phase synthesis by using phosphoramidite chemistry methodology (e.g., Current Protocols in Nucleic Acid Chemistry, Beaucage, SL et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA), H-phosphonate methodology, phosphotriester chemistry, or enzymatic synthesis. Automated commercially available synthesizers, such as the MerMade™ 12 from LGC Biosearch Technologies, or other synthesizers from BioAutomation or Applied Biosystems, can be used. Phosphorothioate linkages can be introduced using sulfurizing agents such as phenylacetyl disulfide or DDTT (((dimethylaminomethylidene)amino)-3H-1,2,4-dithiazoline-3-thione). It is well known to use similar techniques as well as commercially available modified amidites and Controlled-Pore Glass (CPG) products to synthesize modified and conjugated oligonucleotides.

[0066] Purification methods can be used to eliminate undesired 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 and antisense strands can be annealed to form a duplex.

[0067] In another aspect, provided herein is a pharmaceutical composition comprising the SARM1 RNAi agent described herein and a pharma- ceutically acceptable carrier. Also provided herein is a pharmaceutical composition comprising a means for reducing SARM1 expression in a cell and a pharma- ceutically acceptable carrier. Such pharmaceutical compositions may also comprise one or more pharma- ceutically acceptable excipients, diluents, or carriers. Pharmaceutical compositions may 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).

[0068] In a further aspect, a method for reducing SARM1 expression in a cell (e.g., a neuronal cell) is provided herein, which may include introducing a SARM1 RNAi agent described herein into the cell and incubating the cell for a time sufficient for degradation of SARM1 mRNA, thereby reducing SARM1 expression in the cell. The SARM1 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 uptake by the cell via natural transport mechanisms.

[0069] In another aspect, provided herein is a method for reducing SARM1 expression in a patient in need thereof, comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition described herein.

[0070] In another aspect, provided herein is a method for reducing axonal degeneration in a patient in need thereof, comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition described herein.

[0071] In another aspect, provided herein is a method for treating a SARM1-mediated neurological disease in a patient in need thereof, comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition described herein. Exemplary SARM1-mediated neurological disorders include amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Alzheimer's disease, Parkinson's disease, Multiple Sclerosis (MS), Huntington's Disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler's syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy, and the like. Atrophy, SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus-Merzbach disease, periventricular leukomalacia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, dementia with Lewy bodies, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strampel-Lorraine disease, non-alcoholic fatty liver disease steatohepatitis (NASH), adrenomyeloneuropathy, Progressive Supra nuclear Palsy (PSP), Friedreich's ataxia, spinal cord injury, Acute Optic Neuropathy (AON), hereditary or idiopathic retinal disease, Leber Congenital Amaurosis (LCA), Leber Hereditary Optic Neuropathy (LEA),Neuropathy (LHON), Primary Open-Angle Glaucoma (POAG), Acute Angle-Closure Glaucoma (AACG), Autosomal Dominant Optic Atrophy, Retinal Ganglion Degeneration, Retinitis Pigmentosa, Outer Retinal Neuropathy, Optic Neuritis, Optic Nerve Degeneration Associated with Multiple Sclerosis, Kjer's optic neuropathy, Ischemic Optic Neuropathy, Chemotherapy-Induced Peripheral Neuropathy (CIPN), Neuromyelitis Optica, Charcot-Marie-Tooth Disease, Vitamin B12 Deficiency, Folate (Vitamin B9) Deficiency, Isolated Vitamin E Deficiency Syndrome, Nonarteritic Anterior Ischemic Optic Neuropathy, Ethambutol Exposure, Cyanide Exposure, Traumatic Brain Injury In some embodiments, the SARM1-mediated neurological disease includes, but is not limited to, amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN), tauopathy, or Charcot-Marie-Tooth disease. In some embodiments, the SARM1-mediated neurological disease is amyotrophic lateral sclerosis.

[0072] The SARM1 RNAi agent can be administered to the patient via intrathecal, intracerebroventricular, or intracisternal injection. In some embodiments, the SARM1 RNAi agent is administered to the patient intrathecally, for example, via a catheter or by direct injection into the intrathecal space.

[0073] 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.

[0074] Dosage values ​​may 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 will be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0075] In another aspect, provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in reducing SARM1 expression. Also provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in reducing axonal degeneration. Also provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in treatment. Also provided herein is a SARM1 RNAi agent or a pharmaceutical composition comprising a SARM1 RNAi agent for use in treating SARM1-mediated neurological disorders. Also provided herein is the use of a SARM1 RNAi agent in the manufacture of a medicament for reducing axonal degeneration. Also provided herein is the use of a SARM1 RNAi agent in the manufacture of a medicament for treating SARM1-mediated neurological disorders.

[0076] 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) are to be construed to cover both the singular and the plural, unless otherwise specified herein or clearly contradicted by context.

[0077] As used herein, the term "alkyl" means a saturated linear or branched monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C 1 -C 20 Alkyl(C 1 -C 20 "alkyl" means a radical having 1 to 20 carbon atoms in a linear or branched arrangement.

