SARM1 RNA interferant

Abstract

To treat neurological diseases mediated by SARM1, we provide therapeutic agents that can inhibit or modulate the expression of SARM1. [Solution] SARM1 RNAi agents and compositions comprising SARM1 RNAi agents are provided herein. Also provided herein are methods for reducing SARM1 expression, reducing axonal degeneration, and / or treating SARM1-mediated neurological diseases in a subject using a SARM1 RNAi agent or a composition comprising a SARM1 RNAi agent.

Description

[Technical Field]

[0001] Sequence List This application is filed together with a sequence listing in ST.26XML format. The sequence listing is provided as a file titled "30243" created on January 13, 2023, and is 361 kilobytes in size. The ST.26XML format sequence listing information 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 inherent self-destructive program known as Wallerian degeneration, which is an active process of retrograde degeneration of the distal end of the axon, while the proximal axonal segment and cell body 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 crucial role in axonal degeneration. Knockdown or elimination of SARM1 expression has been reported to lead to long-term protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., J. Neurosci, 2013, 33, 13569-13580). SARM1 antisense oligonucleotides are described in International Publication No. 2021 / 108602.

[0004] RNA interference (RNAi) is a highly conserved regulatory mechanism in which RNA molecules are involved in sequence-specific gene repression of gene expression by double-stranded RNA (dsRNA) molecules (Fire et al., Nature 391:806-811, 1998).

[0005] To treat SARM1-mediated neurological disorders, there is still a need for therapeutic agents that can inhibit or modulate SARM1 expression, for example, by utilizing RNAi. [Overview of the project]

[0006] SARM1 RNAi agents and compositions comprising SARM1 RNAi agents are provided herein. Also provided herein are methods for reducing SARM1 expression, reducing axonal degeneration, and / or treating SARM1-mediated neurological disorders in a subject using SARM1 RNAi agents or compositions comprising SARM1 RNAi agents.

[0007] In one embodiment, 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 double helix, (a) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 2, (b) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 4, (c) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 5, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 6, (d) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 7, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 8, (e) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 9, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 10, (f) A pair of nucleic acid sequences selected from the group consisting of a sense strand containing a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 11, and an antisense strand containing a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 12, A SARM1 RNAi agent wherein, optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide chains of the sense strand and the antisense strand are modified internucleotide chains.

[0008] In some embodiments, the sense strand and antisense strand of the SARM1 RNAi agent described herein are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 2, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 4, (c) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 6, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 8, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 10, (f) A pair of nucleic acid sequences selected from the group consisting of a sense strand containing the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 12, A SARM1 RNAi agent wherein, optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide chains of the sense strand and the antisense strand are modified internucleotide chains.

[0009] In some embodiments, the sense strand and antisense strand of the SARM1 RNAi agent described herein are (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 1, and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 2, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 3, and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 4, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 5, and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 6, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 7, and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 8, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 9, and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence 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 essentially comprising) the first nucleic acid sequence of Sequence ID No. 11, and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 12.

[0010] The SARM1 RNAi agents described herein may include modifiers. Modification may be performed on one or more nucleotides of the sense strand and / or antisense strand, or on internucleotide chains. In some embodiments, one or more nucleotides of the sense strand are modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, one or more nucleotides of the antisense strand are modified nucleotides. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotides are 2'-fluoromodified nucleotides, 2'-O-methylmodified nucleotides, or 2'-O-alkylmodified nucleotides, for example, 2'-O-C12~16 alkylmodified nucleotides. In some embodiments, the sense strand has four 2'-fluoromodified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methylmodified nucleotides. In some embodiments, the antisense strand has four 2'-fluoromodified nucleotides at positions 2, 6, 14, and 16 from the 5' end. In some embodiments, nucleotides at positions other than 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the sense strand has three 2'-fluoromodified nucleotides at positions 9, 10, and 11 from the 5' end. In some embodiments, nucleotides at positions other than 9, 10, and 11 of the sense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the antisense strand has five 2'-fluoromodified nucleotides at positions 2, 5, 7, 14, and 16 from the 5' end. In some embodiments, nucleotides at positions other than 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, such as 5'-vinylphosphonate. In some embodiments, the first nucleotide from the 5' end of the antisense strand has a 5' phosphate. In some embodiments, the sense strand includes a abasic moiety or an inverted abasic moiety.

[0012] In some embodiments, the sense and antisense strands have one or more modified nucleotide 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 the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 27; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 28 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 29; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 28 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30; (j) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 28 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 31; (k) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 28 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 32; (l) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 33; (m) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 34 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 35; (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 36, (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 37, (p) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 34, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 38, (q) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 39, (r) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 41, (s) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 42, (t) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 43, (u) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 44, (v) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 17, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 45, (w) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 46, (x) A SARM1 RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of a sense strand containing the first nucleic acid sequence of Sequence ID No. 23 and an antisense strand containing the second nucleic acid sequence of Sequence 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 double helix, (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 14, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 16, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 18, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 20, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 22, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 24, (g) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 27, (h) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 29, (i) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 30, (j) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 31, (k) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 32, (l) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 33, (m) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 35, (n) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 36, (o) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 37, (p) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 38, (q) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of sequence number 214, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 39, (r) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 41, (s) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 42, (t) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 43, (u) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 44, (v) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 45, (w) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 46, (x) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, A SARM1 RNAi agent having a pair of nucleic acid sequences selected from the group consisting of an antisense strand having (for example, consisting of or essentially consisting of) the second nucleic acid sequence of Sequence ID No. 47.

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

[0016] In a further embodiment, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, the sense strand and the antisense strand form a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, and the sense strand and the antisense strand are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 2, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 4, (c) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 6, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 8, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 10, (f) A pair of nucleic acid sequences selected from the group consisting of a sense strand containing the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 12, If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and if desired, the internucleotide chains of one or more nucleotides of the sense strand and the antisense strand are modified internucleotide chains.

[0017] In some embodiments, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a dsRNA having a sense strand and an antisense strand, the sense strand and the antisense strand forming a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, the sense strand and the antisense strand are (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 1, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 2, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 3, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 4, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 5, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 6, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 7, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 8, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 9, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 10, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 11, and an antisense strand having the second nucleic acid sequence of Sequence ID No. 12 (for example, consisting of or essentially being consisting of the same), having a pair of nucleic acid sequences selected from the group consisting of If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and if desired, the internucleotide chains of one or more nucleotides of the sense strand and the antisense strand are modified internucleotide chains.

[0018] In some embodiments, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a dsRNA having a sense strand and an antisense strand, the sense strand and the antisense strand forming a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, the sense strand and the antisense strand are (a) Sense strand containing the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 14, (b) Sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 16, (c) Sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 18, (d) Sense strand containing the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 20, (e) Sense strand containing the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 22, (f) Sense strand containing the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 24, (g) Sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 27, (h) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 29, (i) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 30, (j) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 31, (k) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 32, (l) Sense strand containing the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 33, (m) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 35, (n) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 36, (o) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 37, (p) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 38, (q) Sense strand containing the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 39, (r) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 41, (s) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 42, (t) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 43, (u) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 44, (v) Sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand containing the second nucleic acid sequence of sequence number 45, (w) Sense strand containing the first nucleic acid sequence of sequence number 19, and an antisense strand containing the second nucleic acid sequence of sequence number 46, (x) Sense strand containing the first nucleic acid sequence of Sequence ID No. 23, The pair of nucleic acid sequences is selected from the group consisting of an antisense strand containing the second nucleic acid sequence of sequence number 47.

[0019] In some embodiments, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a dsRNA having a sense strand and an antisense strand, the sense strand and the antisense strand forming a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, the sense strand and the antisense strand are (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 14, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 16, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 18, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 20, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 22, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 24, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 27, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 29, (g) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 30, (h) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 31, (i) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 32, (j) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 33, (k) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 35, (l) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 36, (m) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 37, (n) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 38, (o) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 39, (p) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 41, (q) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 42, (r) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 43, (s) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 44, (t) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 45, (u) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 46, (v) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, The molecule has a pair of nucleic acid sequences selected from the group consisting of an antisense strand having (for example, consisting of or essentially consisting of) the second nucleic acid sequence of sequence number 47.

[0020] In another embodiment, provided herein are pharmaceutical compositions comprising a SARM1 RNAi agent and a pharmaceutically acceptable carrier as described herein. Pharmaceutical compositions comprising means for reducing SARM1 expression in cells and a pharmaceutically acceptable carrier are also provided herein.

[0021] In another embodiment, the Specified herein provides a method for reducing SARM1 expression in a patient in need, such a method comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition as described herein.

[0022] In another embodiment, the Specified herein provides a method for reducing axonal degeneration in patients in need, such a method comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition as described herein.

[0023] In another embodiment, the Specified herein provides a method for treating a SARM1-mediated neurological disorder in a patient in need thereof, which includes administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition as described herein.

