ATXN2 RNA interference agent

Abstract

An ATXN2 RNAi agent and a composition comprising the ATXN2 RNAi agent are provided herein. Also provided herein are methods of using the ATXN2 RNAi agent, or a composition comprising the ATXN2 RNAi agent, to reduce ATXN2 expression and / or to treat an ATXN2-related neurological disorder in a subject.

Description

Technical Field

[0001] (Sequence Listing) This application has been filed together with a sequence listing in ST.26 XML format. The sequence listing is provided as a file entitled "30344v2" created on June 7, 2023, and is 412 kilobytes in size. The sequence listing information in ST.26 XML format is hereby incorporated by reference in its entirety into this specification.

Background Art

[0002] Ataxin-2 is encoded by the gene ATXN2 (also known as ATX2, SCA2, TNRC13). The ATXN2 gene contains a CAG trinucleotide repeat, which results in a polyglutamine (polyQ) stretch in the N-terminal region of the ataxin-2 protein. More than 90% of normal individuals have an ATXN2 allele with 22 polyQ repeats. CAG expansions of more than 22 repeats in ATXN2 are associated with certain neurodegenerative diseases.

[0003] Spinocerebellar ataxia 2 (SCA2) is caused by CAG expansions of 31 repeats or more in ATXN-2. The most common SCA2-related ATXN2 alleles have 37 - 39 CAG repeats, and longer CAG repeat expansions are associated with earlier onset of SCA2. SCA2 is an autosomal dominant neurodegenerative disease characterized by progressive degeneration of neurons in the cerebellum, brainstem, and / or spinal cord. Patients with SCA2 exhibit progressive gait ataxia and often show inadequate coordination of the hands, speech, and eye movements, likely due to cerebellar degeneration with various involvements of the brainstem and spinal cord. Moderate CAG expansions in the ATXN2 gene (more than 23 repeats but below the threshold for SCA2) are also associated with amyotrophic lateral sclerosis (ALS).

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

[0005] For example, there is still a need for therapeutic agents that can inhibit or regulate the expression of ATXN2 in order to treat ATXN2-related neurodegenerative diseases such as SCA2 or ALS by utilizing RNAi. SUMMARY OF THE INVENTION

[0006] Provided herein are ATXN2 RNAi agents and compositions comprising an ATXN2 RNAi agent. Also provided herein are methods of using an ATXN2 RNAi agent or a composition comprising an ATXN2 RNAi agent to reduce ATXN2 expression and / or to treat an ATXN2-related neurodegenerative disease in a subject.

[0007] In one aspect, an ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 1 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 2; (b) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 3 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 4; (c) a sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 5 and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 6; (d) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 7, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8, (e) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10, (f) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12, (g) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 14, (h) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16, (i) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 18, (j) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 20, (k) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 22, (l) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 24, (m) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 26, (n) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 28, (o) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 30, Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. An ATXN2 RNAi agent comprising the sense strand and the antisense strand is provided herein.

[0008] In some embodiments, the sense strand and the antisense strand of the ATXN2 RNAi agent described herein are (a) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2, (b) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4, (c) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6, (d) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8, (e) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10, (f) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 14, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 16, (i) 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: 18, (j) 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: 20, (k) 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: 22, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 24, (m) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 26, (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 28, (o) 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: 29 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 30, Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[0009] In some embodiments, the ATXN2 RNAi agents described herein may include a sense strand that contains a sequence having one, two, or three differences from SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29. In some embodiments, the ATXN2 RNAi agents described herein may include an antisense strand that contains a sequence having one, two, or three differences from SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30.

[0010] The ATXN2 RNAi agents described herein may include modifications. The modifications can be made to one or more nucleotides of the sense strand and / or the antisense strand, or to the internucleotide linkages. In some embodiments, one or more nucleotides of the sense strand are modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, one or more nucleotides of the antisense strand are modified nucleotides. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotides are 2'-fluoro modified nucleotides, 2'-O-methyl modified nucleotides, or 2'-O-alkyl modified nucleotides. In some embodiments, the sense strand has four 2'-fluoro modified nucleotides at positions 7, 9, 10, and 11 from the 5'-end of the sense strand. In some embodiments, the nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro modified nucleotides at positions 2, 6, 14, and 16 from the 5'-end of the antisense strand. In some embodiments, the nucleotides at positions other than 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides. 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 sense strand includes a abasic moiety or an inverted abasic moiety, for example, at position 9, 10, or 11. In some embodiments, the sense strand and the antisense strand have one or more modified internucleotide linkages, such as phosphorothioate linkages. In some embodiments, the sense strand has four or five phosphorothioate linkages. In some embodiments, the antisense strand has four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has four phosphorothioate linkages.