[0078] As used herein, "antisense strand" refers to a single-stranded oligonucleotide that is complementary to a region of a target sequence. Similarly, as used herein, "sense strand" refers to a single-stranded oligonucleotide that is complementary to a region of the antisense strand.

[0079] 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, e.g., a hairpin) that allows the two nucleotides to base pair with each other. For example, purine nucleotides of one nucleic acid that are complementary to pyrimidine nucleotides of an opposing nucleic acid may base pair with each other by forming hydrogen bonds. 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.

[0080] As used herein, a "delivery moiety" refers to a 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 combinations thereof.

[0081] As used herein, "duplex," with respect to a nucleic acid or oligonucleotide, means a structure formed through complementary base pairing of two antiparallel sequences of nucleotides (i.e., in opposite orientations), whether formed by two covalently separated nucleic acid strands or by a single folded strand (e.g., via a hairpin).

[0082] "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, and the ability of the RNAi agent to induce a desired response in the individual. An effective amount is also an amount in which any toxic or harmful effects of the RNAi agent are outweighed by the therapeutically beneficial effects.

[0083] The term "knockdown" or "expression knockdown" refers to the reduction of mRNA or protein expression of a gene following treatment with a reagent, e.g., an RNAi agent.

[0084] As used herein, "modified internucleotide linkage" refers to an internucleotide linkage that has one or more chemical modifications when compared to a reference internucleotide linkage having a phosphodiester bond. The modified internucleotide linkage may be a non-naturally occurring linkage. In some embodiments, the modified internucleotide linkage is a phosphorothioate linkage.

[0085] As used herein, "modified nucleotide" refers to a nucleotide having one or more chemical modifications when compared to a corresponding reference nucleotide selected from adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide. The modified nucleotide may have one or more chemical modifications, for example, at 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'-alkyl modified nucleotide. In some embodiments, the modified nucleotide has a phosphate analog, for example, a 5'-vinyl phosphonate. In some embodiments, the modified nucleotide has an abasic moiety or an inverted abasic moiety, for example, those shown in Table 3.

[0086] As used herein, the term "SARM1-mediated neurological disease" refers to a neurological disease, disorder, or injury mediated by SARM1 and / or axonal degeneration.

[0087] As used herein, "nucleotide" refers to an organic compound having a nucleoside (a nucleic acid base, such as adenine, cytosine, guanine, thymine, or uracil, and a pentose sugar, such as ribose or 2'-deoxyribose) linked to a phosphate group. A "nucleotide" can function as a monomeric unit of nucleic acid polymers, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0088] As used herein, "oligonucleotide" refers to a polymer of linked nucleotides, each of which may be modified or unmodified. Oligonucleotides are typically less than about 100 nucleotides in length.

[0089] As used herein, "overhang" refers to an unpaired nucleotide or nucleotides that protrude from the duplex structure of a double-stranded oligonucleotide. An overhang may include one or more unpaired nucleotides that extend from the duplex region at the 5' or 3' end of a double-stranded oligonucleotide. An overhang may be a 3' overhang or a 5' overhang on the antisense or sense strand of a double-stranded oligonucleotide.

[0090] As used herein, the term "patient" refers to a human patient.

[0091] 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.

[0092] The term "% sequence identity" or "percentage sequence identity" with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleic acid bases in a candidate sequence that are identical to the nucleotides, nucleosides, or nucleic acid bases 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 that are 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), BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), Clustal W2.0, or Clustal X2.0 software. Those skilled in the art can determine the appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment over 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 fragment of the nucleic acid sequence 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 determining 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.

[0093] As used herein, "RNAi", "RNAi agent", "iRNA", "iRNA agent", and "RNA interference agent" refer to an agent that mediates sequence-specific degradation of a target mRNA by RNA interference, for example, via the RNA-induced silencing complex (RISC) pathway. In some embodiments, an RNAi agent has a sense strand and an antisense strand, and the sense strand and the antisense strand form a duplex (e.g., a duplex RNA). In some embodiments, the sense strand has a delivery moiety conjugated to the 5' or 3' end of the sense strand or to a nucleotide of the sense strand.

[0094] As used herein, a "strand" refers to a single, contiguous sequence of nucleotides linked 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).

[0095] As used herein, "SARM1" (also known as sterile alpha and TIR motif containing 1 (SARM, HsTIR, SAMD2, hSARM1, MyD88-5)) refers to the human SARM1 mRNA transcript, or the human SARM1 protein. The nucleotide sequence of human SARM1 mRNA can be found in NM_015077.4:

[0096] [Table 7-1]

[0097] [Table 7-2]

[0098] [Table 7-3]

[0099] [Table 7-4]

[0100] [Table 7-5] (Sequence number 25).

[0101] The corresponding amino acid sequence of the human SARM1 protein can be found in NP_055892.2:

[0102] [Table 8] (Sequence number 26).

[0103] As used herein, "subject" means a mammal, including a cat, a dog, a mouse, a rat, a chimpanzee, an ape, a monkey, and a human. Preferably, the subject is a human.