[0024] Methods for reducing SARM1 expression in cells (e.g., nerve cells (neurons)) are also provided herein, which may include introducing a SARM1 RNAi agent described herein into cells and incubating the cells for a sufficient time to degrade SARM1 mRNA, thereby reducing SARM1 expression in the cells.

[0025] In another embodiment, provided herein are SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in reducing SARM1 expression. In another embodiment, provided herein are SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in reducing axonal degeneration. SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in therapy are also provided herein. SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in the treatment of SARM1-mediated neurological diseases are also provided. The use of SARM1 RNAi agents in the manufacture of pharmaceuticals for reducing axonal degeneration is also provided herein. The use of SARM1 RNAi agents in the manufacture of pharmaceuticals for the treatment of SARM1-mediated neurological diseases is also provided herein. [Modes for carrying out the invention]

[0026] SARM1 RNAi agents and compositions comprising SARM1 RNAi agents are provided herein. Also provided herein are methods for reducing SARM1 expression, reducing axonal degeneration, and / or treating SARM1-mediated neurological disorders in a subject using SARM1 RNAi agents or compositions comprising SARM1 RNAi agents.

[0027] In some embodiments, SARM1 RNAi agents having a sense strand and an antisense strand are provided herein, the sense strand and the antisense strand forming a double helix. The antisense strand is complementary to the region of SARM1 mRNA. In further embodiments, the sense strand and the antisense strand are each 15 to 30 nucleotides long, for example, 20 to 25 nucleotides long. In some embodiments, SARM1 RNAi agents having a 21-nucleotide sense strand and a 23-nucleotide antisense strand are provided herein. In some embodiments, the sense strand and antisense strand of the SARM1 RNAi agent may have an overhang at either the 5' or 3' end (i.e., a 5' overhang or a 3' overhang). For example, the sense strand and the antisense strand may have a 5' overhang or 3' overhang of 1 to 5 nucleotides or 1 to 3 nucleotides. In some embodiments, the antisense strand includes a 3' overhang of two nucleotides. In some embodiments, the sense strand sequence and antisense strand sequence of the 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 double helix, (a) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity with respect to sequence number 1, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity with respect to Sequence ID No. 2, (b) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity with respect to sequence number 3, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity with respect to sequence number 4, (c) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity with respect to sequence number 5, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity with respect to sequence number 6, (d) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity with respect to sequence number 7, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity with respect to sequence number 8, (e) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity with respect to sequence number 9, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity with respect to sequence number 10, (f) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity with respect to sequence number 11, A pair of nucleic acid sequences selected from the group consisting of and an antisense strand containing a second nucleic acid sequence having at least 90% sequence identity with respect to sequence number 12, A SARM1 RNAi agent wherein, optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide chains of the sense strand and the antisense strand are modified internucleotide chains.

[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 double helix, (a) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 1, A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 2, (b) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 4, (c) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 5, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with respect to sequence number 6, (d) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 7, A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 7, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 8, (e) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 9, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 10, (f) A pair of nucleic acid sequences selected from the group consisting of a sense strand containing a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 11, and an antisense strand containing a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 12, A SARM1 RNAi agent wherein, optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide chains of the sense strand and the antisense strand are modified internucleotide chains.

[0030] In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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 chains of the sense strand and the antisense strand are modified internucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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 chains of the sense strand and the antisense strand are modified internucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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 chains of the sense strand and the antisense strand are modified internucleotide chains.In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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 chains of the sense strand and the antisense strand are modified internucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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 nucleotide-to-nucleotide chains of the sense strand and the antisense strand are modified nucleotide-to-nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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 chains of the sense strand and the antisense strand are modified internucleotide chains.

[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 strand and antisense strand of the SARM1 RNAi agent described herein are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 2, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 4, (c) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 6, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 8, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 10, (f) A pair of nucleic acid sequences selected from the group consisting of a sense strand containing the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 12, If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and if desired, the internucleotide chains of one or more nucleotides of the sense strand and the antisense strand are modified internucleotide chains.

[0033] In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, the sense strand and the antisense strand forming a double helix, 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, one or more nucleotides of the sense strand and the antisense strand independently being modified nucleotides, and optionally, one or more nucleotide-to-nucleotide chains of the sense strand and the antisense strand being modified nucleotide-to-nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, 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, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains.In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, the sense strand and the antisense strand forming a double helix, 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, one or more nucleotides of the sense strand and the antisense strand independently being modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand being modified nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, the sense strand and the antisense strand forming a double helix, 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, one or more nucleotides of the sense strand and the antisense strand independently being modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand being modified nucleotide chains.

[0034] In some embodiments, the sense strand and antisense strand of the SARM1 RNAi agent described herein are (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 1, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 2, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 3, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 4, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 5, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 6, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 7, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 8, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 9, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 10, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 11, and an antisense strand having the second nucleic acid sequence of Sequence ID No. 12 (for example, consisting of or essentially being consisting of the same), having a pair of nucleic acid sequences selected from the group consisting of If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and if desired, the internucleotide chains of one or more nucleotides of the sense strand and the antisense strand are modified internucleotide chains.

[0035] In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 2, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 4, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 6, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 8, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains.In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 10, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains. In some embodiments, a SARM1 RNAi agent having a sense strand and an antisense strand is provided herein, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 12, and one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and one or more nucleotide chains between the sense strand and the antisense strand are modified nucleotide chains.

[0036] The SARM1 RNAi agents described herein may include modifiers. Modifications may be made to one or more nucleotides of the sense strand and / or antisense strand, or to internucleotide chains, which are bonds between two nucleotides in the sense strand or antisense strand. For example, certain 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 antisense strand are independently modified nucleotides, meaning that the sense strand and the antisense strand may 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 nucleotides are 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, or 2'-O-alkyl-modified nucleotides, for example, 2'-OC 12~16 These are alkyl-modified nucleotides. In some embodiments, each nucleotide of the sense strand and antisense strand is independently a modified nucleotide, for example, a 2'-fluoro-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a 2'-O-alkyl-modified nucleotide, for example, 2'-OC 12~16 It is an alkyl-modified nucleotide.

[0038] In some embodiments, the sense strand has four 2'-fluoromodified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoromodified nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand. In some embodiments, nucleotides at positions other than 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the sense strand has three 2'-fluoromodified nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand. In some embodiments, nucleotides at positions other than 9, 10, and 11 of the sense strand are 2'-O-methyl-modified nucleotides. In some embodiments, the antisense chain has five 2'-fluoromodified nucleotides at positions 2, 5, 7, 14, and 16 from the 5' end of the antisense chain. In some embodiments, the nucleotides at positions other than 2, 5, 7, 14, and 16 of the antisense chain are 2'-O-methyl-modified nucleotides. In some embodiments, the antisense chain has five 2'-fluoromodified nucleotides at positions 2, 5, 8, 14, and 16 from the 5' end of the antisense chain. In some embodiments, the nucleotides at positions other than 2, 5, 8, 14, and 16 of the antisense chain are 2'-O-methyl-modified nucleotides. In some embodiments, the antisense chain has five 2'-fluoromodified nucleotides at positions 2, 3, 7, 14, and 16 from the 5' end of the antisense chain. In some embodiments, 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, 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, for example, 2'-OC 12~16 The alkyl-modified nucleotide can function as a delivery portion. In some embodiments, the 2'-O-alkyl-modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine. In some embodiments, 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine is 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, such as 5'-vinylphosphonate (5'-VP(vinylphosphonate)). In some embodiments, the first nucleotide from the 5' end of the antisense strand has a 5' phosphate group.

[0041] In some embodiments, the sense strand includes a debasidized portion or an inverted debasidized portion, for example, the portion shown in Table 3.

[0042] In some embodiments, the sense strand and antisense strand have one or more modified nucleotide chains. In some embodiments, the modified nucleotide chain is a phosphorothioate chain. In some embodiments, the sense strand has four or five phosphorothioate chains. In some embodiments, the antisense strand has four or five phosphorothioate chains. In some embodiments, the sense strand and antisense strand each have four or five phosphorothioate chains. In some embodiments, the sense strand has four phosphorothioate chains and the antisense strand has four phosphorothioate chains.

[0043] In a further embodiment, 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 double helix, (a) Sense strand containing the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 14, (b) Sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 16, (c) Sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 18, (d) Sense strand containing the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 20, (e) Sense strand containing the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 22, (f) Sense strand containing the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 24, (g) Sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 27, (h) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 29, (i) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 30, (j) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 31, (k) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 32, (l) Sense strand containing the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 33, (m) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 35, (n) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 36, (o) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 37, (p) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 38, (q) Sense strand containing the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 39, (r) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 41, (s) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 42, (t) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 43, (u) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 44, (v) Sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand containing the second nucleic acid sequence of sequence number 45, (w) Sense strand containing the first nucleic acid sequence of sequence number 19, and an antisense strand containing the second nucleic acid sequence of sequence number 46, (x) Sense strand containing the first nucleic acid sequence of Sequence ID No. 23, The pair of nucleic acid sequences is selected from the group consisting of an antisense strand containing the second nucleic acid sequence of sequence number 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14. 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16. 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18. 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20. 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22. 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24.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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 31. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 32. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises 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 double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 44. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, 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. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, 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. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 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 double helix, (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 14, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 16, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 18, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 20, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 22, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 24, (g) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 27, (h) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 29, (i) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 30, (j) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 31, (k) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, (l) and an antisense strand having (e.g., consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 32, (m) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 33, (n) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 35, (o) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 36, (p) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 37, (q) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 38, (r) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 39, (s) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 41, (t) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 42, (u) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 43, (v) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 44, (v) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 45, (w) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 46, (x) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, A SARM1 RNAi agent having a pair of nucleic acid sequences selected from the group consisting of an antisense strand having (for example, consisting of or essentially consisting of) the second nucleic acid sequence of Sequence ID No. 47.

[0046] In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 14. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 16. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 18. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 20. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 22. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 24.In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 27. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 29. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 30. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 31. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 32. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand has 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 double helix, the sense strand has the first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand has the 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 double helix, the sense strand has the first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand has the 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 double helix, the sense strand has the first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand has the second nucleic acid sequence of SEQ ID NO: 37. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 38. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 39. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 41.In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 42. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 43. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 44. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 45. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 46. In some embodiments, the present invention provides a SARM1 RNAi agent having a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double helix, the sense strand has a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand has a second nucleic acid sequence of SEQ ID NO: 47.

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

[0048] (Continued from Table 2) [Table 2-2] Abbreviations - "m" stands for 2'-OMe, and "f" stands for 2'-fluoro, * " indicates a phosphorothioate chain, "VP" indicates 5'-vinylphosphonate, "S" means sense chain, and "AS" means antisense chain. Unless otherwise specified, the 5' position of AS may contain 5'-phosphate or 5'-vinylphosphonate.

[0049] Table 3. Debase portion or inverse debase (iAb) portion [Table 3] "5'" and "3'" indicate the direction from 5' to 3' in the sequence.

[0050] In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery portion. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery portion conjugated to the 3' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has a delivery portion conjugated to the 5' end of the sense strand. In some embodiments, the sense strand of the SARM1 RNAi agent has delivery portions 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 portion conjugated to a nucleotide of the sense strand. The delivery portion can facilitate the entry of the RNAi agent into the cell. In some embodiments, the delivery portion is α-tocopherol, palmitic acid, or another portion listed in Table 4. In some embodiments, the delivery portion is a well-known delivery portion for delivering the RNAi agent into the cell. The placement of the delivery portion on the RNAi agent must overcome potential inefficient loading of AGO2 (Argonaut-2) or other impairments of 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 portion.

[0051] In some embodiments, the delivery portion is conjugated to the 5' or 3' end of the sense strand via a linker. In some embodiments, the linker is selected from linker 1, linker 2, linker 3, or linker 4 in Table 5. Other suitable linkers are well known in the art. Exemplary linker-delivery portion pairs are shown in Table 6. In some embodiments, the SARM1 RNAi agent has the linker-delivery portion pairs shown in Table 6.

[0052] In some embodiments, the delivery portion is conjugated to a nucleotide on the sense strand. In this case, the delivery portion is conjugated to a modified nucleotide located on the sense strand (e.g., 2'-OC). 12~16The modified nucleotide is an alkyl-modified nucleotide. In 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] (Continued from Table 4) [Table 4-2]

[0055] (Continued from Table 4) [Table 4-3]

[0056] [Table 5]

[0057] [Table 6-1]

[0058] [Table 6-2]

[0059] [Table 6-3]

[0060] In a further embodiment, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, the sense strand and the antisense strand form a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, and the sense strand and the antisense strand are (a) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 2, (b) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 4, (c) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 5, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 6, (d) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 8, (e) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 9, and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 10, (f) A pair of nucleic acid sequences selected from the group consisting of a sense strand containing the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 12, If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and if desired, the internucleotide chains of one or more nucleotides of the sense strand and the antisense strand are modified internucleotide chains.

[0061] In some embodiments, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, the sense strand and the antisense strand forming a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, the sense strand and the antisense strand are (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 1, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 2, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 3, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 4, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 5, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 6, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 7, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 8, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 9, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 10, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 11, and an antisense strand having the second nucleic acid sequence of Sequence ID No. 12 (for example, consisting of or essentially being consisting of the same), having a pair of nucleic acid sequences selected from the group consisting of If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and if desired, the internucleotide chains of one or more nucleotides of the sense strand and the antisense strand are modified internucleotide chains.

[0062] In some embodiments, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, the sense strand and the antisense strand forming a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, the sense strand and the antisense strand are (a) Sense strand containing the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 14, (b) Sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 16, (c) Sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 18, (d) Sense strand containing the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 20, (e) Sense strand containing the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 22, (f) Sense strand containing the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 24, (g) Sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 27, (h) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 29, (i) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 30, (j) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 31, (k) Sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 32, (l) Sense strand containing the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 33, (m) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 35, (n) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 36, (o) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 37, (p) Sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 38, (q) Sense strand containing the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 39, (r) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 41, (s) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 42, (t) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 43, (u) Sense strand containing the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand containing the second nucleic acid sequence of Sequence ID No. 44, (v) Sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand containing the second nucleic acid sequence of sequence number 45, (w) Sense strand containing the first nucleic acid sequence of sequence number 19, and an antisense strand containing the second nucleic acid sequence of sequence number 46, (x) Sense strand containing the first nucleic acid sequence of Sequence ID No. 23, The pair of nucleic acid sequences is selected from the group consisting of an antisense strand containing the second nucleic acid sequence of sequence number 47.

[0063] In some embodiments, provided herein are SARM1 RNAi agents of formula (I):RLD, where R is a double-stranded RNA (dsRNA) having a sense strand and an antisense strand, the sense strand and the antisense strand forming a double helix, where D is a delivery means (e.g., a delivery portion) 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 optionally absent, the sense strand and the antisense strand are (a) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially comprising) the second nucleic acid sequence of Sequence ID No. 14, (b) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 16, (c) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 18, (d) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 20, (e) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 22, (f) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 24, (g) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 15, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 27, (h) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 29, (i) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 30, (j) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 31, (k) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 28, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 32, (l) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 13, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 33, (m) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 35, (n) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 36, (o) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 37, (p) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 34, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 38, (q) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 21, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 39, (r) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 41, (s) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 42, (t) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 43, (u) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 40, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 44, (v) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 17, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 45, (w) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 19, and an antisense strand having (for example, consisting of or essentially being) the second nucleic acid sequence of Sequence ID No. 46, (x) A sense strand having (e.g., consisting of or essentially comprising) the first nucleic acid sequence of Sequence ID No. 23, A SARM1 RNAi agent having a pair of nucleic acid sequences selected from the group consisting of an antisense strand having (for example, consisting of or essentially consisting of) the second nucleic acid sequence of Sequence 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 part 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 may be synthesized using any nucleic acid polymerization method known in the art, such as solid-phase synthesis (e.g., Current Protocols in Nucleic Acid Chemistry, Beaucage, SL et al., John Wiley & Sons, Inc., New York, NY, USA), H-phosphonate method, phosphotriester chemistry, or enzymatic synthesis, using phosphoramidite chemistry methodologies. Automated, commercially available synthesizers, such as MerMade®12 from LGC Biosearch Technologies, or other synthesizers from BioAutomation or Applied Biosystems, may be used. Phosphothioate chains can be introduced using sulfidating reagents such as phenylacetyl disulfide or DDTT (((dimethylaminomethylidene)amino)-3H-1,2,4-dithiazoline-3-thione). Similar techniques, as well as commercially available modified amidites and controlled-pore glass (CPG) products, are well known to be used for the synthesis of modified and conjugated oligonucleotides.

[0066] Undesirable impurities can be removed from the final oligonucleotide product using purification methods. Common 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, the oligonucleotide can be analyzed by mass spectrometry and quantified by spectrophotometric analysis at a wavelength of 260 nm. The sense and antisense strands can then be annealed to form a double helix.

[0067] In another embodiment, provided herein are pharmaceutical compositions comprising a SARM1 RNAi agent described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions comprising means for reducing SARM1 expression in cells and a pharmaceutically acceptable carrier are also provided herein. Such pharmaceutical compositions may also comprise one or more pharmaceutically 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 embodiment, methods for reducing SARM1 expression in cells (e.g., nerve cells) are provided herein, which may include introducing a SARM1 RNAi agent described herein into cells and incubating the cells for a time sufficient to allow degradation of SARM1 mRNA, thereby reducing SARM1 expression in the cells. SARM1 RNAi agents can be introduced into cells (e.g., nerve cells) using methods well known in the art, such as transfection, electroporation, microinjection, or cellular uptake via natural transport mechanisms.

[0069] In another embodiment, the Specified herein provides a method for reducing SARM1 expression in a patient in need, such a method comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition as described herein.