[0104] 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 symptoms of the disorder or disease. 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. EXAMPLES

[0105] 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. "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" stands for triethylamine, "THF" stands for tetrahydrofuran, "TLC" stands for Thin Layer Chromatography, "TMP" stands for 2,2,6,6-tetramethylpiperidine, "UPLC" stands for Ultra-Performance Liquid Chromatography, and "UV" stands for ultraviolet light.

[0106] [ka]

[0107] Step A of Scheme 1 illustrates the coupling of compound (1) and (2) using a suitable base such as DMAP in a suitable solvent such as DCM to give compound (3). Step B illustrates 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).

[0108] [ka]

[0109] 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).

[0110] [ka]

[0111] 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).

[0112] [ka]

[0113] Step A of Scheme 4 shows 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 shows 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 shows 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 work-up to give compound (14).

[0114] Preparation 1 2,5-Dioxopyrrolidin-1-ylpalmitic acid

[0115] [ka]

[0116] 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 min, then N-hydroxysuccinimide (0.99 mg, 8.58 mmol) was added and stirred at ambient temperature for 18 h. 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-d 6 )δ2.81(s,4H), 2.66(t,2H), 1.62(m,2H), 1.25(br s,24H), 0.87(t,3H).

[0117] Preparation 2 3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid

[0118] [ka]

[0119] 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 .about.3 with 1N 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).

[0120] 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

[0121] [ka]

[0122] (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 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 (CDCl 3 ):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).

[0123] Preparation 4 3-[2-[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

[0124] [ka]

[0125] tert-Butyl 3-[2-[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 4M HCl in dioxane (22.6 mL, 90.6 mmol) and stirred at ambient temperature for 16 h. 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).

[0126] Preparation 5 (2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H-fluoren-9ylmethoxycarbonylamino)propanoic acid

[0127] [ka]

[0128] 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 inert atmosphere, DIEA (64 mL, 0.366 mol) was added. To this mixture was slowly added a solution of DMTCl (49.6 g, 0.146 mol) in DCM (200 mL). Allowed to warm 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 / CH 2 Cl 2 (R f :0.5)UV, 254nM.

[0129] Preparation 6 9H-Fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate

[0130] [ka]

[0131] 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 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-d 6 )δ7.88(br d, J=7.5Hz, 2H), 7.79-7.59(m, 3H), 7.45-7.12(m, 13H), 6.92-6.76(m, 4H), 4.79-4.44(m, 2H), 4.32(br d, J=11.4Hz, 2H), 4.20(br s, 2H), 3.71(s, 6H), 3.21(br s, 4H), 2.99-2.79(m, 1H), 2.69(br s, 2H), 1.81-1.43(m, 3H), 1.08-0.73(m, 2H).

[0132] Preparation 7 (2S)-2-Amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one

[0133] [ka]

[0134] A solution of 20% piperidine in DMF (400 mL) is 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 is allowed to warm to ambient temperature and stirred for 1 h. After this time, the mixture is diluted with water and extracted with EtOAc. The organics are dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel flash chromatography eluting with 1-8% MeOH / DCM to give the title compound as an off-white solid (13 g, 47%). ES / MS m / z 1009.5 (2M+H).

[0135] 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

[0136] [ka]

[0137] 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 min. (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 h. 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%). 1H NMR (DMSO-d 6 )8.21(d,J=8.5Hz,1H),7.80(t,J=5.6Hz,1H),7.37-7.28(m,4H),7.23-7.20(m,5H),6.88(d,J=8.3Hz,4H),5.0 6-5.02(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).

[0138] 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

[0139] [ka]

[0140] 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 purified directly 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-d 6 )12.65-12.64(m,1H),8.24-8.19(m,1H),7.80(t,J=5.6Hz,1H),7.37-7.28(m,4H),7.24-7.20(m ,5H),6.88(d,J=8.6Hz,4H),5.05-5.01(m,1H),4.44-4.40(m,1H),3.97-3.95(m,3H),3.74(s,6H) ,3.61-3.56(m,2H),3.49-3.45(m,11H),3.38(t,J=5.9Hz,3H),3.22-3.14(m,6H),2.48-2.31(m,7 H),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).

[0141] 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

[0142] [ka]

[0143] 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 (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.

[0144] A mixture of 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) was stirred at ambient temperature for 16 h. 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 (MH).

[0145] 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

[0146] [ka]

[0147] 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 dropping 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. Natural 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 min. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), then diethyl ether (50 mL). The CPG was dried under nitrogen for 30 min 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 h at ambient temperature. The CPG was drained and dried under nitrogen for 5 min. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), then diethyl ether (50 mL). The CPG was dried under nitrogen for 45 min and the ligand loading was determined at 505 nm to give the title compound (1.92 mg, 75.5 μmol / g).

[0148] 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

[0149] [ka]

[0150] 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).