[0070] In another embodiment, the Specified herein provides a method for reducing axonal degeneration in patients in need, such a method comprising administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition as described herein.

[0071] In another embodiment, the Specified herein provides a method for treating a SARM1-mediated neurological disorder in a patient in need thereof, which includes administering to the patient an effective amount of a SARM1 RNAi agent or pharmaceutical composition as described herein. Exemplary neurological diseases involving SARM1 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 disease, Harler syndrome, progressive multifocal leukoencephalopathy, Alexander disease, congenital myelin dysplasia, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, and 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, infectious spongiform encephalopathy, Lewy body dementia, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globular cell leukoatrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strumper-Lorraine disease, non-alcoholic steatohepatitis Steatohepatitis (NASH), adrenal spinal nerve disorder, Progressive Supranuclear Palsy (PSP), Friedreich's ataxia, spinal cord injury, Acute Optic Neuropathy (AON), hereditary or idiopathic retinal diseases, Leber's congenital amaurosis (LCA), Leber's hereditary optic neuropathyNeuropathy (LHON), Primary Open-Angle Glaucoma (POAG), Acute Angle-Closure Glaucoma (AACG), Autosomal Dominant Optic Atrophy, Retinal Ganglion Degeneration, Retinitis Pigmentosa, Lateral Retinal Neuropathy, Optic Neuritis, Optic Neurodegeneration 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, Folic Acid (Vitamin B9) Deficiency, Isolated Vitamin E Deficiency Syndrome, Non-Arteritic Anterior Ischemic Optic Neuropathy, Exposure to Ethambutol, Exposure to Cyanide, Traumatic Brain Injury This includes, but is not limited to, injuries (TBI), spinal cord injury, traumatic axonal injury, or chronic traumatic encephalopathy (CTE). In some embodiments, SARM1-mediated neurological disorders include amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN), tauopathy, or Charcot-Marie-Tooth disease. In some embodiments, SARM1-mediated neurological disorders include amyotrophic lateral sclerosis.

[0072] SARM1 RNAi agents can be administered to patients via intrathecal, intraventricular, or intracisional injection. In some embodiments, SARM1 RNAi agents are administered intrathecally to patients, for example, via a catheter or by direct injection into the intrathecal space.

[0073] RNAi drug regimens may be modified to provide the optimal desired response (e.g., 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 urgency of the treatment situation.

[0074] The dosage values ​​may vary depending on the type and severity of the condition to be alleviated. It should be further understood that for any particular subject, the specific medication regimen should be adjusted over time according to the individual needs and the professional judgment of the person managing or supervising the administration of the composition.

[0075] In another embodiment, provided herein are SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in reducing SARM1 expression. Also provided herein are SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in reducing axonal degeneration. Also provided herein are SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in therapeutic use. Also provided herein are SARM1 RNAi agents or pharmaceutical compositions comprising SARM1 RNAi agents for use in the treatment of SARM1-mediated neurological diseases. The use of SARM1 RNAi agents in the manufacture of pharmaceuticals for reducing axonal degeneration is also provided herein. The use of SARM1 RNAi agents in the manufacture of pharmaceuticals for the treatment of SARM1-mediated neurological diseases is also provided herein.

[0076] When used herein, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (particularly in the context of the claims) should be construed to cover both singular and plural forms, unless otherwise specified herein or unless the context clearly contradicts this.

[0077] As used herein, the term "alkyl(alkyl)" means a saturated linear or branched monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, "C1-C 20 Alkyl (C1-C 20 "Alkyl)" refers to a radical having 1 to 20 carbon atoms in a linear or branched chain configuration.

[0078] As used herein, “antisense strand” means a single-stranded oligonucleotide complementary to the region of the target sequence. Similarly, as used herein, “sense strand” means a single-stranded oligonucleotide complementary to the region of the antisense strand.

[0079] As used herein, “complementary” means a structural relationship between two nucleotides (e.g., on two opposing nucleic acids, or on opposing regions of a single nucleic acid chain, e.g., a hairpin) that enables the two nucleotides to form base pairs with each other. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair with each other by forming a hydrogen bond. Complementary nucleotides may base pair in the Watson-Crick manner or in any other manner that enables the formation of a stable double helix. Similarly, two nucleic acids may have multiple nucleotide regions that are complementary to each other and form a complementary region, as described herein.

[0080] As used herein, “delivery moiety” refers to the portion that facilitates the entry of an oligonucleotide or RNAi agent into a cell. The delivery moiety may be a lipid, cholesterol, vitamin E, carbohydrate, amino sugar, polypeptide, or a combination thereof.

[0081] As used herein, “duplex” with respect to nucleic acids or oligonucleotides means a structure formed by complementary base pairing (i.e., in opposite directions) of two antiparallel sequences of nucleotides, whether formed by two covalently separated nucleic acid chains or by a single folded chain (e.g., via a hairpin).

[0082] The "effective amount" refers to the quantity (duration and method of administration) required to achieve the desired therapeutic outcome. The effective amount of RNAi agents may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the RNAi agent's ability to induce the desired response in the individual. The effective amount is also the amount in which the therapeutically beneficial effects of the RNAi agent outweigh any toxic or adverse effects.

[0083] The terms "knockdown" or "expression knockdown" refer to the reduction of mRNA or protein expression of a gene after treatment with a reagent, such as an RNAi agent.

[0084] As used herein, “modified internucleotide linkage” means an internucleotide linkage having one or more chemical modifications compared to a reference internucleotide linkage having a phosphodiester bond. The modified internucleotide linkage may be a linkage that does not exist in nature. In some embodiments, the modified internucleotide linkage is a phosphorothioate linkage.

[0085] As used herein, “modified nucleotide” means a nucleotide having one or more chemical modifications 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. A modified nucleotide may have one or more chemical modifications to its sugar, nucleic acid base, and / or phosphate group, for example. Additionally or alternatively, a 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, such as a 5'-vinylphosphonate. In some embodiments, the modified nucleotide has a debasic or inverted debasic moiety, such as the moieties shown in Table 3.

[0086] As used herein, the term “SARM1-mediated neurological disease” means a neurological disorder, impairment, or injury mediated by SARM1 and / or axonal degeneration.

[0087] As used herein, “nucleotide” means an organic compound having a nucleoside linked to a phosphate group (e.g., nucleic acid bases such as adenine, cytosine, guanine, thymine, or uracil, and pentose sugars such as ribose or 2'-deoxyribose). A “nucleotide” can function as a monomer unit of nucleic acid polymers such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0088] As used herein, “oligonucleotide” means a polymer of linked nucleotides, each of which may or may not be modified. Oligonucleotides are typically less than about 100 nucleotides in length.

[0089] As used herein, “overhang” means one or more unpaired nucleotides that protrude from the double-strand structure of a double-stranded oligonucleotide. An overhang may include one or more unpaired nucleotides extending from the 5' or 3' terminal double-strand region of a double-stranded oligonucleotide. An overhang may be a 3' or 5' overhang on the antisense or sense strand of the 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 instead of 5'-phosphate, which is often susceptible to enzymatic removal. The 5'-phosphate analog may contain a phosphatase-resistant chain. Examples of phosphate analogs include 5'-methylenephosphonate (5'-MP) and 5'-(E)-vinylphosphonate (5'-VP). In some embodiments, the phosphate analog is 5'-VP.

[0092] The terms “% sequence identity” or “percentage sequence identity” with respect to a reference nucleic acid sequence are defined as the percentage of nucleotides, nucleosides, or nucleic acid bases in a candidate sequence that are identical to a nucleotide, nucleoside, or nucleic acid base in the reference nucleic acid sequence, after the sequence has been optimally aligned and gaps or overhangs have been introduced as necessary to achieve the maximum sequence identity percentage. Alignment for the purpose of determining the nucleic acid sequence identity percentage can be achieved in various ways within the scope of the skills of the art, for example, using publicly available computer software programs, such as those described in Current Protocols in Molecular Biology (Ausubel et al., ed., 1987, Supp. 30, Section 7.7.18, Table 7.7.1), including BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), Clustal W2.0, or Clustal X2.0 software. A person skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm required to achieve the maximum alignment over the entire length of the sequences being compared. The "sequence identity" percentage can be determined by comparing two optimally aligned sequences across a comparison window, although the nucleic acid sequence fragments within the comparison window may contain additions or deletions (e.g., gaps or overhangs) compared to a reference sequence (without additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions in both sequences where identical nucleotides, nucleosides, or nucleic acid bases are present, finding the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the sequence identity percentage. The output is the identity percentage of the subject sequence to the query sequence.

[0093] As used herein, “RNAi,” “RNAi agent,” “iRNA,” “iRNA agent,” and “RNA interference agent” refer to agents that mediate sequence-specific degradation of target mRNA, for example, through RNA interference via the RNA-induced silencing complex (RISC) pathway. In some embodiments, the RNAi agent has a sense strand and an antisense strand, which together form a double helix (e.g., double-stranded RNA). In some embodiments, the sense strand has a delivery portion at its 5' or 3' end, or conjugated to a nucleotide of the sense strand.

[0094] As used herein, “strand” means a single, continuous sequence of nucleotides linked together by internucleotide chains (e.g., phosphodiester chains or phosphorothioate chains). A strand may have two free ends (e.g., a 5' end and a 3' end).

[0095] As used herein, "SARM1" (sterile alpha and TIR motif containing 1 (also known as 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 at NM_015077.4:

[0096] [Table 7-1]

[0097] [Table 7-2]

[0098] [Table 7-3]

[0099] [Table 7-4]

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

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

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

[0103] As used herein, “subject” means a mammal (including cats, dogs, mice, rats, chimpanzees, apes, monkeys, and humans). Preferably, the subject is a human.

[0104] As used herein, “treatment” or “treating” refers to all processes that may slow, control, delay, or halt the progression of a disorder or disease disclosed herein, or improve the symptoms of a disorder or disease, but does not necessarily imply the complete elimination of all symptoms of a disorder or disease. Treatment includes the administration of proteins or nucleic acids or vectors or compositions for the treatment of a patient, in particular a disease or condition in a human. [Examples]

[0105] Example 1. Synthesis of linker-delivery portion pair 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. "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."Chromatography-Mass Spectrometry" is the term used in chromatography. "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. "siRNA" refers to small interfering ribonucleic acid. "TEA" refers to triethylamine, "THF" refers to tetrahydrofuran, "TLC" refers to thin-layer chromatography, "TMP" refers to 2,2,6,6-tetramethylpiperidine, "UPLC" refers to ultra-high-performance liquid chromatography, and "UV" refers to ultraviolet light.

[0106] [ka]

[0107] Step A of Scheme 1 shows that compound (1) and (2) are coupled using a suitable base such as DMAP in a suitable solvent such as DCM to obtain compound (3). Step B shows that compound (3) and 1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid are coupled in a solvent system such as water and THF in the presence of a base such as potassium carbonate to obtain compound (4).

[0108]

Chemical formula

[0109] Step A of Scheme 2 shows that compound (5) and tert-butyl 1-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate are subjected to the Mitsunobu reaction using triphenylphosphine and diisopropyl azodicarboxylate in a solvent such as THF to obtain compound (6). Step B shows that compound (6) is deprotected acidically using an acid such as HCl (hydrochloric acid) in a solvent such as 1,4-dioxane to obtain compound (7).

[0110]

Chemical formula

[0111] Step A of Scheme 3 shows that compound (8) is protected using DMTCl with a suitable base such as DIEA in a solvent such as DCM to obtain compound (9). Step B shows that compound (9) and piperidin-4-ylmethanol are subjected to amide coupling using HBTU and HOBt together with TMP in a solvent such as DCM to obtain compound (10). Step C shows that compound (10) is deprotected with 20% piperidine in DMF to obtain compound (11).

[0112]

Chemical formula

[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 together with a base such as DIEA in a solvent such as DMF to obtain compound (12). Those skilled in the art will recognize the various conditions that can be used to carry out this amide coupling. Step B shows the coupling of compound (12) with succinic anhydride using a base such as TEA and the catalyst DMAP in a solvent such as DCM to obtain compound (13). Step C shows the amide coupling of compound (13) to amino LCAA CPG using HBTU together with a base such as DIEA in a solvent such as ACN, followed by a multi-step workup to obtain compound (14).

[0114] Preparation 1 Palmitic acid (2,5-dioxopyrrolidin-1-yl)

[0115] [Chemical formula]

[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 minutes, then N-hydroxysuccinimide (0.99 mg, 8.58 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The resulting crude material was concentrated in vacuo and purified by silica gel flash chromatography eluting with a gradient of 0 - 80% EtOAc in hexanes to afford the title compound as a white solid (2.65 g, 96%). 1 H NMR (DMSO-d6) δ 2.81 (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]

Chem.

[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-yl palmitic acid (0.18 mg, 0.51 mmol) was added and the reaction was stirred at ambient temperature for 18 h. The reaction was quenched with water (30 mL) and the pH was adjusted to ~3 with 1N 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]

Chem.

[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-tetraoxapentadecane-15-oate (2.50 mg, 7.60 mmol), and triphenylphosphine (2.00 mg, 7.60 mmol) were mixed in THF (28.0 mL), and diisopropyl azodicarboxylate (1.50 mL, 7.60 mmol) was added dropwise over 5 minutes. The mixture was heated at 60°C for 16 hours. The mixture was cooled to ambient temperature, silica gel was added, and the mixture was concentrated in vacuum to obtain an off-white solid. The mixture was purified by silica gel flash chromatography and eluted with 0-40% toluene / hexane to obtain the title compound as an oily substance (3.33 g, 66%). 1 H NMR(CDCl3):3.84(s,4H),3.77-3.71(m,13H),2.59(t,J=6.8Hz,2H),2.52(t,J=6.6Hz,2H),2.20-2.20(m,3H),2.15- 2.12(m,3H),2.10(s,3H),1.87-1.73(m,2H),1.58-1.51(m,4H),1.47(s,9H),1.35-1.27(m,21H),0.90-0.86(m,12H).

[0123] Preparation 4 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoic acid

[0124] [ka]

[0125] 3.33 mg, 4.53 mmol of 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 was dissolved in 4 M HCl (22.6 mL, 90.6 mmol) in dioxane and stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to obtain 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] Under an inert atmosphere at 0°C, DIEA (64 mL, 0.366 mol) was added to a stirred solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-hydroxypropanoic acid (40 g, 0.122 mol) in dry DCM (400 mL). To this mixture, a solution of DMTCl (49.6 g, 0.146 mol) in DCM (200 mL) was slowly added. The mixture was heated to ambient temperature and stirred for 16 hours. After this, the reaction mixture was diluted with water and extracted with DCM. The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude residue was washed with 10% ethyl acetate / hexane and dried under vacuum to obtain the crude title compound as a light brown solid (62 g, crude). TLC: 5% MeOH / CH2Cl2(R f :0.5) UV, 254 nM.

[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), HBTU (78.3 mg, 0.206 mol), HOBt (27.9 mg, 0.206 mol), and piperidine-4-ylmethanol (15.4 mg, 0.134 mol), followed by TMP (15 mL, 0.113 mol), were slowly added at 0°C under an inert atmosphere. The resulting reaction mixture was allowed to return to room temperature and stirred for 4 hours. After this, the mixture was diluted with water and extracted with DCM. The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography eluting with 20-40% siRNA / hexane and 1% MeOH / DCM to obtain the title compound (40 g, 52% obtained in two steps). 1 H NMR (DMSO-d6) δ7.88(br d, J=7.5Hz, 2H), 7.79-7.59(m, 3H), 7.45-7.12(m, 13H), 6.92-6.76(m, 4H), 4.79-4.44(m, 2H), 4.32(br d.

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

[0133] [ka]

[0134] A 20% piperidine solution in DMF (400 mL) was slowly added to 9H-fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate (40 g, 0.055 mol) under an inert atmosphere at 0°C. The mixture was warmed to ambient temperature and stirred for 1 hour. After this, the mixture was diluted with water and extracted with ethyl acetate. The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography eluted with 1-8% MeOH / DCM to obtain 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) in DMF (9.84 mL) were mixed and stirred at ambient temperature for 10 minutes. (2S)-2-amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one (546 mg, 1.08 mmol) was added to the mixture and stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and saturated sodium chloride aqueous solution. The layers were separated, and the organic matter was washed with saturated sodium chloride aqueous solution. The organic matter was dried on sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography eluted with 0-10% MeOH / DCM to obtain the title compound as an oily substance (327 mg, 34%). ¹H NMR (DMSO-d6): 8.21 (d, J=8.5 Hz, ¹H), 7.80 (t, J=5.6 Hz, ¹H), 7.37-7.28 (m, ₄H), 7.23-7.20 (m, ₅H), 6.88 (d, J=8.3 Hz, ₄H), 5.06-5.02 (m, ₄H), 4.51-4.49 (m, ₄H), 4.45-4.40 (m, ₄H), 3.97-3.93 (m, ₄H), 3.74 (s, ₅H), 3.63-3.56 (m, ₄H) ,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) were mixed in DCM (6.46 mL), and the mixture was stirred at ambient temperature for 16 hours. The mixture was directly purified by silica gel flash chromatography and eluted with 0% to 40% MeOH / DCM to obtain the title compound as an oily substance (279 mg, 79%). 1 H NMR(DMSO-d6)12.65-12.64(m,1H),8.24-8.19(m,1H),7.80(t,J=5.6Hz,1H),7.37-7.28(m,4H),7.2 4-7.20(m,5H),6.88(d,J=8.6Hz,4H),5.05-5.01(m,1H),4.44-4.40(m,1H),3.97-3.95(m,3H),3.74( s,6H),3.61-3.56(m,2H),3.49-3.45(m,11H),3.38(t,J=5.9Hz,3H),3.22-3.14(m,6H),2.48-2.31( m,7H),2.04(t,J=7.4Hz,2H),1.90-1.87(m,5H),1.24(s,23H),0.98-0.96(m,1H),0.87-0.82(m,4H).