[0151] 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

[0152] [ka]

[0153] The title compound was prepared according to the protocol described in WO2019217459. 1 H NMR (CD 3 CN):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),4.1 0-3.56(m,13H),3.50-3.34(m,2H),2.75-2.62(m,1H),2.55(t,J=6.0Hz,1H),1.6 6-1.51(m,2H),1.40-1.14(m,35H),1.08(d,J=6.8Hz,3H),0.91(t,J=6.8Hz,3H).31 P NMR (CD 3 CN):149.6,149.2.

[0154] Preparation 14 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecoxyl-tetrahydrofuran-2-yl]purin-6-yl]benzamide

[0155] [ka]

[0156] The title compound was prepared according to the protocol described in WO2019217459. 1 H-NMR (CD 3 CN)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 (CD 3 CN) δ 151.19, 150.78.

[0157] 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

[0158] [ka]

[0159] The title compound was prepared according to the protocol described in WO2019217459. 1 H-NMR (CD 3 CN)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),4.0 4(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 (CD 3 CN) δ151.10, 150.19.

[0160] Preparation 16 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecoxyl-tetrahydrofuran-2-yl]-6-oxo-1H-purin-2-yl]-2-methyl-propanamide

[0161] [ka]

[0162] The title compound was prepared according to the protocol described in WO2019217459. 1 H-NMR (CDCl 3 )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 (CDCl 3 ) δ 150.20, 149.92.

[0163] Preparation 17 4-[[1-[(2S)-2-[6-[[(2S)-2-[5-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypentanoylamino]-5-[bis[2-[5-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypentanoylamino]ethyl]amino]-5-oxo-pentanoyl]amino]hexanoylamino]-3-[bis(4-methoxyphenyl)-phenyl-methoxy]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid

[0164] [ka]

[0165] The title compound was prepared according to the protocol described in WO2022271806. ES / MS m / z 1109.60(M-2H) / 2.

[0166] Preparation 18 Resin Loading

[0167] [ka]

[0168] The title compound was prepared from 4-[[1-[(2S)-2-[6-[[(2S)-2-[5-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypentanoylamino]-5-[bis[2-[5-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypentanoylamino]ethyl]amino]-5-oxo-pentanoyl]amino]hexanoylamino]-3-[bis(4-methoxyphenyl)-phenyl-methoxy]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid according to the protocol described in WO 2022271806. The resin loading was calculated to be 34.7 μmol / g.

[0169] Example 2. Synthesis of SARM1 RNAi Agents and Conjugated RNAi Agents 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 5, 10, 25 or 50 μmol scale.

[0170] 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 No. AT273-27), 3'Teg-Tocopherol (LGC Biosearch Technologies, Catalog No. BG7-1190), and 3'-Cholesterol-TEG CPG (Glen Research, Catalog No. 20-2975) were purchased commercially. For all antisense strands, commercially available standard supports mA were utilized. Standard reagents were used for oligo synthesis (Table 7), where 0.1 M hydrogenated xanthane 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.

[0171] Oligonucleotides were cleaved and deprotected (C / D) at 45°C for 20 hours. The sense strand was C / Ded from the CPG using ammonia hydroxide (28-30%, cold), while 3% DEA in ammonia hydroxide (28-30%, cold) was used for the antisense strand. C / D was determined to be complete by IP-RP LCMS when the mass data obtained confirmed sequence identity. Depending on scale, the CPG was filtered through a 0.45um PVDF syringeless filter, a 0.22um PVDF Steriflip® vacuum filtration, or a 0.22um PVDF Stericup® Quick release. 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 into 50 mL Falcon tubes and the organics removed via Genevac™. After concentration, it was diluted back to synthesis scale with RNase-free water and the crude oligonucleotides were 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.

[0172] Crude oligonucleotides were purified via the AKTA™ Pure purification system using either anion exchange (AEX) or reversed phase (RP) Source 15Q-RP columns. For AEX, MPA: 20 mM NaH 2 PO 4 , 15% ACN, pH 7.4, and MPB: 20 ​​mM NaH 2 PO 4For RP, it was a Source™ 15Q 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.

[0173] The purified oligonucleotides were desalted using 15mL 3K MWCO centrifuge spin tubes at 3500xg for approximately 30 minutes. The oligonucleotides were rinsed with RNase-free water until the conductivity of the eluate reached <100 usemi / cm. After desalting was complete, 2-3mL of RNase-free water was added, then aspirated 10 times and the retention was transferred to a 50mL Falcon tube, which was repeated until complete transfer of the oligos by measuring the concentration of the compounds on the filter via a nanodrop. The final oligonucleotides were then nanofiltered twice via 15mL 100K MWCO centrifuge spin tubes at 3500xg for 2 minutes. 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.

[0174] For duplex preparation, equimolar amounts of sense and antisense strands were combined and heated at 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 by Charles River Endosafe Cartridge Device to obtain the final conjugated RNAi compounds (Table 9). For in vitro (in vivo) analysis, appropriate amounts of duplexes were lyophilized and then reconstituted in 1x PBS for rodent studies and in CSF for non-human primate studies.