[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 toluene and a saturated sodium chloride aqueous solution. The layers were separated, and the organic matter was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography and eluted with 0-10% MeOH / DCM to obtain 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 oily substance.

[0144] 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) were mixed in DCM(24.9) and stirred at ambient temperature for 16 hours. The obtained residue was concentrated under vacuum, purified by silica gel flash chromatography, and eluted with 0-40% MeOH / DCM to obtain the title compound as an oily substance (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 frit 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 minutes. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). The CPG was dried under nitrogen for 30 minutes and then resuspended in pyridine (15 mL). Acetic anhydride (3.30 mL, 35.0 mmol) and TEA (0.50 mL) were added, and the mixture was shaken at 500 RPM for 2 hours at ambient temperature. The CPG was drained and dried under nitrogen for 5 minutes. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). The CPG was dried under nitrogen for 45 minutes, and the ligand loading was determined at 505 nm to obtain 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]

[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 by a method essentially similar to that of preparation 11. Ligand loading was determined at 505 nm to obtain 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-oxopyrimidine-1-yl)THF-3-yl]oxy-(diisopropylamino)phosphanyl]oxypropanenitrile

[0152] [ka]

[0153] The title compound was prepared according to the protocol described in International Publication No. 2019217459. 1 H NMR(CD3CN):7.86-7.73(m,1H),7.51-7.43(m,2H),7.40-7.23(m,7H),6.95-6.87( m,4H),5.90-5.84(m,1H),5.29-5.21(m,1H),4.54-4.40(m,1H),4.21-4.13(m,1H), 4.10-3.56(m,13H),3.50-3.34(m,2H),2.75-2.62(m,1H),2.55(t,J=6.0Hz,1H),1 .66-1.51(m,2H),1.40-1.14(m,35H),1.08(d,J=6.8Hz,3H),0.91(t,J=6.8Hz,3H). 311P NMR (CD3CN): 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-hexadecoxytetrahydrofuran-2-yl]purin-6-yl]benzamide

[0155] [ka]

[0156] The title compound was prepared according to the protocol described in International Publication No. 2019217459. 1 H-NMR(CD3CN)δ9.37(s,1H),8.57(d,J=9.4Hz,1H),8.27(d,J=10.3Hz,1H),7.99(d,J=7.6Hz,2H),7.61( d,J=7.4Hz,1H),7.52(t,J=7.6Hz,2H),7.42(t,J=7.3Hz,2H),7.34-7.16(m,7H),6.85-6.77(m,4H),6.1 1(dd,J=5.0,2.5Hz,1H),4.80(m,1H),4.69(m,1H),4.32(m,1H),3.97-3.78(m,1H),3.74(d,J=3.1Hz,7H),3.64(m,4H),3.56-3.40(m,2H), 3.33(m,1H),2.73-2.59(m,1H),2.50(t,J=6.0Hz,1H),1.52-1.45(m,2H),1.33-1.12(m,37H),1.09(d,J=6.8Hz,3H),0.87(t,J=6.8Hz,3H). 31 P NMR (CD3CN) δ151.19, 150.78.

[0157] Preparation 15 N-[1-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecoxytetrahydrofuran-2-yl]-2-oxopyrimidine-4-yl]acetamide

[0158] [ka]

[0159] The title compound was prepared according to the protocol described in International Publication No. 2019217459. 1 H-NMR(CD3CN)9.15(s,1H),8.46(dd,J=7.5Hz,1H),7.95(d,J=7.6Hz,2H),7.63(t,J=7.5Hz,1H),7.57-7.41(m,5H),7.41-7.31(m ,6H),7.28(m,1H),7.04(d,J=15.8Hz,1H),6.90(t,J=7.9Hz,4H),5.90(d,J=7.8Hz,1H),4.51(m,1H),4.20(dd,J=10.6,8.1Hz,1H) ,4.04(dd,J=31.3,4.6Hz,1H),3.91-3.81(m,2H),3.79(d,J=3.1Hz,6H),3.74(m,2H),3.69-3.41(m,6H),2.67-2.59(m,1H),2.54 -2.48(m,1H),1.58(m,2H),1.36(m,2H),1.25(d,J=4.7Hz,26H),1.21-1.09(m,10H),1.04(d,J=6.8Hz,3H),0.87(t,J=6.8Hz,3H). 31 P NMR(CD3CN)δ151.10,150.19.

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

[0161] [ka]

[0162] The title compound was prepared according to the protocol described in International Publication No. 2019217459. 1 H-NMR(CDCl3)δ12.01-11.96(m,1H),7.82-7.78(m,1H),7.59-7.53(m,1H),7.47-7.42(m,1H),7.41-7.37(m, 2H),7.34-7.29(m,2H),7.27-7.22(m,3H),6.85-6.80(m,4H),5.99-5.82(m,1H),4.40-4.36(m,1H),4.17-4. 11(m,1H),3.80-3.77(m,6H),3.76-3.68(m,6H),3.22-3.17(m,1H),2.84-2.79(m,1H),1.60-1.54(m,4H),1. 35-1.30(m,6H),1.27(s,19H),1.24-1.15(m,13H),1.06-1.03(m,5H),0.93-0.88(m,6H),0.74-0.70(m,1H). 31 P NMR(CDCl3)δ150.20, 149.92.

[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 International Publication No. 2022271806. 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 International Publication No. 2022271806. The resin loading was calculated to be 34.7 μmol / g.

[0169] Example 2. Synthesis of SARM1 RNAi agent and conjugated RNAi agent RNA double helix single strands (sense and antisense) were synthesized on a solid support via MerMade® 12 (manufactured by LGC Biosearch Technologies). The sequences of the sense and antisense strands are shown in Table 2. Oligonucleotides were synthesized via phosphoramidite chemistry in 5, 10, 25, or 50 μmol scales.

[0170] For the sense chains, the solid support type was Universal CPG: (3'-Piperidinol-PEG-Palmitic Acid) and (3'-Piperidinol-PEG-Tocopherol) were synthesized in-house (see Example 1), while Universal UnyLinker (Chemgenes, catalog number AT273-27), 3'Teg-Tocopherol (LGC Biosearch Technologies, catalog number BG7-1190), and 3'-Cholesterol-TEG CPG (Glen Research, catalog number 20-2975) were purchased commercially. For all antisense chains, commercially available standard support mA was used. Standard reagents were used for oligonucleotide synthesis (Table 7), with 0.1 M xanthan hydride in pyridine used as the sulfidating agent, and 20% DEA in ACN used as an auxiliary wash after synthesis. All monomers (Table 8) were prepared in 0.1 M ACN and contained in molecular sieve trap bags.

[0171] Oligonucleotides were cleaved and deprotected (C / D) at 45°C for 20 hours. The sense strand was C / D from the CPG using 28-30% ammonium hydroxide (cold), while 3% DEA in 28-30% ammonium hydroxide (cold) was used for the antisense strand. C / D was determined to be complete by IP-RP LCMS when the obtained mass data confirmed sequence identity. Depending on the scale, the CPG was filtered through a 0.45 μm PVDF syringeless filter, a 0.22 μm PVDF Steriflip® vacuum filter, or a 0.22 μm PVDF Stericup® Quick release filter. The CPG was backwashed / rinsed with either 30% ACN / RNase-free water or 30% EtOH / RNase-free water, then filtered through the same filtration device and mixed with the initial filtrate. This was repeated twice. Next, the material was evenly divided into 50 mL Falcon tubes and organic matter was removed via Genevac®. After concentration, it was diluted with RNase-free water and returned to the synthesis scale, and the crude oligonucleotide was filtered using 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, an ES Industry Source® 15Q column was used, maintained at a column temperature of 65°C, with MPA: 20 mM NaH₂PO₄, 15% ACN, pH 7.4, and MPB: 20 ​​mM NaH₂PO₄, 1 M NaBr, 15% ACN, pH 7.4. For RP, a Source® 15Q-RP column was used, with MPA: 50 mM NaOAc containing 10% ACN, and MPB: 50 mM NaOAc containing 80% ACN. In all cases, fractions containing more than 85% mass purity and no impurities >5% were mixed.

[0173] The purified oligonucleotides were desalted at 3500xg for approximately 30 minutes using a 15 mL 3K MWCO centrifuge spin tube. The oligonucleotides were rinsed with RNase-free water until the conductivity of the eluate reached <100 usei / cm. After desalting was complete, 2-3 mL of RNase-free water was added, followed by 10 aspirates. The retained material was transferred to a 50 mL Falcon tube, and this process was repeated until the oligonucleotides were completely transferred by measuring the concentration of the compound on the filter via nanodrops. The final oligonucleotides were then nanofiltered twice at 3500xg for 2 minutes through a 15 mL 100K MWCO centrifuge spin tube. The final desalted oligonucleotides were analyzed for concentration (nanodrops at A260), characterized by mass purity by IP-RP LCMS, and UV purity by ULC.