[0175] Table 7 - Oligonucleotide synthesis reagents [Table 9]

[0176] Table 8 - Phosphoramidites [Table 10]

[0177] Table 9 - Conjugated SARM1 RNAi Agents [Table 11-1]

[0178] (Continued from Table 9) [Table 11-2] "S" refers to the sense strand and "AS" refers to the antisense strand. * LDP1, 8, 9 are linked to the 3' end of the sense strand. The AS of SEQ ID NOs: 14, 16, 18, 20, 22, and 24 contain a 5'-vinyl phosphonate, and all other AS in this table contain a 5'-phosphate.

[0179] Example 3. Characterization of SARM1 RNAi Agents Selected SARM1 RNAi agents were tested in vitro for SARM1 inhibition in cultured cells, including SH-SY5Y cells and / or human induced pluripotent stem cells (hiPSCs).

[0180] 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). 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 cultured at 37 °C for 24 h at 37 °C for 3 h at 5% CO. 2 The cells were incubated at 37°C in a humidified atmosphere at 4°C. 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 agent for 72 hours before gene expression was analyzed. Analysis of gene expression changes in RNAi-treated SH-SY5Y cells was performed using Cells-to-C following the manufacturer's protocol (A35377 from ThermoFisher). T The expression assays were measured using a kit. Predesigned gene expression assays (supplied as a 20x mixture) were selected from Applied Bio-systems (Foster City, CA, USA). The efficiency of these assays (Thermo Fisher Hs00240906_m1 SARM1 and Thermo Fisher Hs99999905_m1 GAPDH) was characterized using a dilution series of cDNA. RT-QPCR was performed in MicroAmp Optical 384-well reaction plates 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 was determined using a 4-parameter logistic fit using GraphPad Prism v9.0.

[0181] Human Induced Pluripotent Stem Cell-derived Neuron (hiPSC) Culture and RNAi Treatment and Analysis: Doxycycline-inducible Neurogenin2 (NGN2) human induced pluripotent stem cells (hiPSCs) were developed by Eli Lilly Bioneer. hiPSCs were doxycycline-induced for 3 days (DIV3) to initiate neuronal differentiation, seeded at 30k / well on 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% CO2). 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 1xRNAi. After treatment, cells were half-fed every 7 days by removing half the medium and adding back fresh NDM. Cell lysates were harvested on DIV35 (14 days after RNAi treatment) or DIV42 (21 days after RNAi treatment) and analyzed using TaqMan Fast Advanced Cells-to-C. T RT-qPCR was performed using a kit (Thermo Fisher, A35377) and mRNA knockdown was determined using a SARM1 probe (Thermo Fisher, Hs00240907_m1) as the gene of interest and an ACTb probe (Thermo Fisher, Hs99999903_m1) as the housekeeping gene.

[0182] result Table 10 summarizes the knockdown rate of SARM1 mRNA in human SH-SY5Y cells and IC50 of SARM RNAi agents. The tested SARM1 RNAi agents achieved strong SARM1 mRNA knockdown in human SH-SY5Y cells.

[0183] Table 10. In vitro activity of selected SARM1 RNAi agents [Table 12] "NA" means not available.

[0184] Example 4. Knockdown of SARM1 mRNA in cynomolgus monkeys following a single intrathecal administration of selected RNAi agents The efficacy of selected SARM1 RNAi agents was tested in cynomolgus monkeys (Macaca fascicularis). Evaluate the efficacy of RNAi agents in knocking down SARM1: Five groups of 4 cynomolgus monkeys per group were implanted with indwelling catheters at L4 / L5 and the catheter tip was placed at T12 / L1. Monkeys were infused with aCSF (cerebrospinal fluid) or 20 mg of conjugated RNAi agent numbers 1-4 (8 mg / ml in aCSF) over 15 minutes and perfused 28 days later. Tissues collected at necropsy included the spinal cord (lumbar, cervical, thoracic) and brain (motor cortex, medulla, pons, and midbrain). qPCR was performed to determine mRNA knockdown in multiple spinal cord and brain regions.

[0185] Table 11 summarizes the knockdown rate of SARM1 mRNA in cynomolgus monkeys. As shown in Table 11, strong SARM1 mRNA knockdown was observed in all test regions 28 days after a single intrathecal administration of the RNAi agent.

[0186] Table 11. Percent knockdown (KD) of SARM1 mRNA in cynomolgus monkeys following a single intrathecal administration of selected RNAi agents. [Table 13]

[0187] Example 5. Knockdown of human SARM1 mRNA in the liver of an AAV mouse model All animals were individually housed in a temperature-controlled facility with a 12 h / 12 ​​h light / dark cycle. The animal protocol in this study was approved by the Animal Use and Care Committee of Eli Lilly and Co. (Protocol No. 20-025). The hepatic centric model overexpressing human SARM1 was developed using approximately 8-week-old C57BL / 6 male mice injected with 10 ml of the AAV8-TBG vector carrying human (Homo sapiens) SARM1 in PBS. 11 Genome copies (GC) were generated by a single intravenous injection. 14 days after AAV administration, selected RNAi agents or control agents (PBS) were subcutaneously injected at 3 mg / kg (n=6 / group). 14 days after subcutaneous injection of RNAi agents or controls, mice were sacrificed and livers were evaluated for human SARM1 mRNA levels. In vivo knockdown levels of human SARM1 mRNA were determined by comparison with the control group.

[0188] Table 12 summarizes the knockdown rate of human SARM1 mRNA in the liver of the AAV mouse model.

[0189] Table 12. Knockdown rate (KD) of human SARM1 mRNA in the liver of AAV mouse models. [Table 14]

[0190] [Table 15-1]

[0191] [Table 15-2]

[0192]

Table 15-3

[0193]

Table 15-4

[0194]

Table 15-5

[0195]

Table 15-6

Claims

1. A SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex; The sense strand and the antisense strand are (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) a pair of nucleic acid sequences selected from the group consisting of: 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; Optionally, one or more nucleotides of the sense strand and the antisense strand are, independently, modified nucleotides; Optionally, the SARM1 RNAi agent has a sense strand and an antisense strand, wherein 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:1, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO:2; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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.

3. The sense strand and the antisense strand are (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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.

4. The SARM1 RNAi agent of any one of claims 1 to 3, wherein one or more nucleotides of the sense strand are modified nucleotides.

5. The SARM1 RNAi agent of any one of claims 1 to 4, wherein each nucleotide of the sense strand is a modified nucleotide.

6. The SARM1 RNAi agent of any one of claims 1 to 5, wherein one or more nucleotides of the antisense strand are modified nucleotides.

7. The SARM1 RNAi agent of any one of claims 1 to 6, wherein each nucleotide of the antisense strand is a modified nucleotide.

8. The SARM1 RNAi agent of any one of claims 1 to 7, wherein said modified nucleotides are 2'-fluoro modified nucleotides, 2'-O-methyl modified nucleotides, or 2'-O-alkyl modified nucleotides.

9. 9. The SARM1 RNAi agent of any one of claims 1-8, 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. 10. The SARM1 RNAi agent of claim 9, wherein a nucleotide at any position other than positions 7, 9, 10, and 11 of the sense strand is a 2'-O-methyl modified nucleotide.

11. 11. The SARM1 RNAi agent of any one of claims 8-10, 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 SARM1 RNAi agent of claim 11, wherein a nucleotide at any position other than 2, 6, 14, and 16 of the antisense strand is a 2'-O-methyl modified nucleotide.

13. The SARM1 RNAi agent of any one of claims 1-8, 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. 14. The SARM1 RNAi agent of claim 13, wherein a nucleotide at a position other than positions 9, 10, and 11 of the sense strand is a 2'-O-methyl modified nucleotide.

15. 15. The SARM1 RNAi agent of any one of claims 1-10, 13, 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. 16. The SARM1 RNAi agent of claim 15, wherein a nucleotide at any position other than 2, 5, 7, 14, and 16 of the antisense strand is a 2'-O-methyl modified nucleotide.

17. 15. The SARM1 RNAi agent of any one of claims 1-10, 13, 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. 18. The SARM1 RNAi agent of claim 17, wherein a nucleotide at any position other than 2, 5, 8, 14, and 16 of the antisense strand is a 2'-O-methyl modified nucleotide.

19. 15. The SARM1 RNAi agent of any one of claims 1-10, 13, 14, wherein the antisense strand has five 2'-fluoro modified nucleotides at positions 2, 3, 7, 14, and 16 from the 5' end of the antisense strand.

20. 20. The SARM1 RNAi agent of claim 19, wherein a nucleotide at any position other than 2, 3, 7, 14, and 16 of the antisense strand is a 2'-O-methyl modified nucleotide.

21. The SARM1 RNAi agent of any one of claims 1 to 10, 13, or 14, wherein the antisense strand has two 2'-fluoro modified nucleotides at positions 2 and 14 from the 5' end of the antisense strand.

22. 22. The SARM1 RNAi agent of claim 21, wherein a nucleotide at a position other than 2 and 14 of the antisense strand is a 2'-O-methyl modified nucleotide.

23. 23. The SARM1 RNAi agent of any one of claims 1-22, wherein said sense strand and said antisense strand comprise one or more modified internucleotide linkages.

24. 24. The SARM1 RNAi agent of claim 23, wherein said modified internucleotide linkage is a phosphorothioate linkage.

25. 25. The SARM1 RNAi agent of claim 24, wherein said sense strand has four or five phosphorothioate linkages.

26. 26. The SARM1 RNAi agent of claim 24 or 25, wherein the antisense strand has four or five phosphorothioate linkages.

27. The SARM1 RNAi agent of any one of claims 1-26, wherein the first nucleotide from the 5' end of the antisense strand is a modified nucleotide having a phosphate analog.

28. 28. The SARM1 RNAi agent of claim 27, wherein said phosphate analog is a 5'-vinyl phosphonate.

29. 29. The SARM1 RNAi agent of any one of claims 1-28, wherein the sense strand comprises an abasic portion or an inverted abasic portion.