[0174] For the preparation of the double helices, equimolar amounts of sense and antisense strands were combined, heated at 65°C for 10 minutes, and then slowly cooled to ambient temperature over 40 minutes. The integrity of the double helices was confirmed by UPLC analysis and characterized by LCMS using IP-RP. All double helices were nanofiltered, and then endotoxin levels were measured using a Charles River Endosafe® Cartridge Device to obtain the final conjugated RNAi compounds (Table 9). For in vivo analysis, appropriate amounts of double helices were lyophilized and then reconstituted in 1×PBS for rodent studies and in CSF for non-human primate studies.

[0175] Table 7 - Reagents for synthesis of oligonucleotides [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" stands for sense chain, and "AS" stands for antisense chain. * LDP1, 8, and 9 are ligated to the 3' end of the sense strand. AS in SEQ ID NOs. 14, 16, 18, 20, 22, and 24 contain 5'-vinylphosphonate, while all other AS in this table contain 5'-phosphate.

[0179] Example 3. Characterization of SARM1 RNAi agents The 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, RNAi treatment, and analysis: SH-SY5Y cells (ATCC CRL-2266) were derived from the SK-N-SH neuroblastoma cell line (Ross, RA, et al., 1983. J Natl Cancer Inst 71, 741-747). The basal medium consisted of a 1:1 mixture of Eagle's Minimum Essential Medium (catalog no. 30-2003) and F12 medium formulated with ATCC. Complete growth medium was supplemented with 10% fetal bovine serum, 1× amino acids, 1× sodium bicarbonate, and 1× penicillin-streptomycin (Gibco), and the cells were incubated at 37°C under a humidified atmosphere of 5% CO2. On day 1, SH-SY5Y cells were seeded into 96-well fibronectin-coated tissue culture plates and allowed to adhere overnight. On day 2, the complete medium was removed and replaced with RNAi agents in serum-free medium. After incubating cells with RNAi agents for 72 hours, gene expression was analyzed. Analysis of changes in gene expression in RNAi-treated SH-SY5Y cells was performed according to the manufacturer's protocol (Thermo Fisher A35377) in Cells-to-C T Measurements were performed using kits. Pre-designed gene expression assays (supplied as 20× mixtures) were selected from Applied Bio-systems (Foster City, California, USA). The efficiency of these assays (Thermo Fisher, Hs00240906_m1 SARM1 and Thermo Fisher, Hs99999905_m1 GAPDH) was characterized using cDNA dilution series. RT-QPCR was performed using a MicroAmp Optical 384-well reaction plate with a QuantStudio 7 Flex system. Relative gene expression levels were determined using the delta-delta CT method, normalized for the housekeeping gene GAPDH. IC50 was determined using a 4-parameter logistic fit with GraphPad Prism v9.0.

[0181] Culture, RNAi treatment, and analysis of human induced pluripotent stem cell-derived neurons (hiPSCs): Doxycycline-inducible neurogenin 2 (NGN2) human induced pluripotent stem cells (hiPSCs) were developed by Eli Lilly's Bioneer. hiPSCs were induced with doxycycline for 3 days (DIV3) to initiate neuronal differentiation, seeded at 30k / well on 96-well PDL and laminin-coated plates, and grown in an incubator (37°C / 5% CO2) in neuronal differentiation media (NDM) consisting of DMEM / F12 (Life Technologies, 11330-057), Neurobasal medium (Gibco 15240062), antibiotics, supplements, growth factors, and doxycycline. Cells were supplied in halves every 7 days and treated with RNAi by sequentially diluting the RNAi agent with NDM in DIV21, aspirating 75 μL according to the dilution, and adding 75 μL of 2x RNAi concentration until the final result was 1x RNAi. After treatment, half of the medium was removed, fresh NDM was added and the cells were supplied in halves every 7 days. Cell lysates were collected in DIV35 (14 days after RNAi treatment) or DIV42 (21 days after RNAi treatment) and subjected to TaqMan Fast Advanced Cells-to-C T RT-qPCR was performed using the Kit (Thermo Fisher, A35377), and mRNA knockdown was determined using the SARM1 probe (Thermo Fisher, Hs00240907_m1) as the target gene and the ACTb probe (Thermo Fisher, Hs99999903_m1) as the housekeeping gene.

[0182] result Table 10 summarizes the knockdown rates of SARM1 mRNA and the IC50 values ​​of SARM RNAi agents in human SH-SY5Y cells. The SARM1 RNAi agents tested 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 unavailable.

[0184] Example 4. Knockdown of SARM1 mRNA in cynomolgus monkeys after single intrathecal administration of a selected RNAi agent. The efficacy of selected SARM1 RNAi agents was tested in cynomolgus monkeys (Macaca fascicularis). To evaluate the efficacy of RNAi agents in SARM1 knockdown, indwelling catheters were implanted at L4 / L5 in five groups of four cynomolgus monkeys each, with the catheter tip positioned at T12 / L1. The monkeys were infused with aCSF (cerebrospinal fluid) or 20 mg of conjugated RNAi agents #1-4 (8 mg / ml in aCSF) over 15 minutes and perfused 28 days later. Tissues collected by necropsy included spinal cord (lumbar, cervical, and 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 SARM1 mRNA knockdown rates 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 RNAi agents.

[0186] Table 11. Knockdown rate (KD) of SARM1 mRNA in cynomolgus monkeys after 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 temperature-controlled facilities with a 12-hour / 12-hour light / dark cycle. The animal protocol used in this study was approved by the Animal Use and Care Committee of Eli Lilly and Co. (Protocol number 20-025). A liver-centered model overexpressing human SARM1 was created using approximately 8-week-old C57BL / 6 male mice, in which 10% of the AAV8-TBG vector containing human (Homo sapiens) SARM1 was added to PBS. 11 Genome copies (GCs) were generated by a single intravenous injection. Fourteen days after AAV administration, the selected RNAi agent or control agent (PBS) was subcutaneously injected at a dose of 3 mg / kg (n=6 / group). Fourteen days after subcutaneous injection of the RNAi agent or control, the mice were sacrificed, and their livers were evaluated for human SARM1 mRNA levels. The in vitro (in vivo) knockdown level of human SARM1 mRNA was determined by comparison with the control group.

[0188] Table 12 summarizes the knockdown rates 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 an AAV mouse model. [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 double helix, The sense chain and the antisense chain are (a) The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to Sequence ID No. 1, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with respect to Sequence ID No. 2, (b) The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 3, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with respect to sequence number 4, (c) The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 5, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with respect to sequence number 6, (d) The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 7, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with respect to sequence number 8, (e) The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with respect to sequence number 9, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with respect to sequence number 10, (f) comprising a pair of nucleic acid sequences selected from the group consisting of a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity with SEQ ID NO: 12, If desired, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides. A SARM1 RNAi agent having a sense strand and an antisense strand, wherein, optionally, one or more internucleotide chains of the sense strand and the antisense strand are modified internucleotide chains.

2. The sense chain and the antisense chain are (a) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 2, (b) The sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4, (c) The sense strand containing the first nucleic acid sequence of Sequence ID No. 5, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 6, (d) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 8, (e) The sense strand containing the first nucleic acid sequence of Sequence ID No. 9, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 10, (f) The SARM1 RNAi agent according to claim 1, 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: 11 and an antisense strand comprising a second nucleic acid sequence of SEQ ID NO:

12.

3. The sense chain and the antisense chain are (a) The sense strand having the first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand having the second nucleic acid sequence of SEQ ID NO: 2, (b) The sense strand having the first nucleic acid sequence of Sequence ID No. 3, and the antisense strand having the second nucleic acid sequence of Sequence ID No. 4, (c) The sense strand having the first nucleic acid sequence of Sequence ID No. 5, and the antisense strand having the second nucleic acid sequence of Sequence ID No. 6, (d) The sense strand having the first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand having the second nucleic acid sequence of SEQ ID NO: 8, (e) The sense strand having the first nucleic acid sequence of Sequence ID No. 9, and the antisense strand having the second nucleic acid sequence of Sequence ID No. 10, (f) The SARM1 RNAi agent according to claim 1 or 2, having a pair of nucleic acid sequences selected from the group consisting of a sense strand having a first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand having a second nucleic acid sequence of SEQ ID NO:

12.

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

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

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

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

8. The SARM1 RNAi agent according to any one of claims 1 to 7, wherein the modified nucleotide is a 2'-fluoromodified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide.

9. The SARM1 RNAi agent according to any one of claims 1 to 8, wherein the sense strand has four 2'-fluoromodified nucleotides at positions 7, 9, 10, and 11 from the 5' end of the sense strand.

10. The SARM1 RNAi agent according to claim 9, wherein the nucleotides at positions other than the 7th, 9th, 10th, and 11th positions of the sense strand are 2'-O-methyl modified nucleotides.