30. 1. A SARM1 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 are (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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: 27; (h) the sense strand comprising a first nucleic acid sequence of SEQ ID NO:28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO:29; (i) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 30; (j) the sense strand comprising a first nucleic acid sequence of SEQ ID NO:28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO:31; (k) the sense strand comprising a first nucleic acid sequence of SEQ ID NO:28, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO:32; (l) 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: 33; (m) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 35; (n) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 36; (o) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 37; (p) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 38; (q) 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:39; (r) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 41; (s) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 42; (t) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 43; (u) the sense strand comprising a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprising a second nucleic acid sequence of SEQ ID NO: 44; (v) 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: 45; (w) 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: 46; and (x) a SARM1 RNAi agent having a sense strand and an antisense strand comprising a pair of nucleic acid sequences selected from the group consisting of: 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:

47.

31. The sense strand and the antisense strand are (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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: 27; (h) the sense strand having a first nucleic acid sequence of SEQ ID NO:28 and the antisense strand having a second nucleic acid sequence of SEQ ID NO:29; (i) the sense strand having a first nucleic acid sequence of SEQ ID NO:28, and the antisense strand having a second nucleic acid sequence of SEQ ID NO:30; (j) the sense strand having a first nucleic acid sequence of SEQ ID NO:28, and the antisense strand having a second nucleic acid sequence of SEQ ID NO:31; (k) the sense strand having a first nucleic acid sequence of SEQ ID NO:28 and the antisense strand having a second nucleic acid sequence of SEQ ID NO:32; (l) 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: 33; (m) the sense strand having a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 35; (n) the sense strand having a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 36; (o) the sense strand having a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 37; (p) the sense strand having a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 38; (q) 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:39; (r) the sense strand having a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 41; (s) the sense strand having a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 42; (t) the sense strand having a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 43; (u) the sense strand having a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand having a second nucleic acid sequence of SEQ ID NO: 44; (v) 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: 45; (w) 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: 46; (x) 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:

47.

32. The SARM1 RNAi agent of any one of claims 1-31, wherein the sense strand has a delivery moiety conjugated to the 3' end of the sense strand.

33. The SARM1 RNAi agent of any one of claims 1 to 32, wherein the sense strand has a delivery moiety conjugated to the 5' end of the sense strand.

34. The SARM1 RNAi agent of any one of claims 1-31, wherein the sense strand has a delivery moiety conjugated to a nucleotide of the sense strand.

35. 34. The SARM1 RNAi agent of claim 32 or 33, wherein said delivery moiety is conjugated to said 5' end and said 3' end of said sense strand via a linker.

36. 36. A pharmaceutical composition comprising the SARM1 RNAi agent of any one of claims 1 to 35 and a pharma- ceutically acceptable carrier.

37. A pharmaceutical composition comprising a means for reducing SARM1 expression in a cell and a pharma- ceutically acceptable carrier.

38. A method of reducing SARM1 expression in a patient in need thereof, said method comprising administering to said patient an effective amount of a SARM1 RNAi agent of any one of claims 1-35, or a pharmaceutical composition of claim 36 or 37.

39. A method of reducing axonal degeneration in a patient in need thereof, said method comprising administering to said patient an effective amount of a SARM1 RNAi agent of any one of claims 1-35, or a pharmaceutical composition of claim 36 or 37.

40. A method of treating a SARM1-mediated neurological disorder in a patient in need thereof, said method comprising administering to said patient an effective amount of a SARM1 RNAi agent of any one of claims 1-35, or a pharmaceutical composition of claim 36 or 37.

41. The neurological disease mediated by SARM1 is selected from the group consisting of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler's syndrome, progressive multifocal alveolar necrosis factor syndrome, and the like. encephalopathy, Alexander disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy Atrophy, SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus-Merzbach disease, periventricular leukomalacia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, dementia with Lewy bodies, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strampel-Lorraine disease, non-alcoholic fatty liver disease steatohepatitis (NASH), adrenomyeloneuropathy, Progressive Supra nuclear Palsy (PSP), Friedreich's ataxia, spinal cord injury, Acute Optic Neuropathy (AON), hereditary or idiopathic retinal disease, Leber Congenital Amaurosis (LCA), Leber Hereditary Optic Neuropathy (LHON), Primary Open-Angle Glaucoma (POAG), Acute Angle-Closure Glaucoma (AACG), Autosomal Dominant Optic Atrophy, Retinal Ganglion Degeneration, Retinitis Pigmentosa, Outer Retinal Neuropathy, Optic Neuritis, Optic Nerve Degeneration Associated with Multiple Sclerosis, Kjer's Optic Neuropathy41. The method of claim 40, wherein the cause is selected from the group consisting of peripheral neuropathy, ischemic optic neuropathy, chemotherapy-induced peripheral neuropathy, neuromyelitis optica, Charcot-Marie-Tooth disease, vitamin B12 deficiency, folate (vitamin B9) deficiency, isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, exposure to cyanide, traumatic brain injury (TBI), spinal cord injury, traumatic axonal injury, or chronic traumatic encephalopathy (CTE).