11. The SARM1 RNAi agent according to any one of claims 8 to 10, wherein the antisense strand has four 2'-fluoromodified nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand.

12. The SARM1 RNAi agent according to claim 11, wherein the nucleotides at positions other than the 2nd, 6th, 14th, and 16th positions of the antisense strand are 2'-O-methyl modified nucleotides.

13. The SARM1 RNAi agent according to any one of claims 1 to 8, wherein the sense strand has three 2'-fluoromodified nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand.

14. The SARM1 RNAi agent according to claim 13, wherein the nucleotides at positions other than the 9th, 10th, and 11th positions of the sense strand are 2'-O-methyl modified nucleotides.

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

16. The SARM1 RNAi agent according to claim 15, wherein the nucleotides at positions other than the 2nd, 5th, 7th, 14th, and 16th positions of the antisense strand are 2'-O-methyl modified nucleotides.

17. The SARM1 RNAi agent according to any one of claims 1 to 10, 13, or 14, wherein the antisense strand has five 2'-fluoromodified nucleotides at positions 2, 5, 8, 14, and 16 from the 5' end of the antisense strand.

18. The SARM1 RNAi agent according to claim 17, wherein the nucleotides at positions other than the 2nd, 5th, 8th, 14th, and 16th positions of the antisense strand are 2'-O-methyl modified nucleotides.

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

20. The SARM1 RNAi agent according to claim 19, wherein the nucleotides at positions other than the 2nd, 3rd, 7th, 14th, and 16th positions of the antisense strand are 2'-O-methyl modified nucleotides.

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

22. The SARM1 RNAi agent according to claim 21, wherein the nucleotides at positions other than the 2nd and 14th positions of the antisense strand are 2'-O-methyl modified nucleotides.

23. The SARM1 RNAi agent according to any one of claims 1 to 22, wherein the sense strand and the antisense strand have one or more modified nucleotide chains.

24. The SARM1 RNAi agent according to claim 23, wherein the modified nucleotide chain is a phosphorothioate chain.

25. The SARM1 RNAi agent according to claim 24, wherein the sense strand has four or five phosphorothioate chains.

26. The SARM1 RNAi agent according to claim 24 or 25, wherein the antisense strand has four or five phosphorothioate chains.

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

28. The SARM1 RNAi agent according to claim 27, wherein the phosphate analog is a 5'-vinylphosphonate.

29. The SARM1 RNAi agent according to any one of claims 1 to 28, wherein the sense strand includes a debase portion or an inverse debase portion.

30. A SARM1 RNAi agent having a sense strand and an antisense strand, The sense chain and the antisense chain form a double chain, The sense chain and the antisense chain are (a) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 14, (b) The sense strand containing the first nucleic acid sequence of Sequence ID No. 15, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 16, (c) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 18, (d) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 20, (e) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 22, (f) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 24, (g) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 27, (h) The sense strand containing the first nucleic acid sequence of Sequence ID No. 28, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 29, (i) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 30, (j) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 31, (k) The sense strand comprising the first nucleic acid sequence of Sequence ID No. 28, and the antisense strand comprising the second nucleic acid sequence of Sequence ID No. 32, (l) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 33, (m) The sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 35, (n) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 36, (o) The sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 37, (p) The sense strand containing the first nucleic acid sequence of Sequence ID No. 34, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 38, (q) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 39, (r) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 41, (s) The sense strand comprising the first nucleic acid sequence of Sequence ID No. 40, and the antisense strand comprising the second nucleic acid sequence of Sequence ID No. 42, (t) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 43, (u) The sense strand containing the first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 44, (v) The sense strand containing the first nucleic acid sequence of Sequence ID No. 17, and the antisense strand containing the second nucleic acid sequence of Sequence ID No. 45, (w) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 46, (x) A SARM1 RNAi agent having a sense strand and an antisense strand, each comprising a pair of nucleic acid sequences selected from the group consisting of a sense strand comprising a first nucleic acid sequence of Sequence ID No. 23 and an antisense strand comprising a second nucleic acid sequence of Sequence ID No.

47.

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

47.

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

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

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

35. The SARM1 RNAi agent according to claim 32 or 33, wherein the delivery portion is conjugated to the 5' and 3' ends of the sense strand via a linker.

36. A pharmaceutical composition comprising a SARM1 RNAi agent according to any one of claims 1 to 35 and a pharmaceutically acceptable carrier.

37. A pharmaceutical composition comprising means for reducing SARM1 expression in cells and a pharmaceutically acceptable carrier.

38. A method for reducing SARM1 expression in a patient who requires it, the method comprising administering to the patient an effective amount of a SARM1 RNAi agent according to any one of claims 1 to 35, or a pharmaceutical composition according to claim 36 or 37.

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

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

41. Neurological diseases involving SARM1 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 disease, Harler syndrome, and progressive multifocal dementia. Myelopathy, Alexander disease, congenital myelin dysplasia, 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, infectious spongiform encephalopathy, Lewy body dementia, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globular cell leukoatrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strumper-Lorraine disease, non-alcoholic steatohepatitis Steatohepatitis (NASH), adrenal spinal nerve disorder, progressive supranuclear palsy (PSP), Friedreich's ataxia, spinal cord injury, acute optic neuropathy (AON), hereditary or idiopathic retinal diseases, 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, lateral retinal neuropathy, optic neuritis, optic degeneration associated with multiple sclerosis, Kjer's optic neuropathy.The method according to claim 40, selected from neuropathy, ischemic optic neuropathy, chemotherapy-induced peripheral neuropathy, neuromyelitis optica, Charcot-Marie-Tooth disease, vitamin B12 deficiency, folic acid (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 according to claim 40 or 41, wherein the neurological disease mediated by SARM1 is amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN), tauopathy, or Charcot-Marie-Tooth disease.

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

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

45. A method for reducing SARM1 expression in cells, wherein the method is (a) Introducing the SARM1 RNAi agent according to any one of claims 1 to 35 into the cell, (b) A method comprising incubating the cells for a period of time sufficient to degrade the 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 treatment.

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. 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 axonal degeneration.

49. A SARM1 RNAi agent according to any one of claims 1 to 35, or a pharmaceutical composition according to claim 36, for use in the treatment of neurological diseases mediated by SARM1.

50. Neurological diseases involving SARM1 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 disease, Harler syndrome, and progressive multifocal dementia. Myeloencephalopathy, Alexander disease, congenital myelin dysplasia, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, peristaltic 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, etc. Leutzfeldt-Jakob disease, infectious spongiform encephalopathy, Lewy body dementia, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe disease), abetalipoproteinemia, transverse myelitis, motor neuron disease, spinocerebellar degeneration, pre-eclampsia, hereditary spastic paraplegia, spastic paraplegia, familial tonic paraplegia, hereditary spastic paraplegia, Strumper-Lorraine disease, non-alcoholic steatohepatitis (NASH), and other conditions. Renal and spinal nerve disorders, progressive supranuclear palsy (PSP), Friedreich's ataxia, spinal cord injury, acute optic neuropathy (AON), hereditary or idiopathic retinal diseases, Leber's congenital monocular blindness (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, lateral retinal neuropathy, optic neuritis, and optic nerve degeneration associated with multiple sclerosis. A SARM1 RNAi agent or pharmaceutical composition for use according to claim 49, selected from, Kedger optic neuropathy, ischemic optic neuropathy, chemotherapy-induced peripheral neuropathy, neuromyelitis optica, Charcot-Marie-Tooth disease, vitamin B12 deficiency, folic acid (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 neurological disease mediated by SARM1 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 neurological disease mediated by SARM1 is amyotrophic lateral sclerosis.

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

54. Use of a SARM1 RNAi agent according to any one of claims 1 to 35 in the manufacture of a pharmaceutical product for the treatment of a neurological disease mediated by SARM1.

55. Neurological diseases involving SARM1 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 disease, Harler syndrome, and progressive multifocal dementia. Myeloencephalopathy, Alexander disease, congenital myelin dysplasia, encephalomyelitis, acute disseminated encephalomyelitis, central pontine demyelination, permeable 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, infectious spongiform encephalopathy, Lewy body dementia, 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, Strumper-Lorraine disease, non-alcoholic steatohepatitis (NAS) H), adrenal spinal nerve disorders, progressive supranuclear palsy (PSP), Friedreich's ataxia, spinal cord injury, acute optic neuropathy (AON), hereditary or idiopathic retinal diseases, Leber's congenital monocular blindness (LCA), Leber's hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute closed-angle glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, lateral retinal neuropathy, optic neuritis, and multiple sclerosis. The use according to claim 54, selected from optic nerve degeneration, Kager optic neuropathy, ischemic optic neuropathy, chemotherapy-induced peripheral neuropathy, neuromyelitis optica, Charcot-Marie-Tooth disease, vitamin B12 deficiency, folic acid (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. The use according to claim 54 or 55, wherein the neurological disease mediated by SARM1 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 neurological disease involving SARM1 is amyotrophic lateral sclerosis.

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