42. The method of claim 40 or 41, wherein the SARM1-mediated neurological disease is amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN), tauopathy, or Charcot-Marie-Tooth disease.

43. The method of any one of claims 40 to 42, wherein the SARM1 mediated neurological disease is amyotrophic lateral sclerosis.

44. 44. The method of any one of claims 40-43, wherein the SARM1 RNAi agent is administered to the patient via intrathecal, intracerebroventricular, or intracisternal injection.

45. 1. A method for reducing SARM1 expression in a cell, the method comprising: (a) introducing into said cell a SARM1 RNAi agent of any one of claims 1-35; and (b) incubating the cells for a period of time sufficient to degrade SARM1 mRNA, thereby reducing SARM1 expression in the cells.

46. A SARM1 RNAi agent according to any one of claims 1 to 35, or a pharmaceutical composition according to claim 36, for use in therapy.

47. A SARM1 RNAi agent according to any one of claims 1 to 35, or a pharmaceutical composition according to claim 36, for use in reducing SARM1 expression.

48. The SARM1 RNAi agent of any one of claims 1 to 35, or the pharmaceutical composition of claim 36, for use in reducing axonal degeneration.

49. The SARM1 RNAi agent of any one of claims 1 to 35, or the pharmaceutical composition of claim 36, for use in treating a neurological disease mediated by SARM1.

50. The neurological disease mediated by SARM1 is selected from the group consisting of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler's syndrome, progressive multifocal alveolar nephropathy, and glaucoma. encephalopathy, Alexander disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus-Merzbach disease, periventricular leukomalacia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Reutzfeldt-Jakob disease, transmissible spongiform encephalopathy, dementia with Lewy bodies, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strampel-Lorraine disease, nonalcoholic steatohepatitis (NASH), adrenal gland disease Renal spinal neuropathy, Progressive Supranuclear Palsy (PSP), Friedreich's Ataxia, Spinal Cord Injury, Acute Optic Neuropathy (AON), Hereditary or Idiopathic Retinal Disease, Leber's Congenital Amaurosis (LCA), Leber's Hereditary Optic Neuropathy (LHON), Primary Open Angle Glaucoma (POAG), Acute Angle-Closure Glaucoma (AACG), Autosomal Dominant Optic Atrophy, Retinal Ganglionic Degeneration, Retinitis Pigmentosa, Outer Retinal Neuropathy, Optic Neuritis, Optic Nerve Degeneration Associated with Multiple Sclerosis 50. The SARM1 RNAi agent or pharmaceutical composition for use according to claim 49, wherein the cause is selected from: Kedger optic neuropathy, ischemic optic neuropathy, chemotherapy-induced peripheral neuropathy, neuromyelitis optica, Charcot-Marie-Tooth disease, vitamin B12 deficiency, folate (vitamin B9) deficiency, isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, exposure to cyanide, traumatic brain injury (TBI), spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).

51. The SARM1 RNAi agent or pharmaceutical composition for use according to claim 49 or 50, wherein the SARM1 mediated neurological disease is amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN), tauopathy, or Charcot-Marie-Tooth disease.

52. The SARM1 RNAi agent or pharmaceutical composition for use according to any one of claims 49 to 51, wherein the SARM1 mediated neurological disease is amyotrophic lateral sclerosis.

53. 36. Use of a SARM1 RNAi agent according to any one of claims 1 to 35 in the manufacture of a medicament for reducing axonal degeneration.

54. 36. Use of a SARM1 RNAi agent according to any one of claims 1 to 35 in the manufacture of a medicament for the treatment of a SARM1 mediated neurological disorder.

55. The neurological disease mediated by SARM1 is selected from the group consisting of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler's syndrome, progressive multifocal alveolar nephropathy, and glaucoma. encephalopathy, Alexander disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus-Merzbach disease, periventricular leukomalacia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss , Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, dementia with Lewy bodies, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strampel-Lorraine disease, nonalcoholic steatohepatitis (NAS) H), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, spinal cord injury, acute optic neuropathy (AON), hereditary or idiopathic retinal disease, Leber's congenital amaurosis (LCA), Leber's hereditary optic neuropathy (LHON), primary open angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, outer retinal neuropathy, optic neuritis, multiple sclerosis 55. The use of claim 54, wherein the condition is selected from optic nerve degeneration due to glaucoma, Kedger optic neuropathy, ischemic optic neuropathy, chemotherapy-induced peripheral neuropathy, neuromyelitis optica, Charcot-Marie-Tooth disease, vitamin B12 deficiency, folate (vitamin B9) deficiency, isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, exposure to cyanide, traumatic brain injury (TBI), spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).

56. 56. The use of claim 54 or 55, wherein the SARM1-mediated neurological disease is amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN), tauopathy, or Charcot-Marie-Tooth disease.

57. The use according to any one of claims 54 to 56, wherein the SARM1 mediated neurological disease is amyotrophic lateral sclerosis.

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