[0011] In some embodiments, an ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double strand, and the sense strand and the antisense strand are (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 31 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 32; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 34; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 36; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 38; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 40; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 42; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 44; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 46; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 48; (j) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 50; (k) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 52; (l) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 54; (m) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 56; (n) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 58, and (o) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 60, and an ATXN2 RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of a sense strand and an antisense strand are provided herein.

[0012] In some embodiments, the ATXN2 RNAi agents described herein may comprise a sense strand having a sequence that differs from SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59 by one, two, or three differences. In some embodiments, the ATXN2 RNAi agents described herein may comprise an antisense strand having a sequence that differs from SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60 by one, two, or three differences.

[0013] In some embodiments, an ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double strand, and the sense strand and the antisense strand are (a) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 31 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 32, and (b) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 34, and (c) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 36, and (d) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 38, and (e) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 40, (f) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 42, (g) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 44, (h) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 46, (i) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 48, (j) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 50, (k) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 52, (l) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 54, (m) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 56, (n) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 58, (o) An ATXN2 RNAi agent comprising a sense strand and an antisense strand having a pair of nucleic acid sequences selected from the group consisting of a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 60 is provided herein.

[0014] In some embodiments, the sense strand of the ATXN2 RNAi agent has a delivery moiety conjugated to the 3' end of the sense strand. In some embodiments, the sense strand of the ATXN2 RNAi agent has a delivery moiety conjugated to a nucleotide of the sense strand. In some embodiments, the delivery moiety is α-tocopherol, cholesterol, or palmitic acid. In some embodiments, the delivery moiety is conjugated to the 3' end of the sense strand via a linker, such as the linker of Table 5.

[0015] In a further aspect, an ATXN2 RNAi agent of formula (I): R-L-D, wherein R is a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the sense strand and the antisense strand form a duplex, D is a delivery means for delivering the dsRNA to a cell, L is a linking means for linking the dsRNA to the delivery means or is optionally absent, and the sense strand and the antisense strand are (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; (i) A sense strand 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: 18, and (j) 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: 20, and (k) 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: 22, and (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 24, and (m) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 26, and (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 28, and (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 30, and comprising a pair of nucleic acid sequences selected from the group consisting of Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, of formula (I): R-L-D, an ATXN2 RNAi agent is provided herein.

[0016] In some embodiments, an ATXN2 RNAi agent of formula (I): R-L-D, wherein R is a dsRNA comprising a sense strand and an antisense strand, the sense strand and the antisense strand form a duplex, D is a delivery moiety, L is a linker or is 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, and (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, and (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, and (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8, (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10, (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12, (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14, (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16, (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18, (j) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20, (k) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22, (l) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24, (m) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 25 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 26, (n) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 27 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: (o) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30, and comprising a pair of nucleic acid sequences selected from the group consisting of, Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, of formula (I): R-L-D, an ATXN2 RNAi agent is provided herein.

[0017] In some embodiments, the sense strand and the antisense strand of the RNAi agent of formula (I) are (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 31 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 32; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 34; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 36; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 38; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 40; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 42; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 44; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 46; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 48; (j) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 50; (k) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 52; (l) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 54; (m) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 56; (n) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 58; It comprises a pair of nucleic acid sequences selected from the group consisting of a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 60.

[0018] In another aspect, there is provided herein a pharmaceutical composition comprising an ATXN2 RNAi agent described herein and a pharmaceutically acceptable carrier. Also provided herein is a pharmaceutical composition comprising a means for reducing ATXN2 expression in a cell and a pharmaceutically acceptable carrier.

[0019] In another aspect, there is provided herein a method of reducing ATXN2 expression in a patient in need thereof, such method comprising administering to the patient an effective amount of an ATXN2 RNAi agent or pharmaceutical composition described herein.

[0020] In another aspect, there is provided herein a method of treating an ATXN2-related neurological disorder in a patient in need thereof, such method comprising administering to the patient an effective amount of an ATXN2 RNAi agent or pharmaceutical composition described herein.

[0021] Also provided herein is a method of reducing ATXN2 expression in a cell (e.g., a nerve cell), such method may comprise introducing an ATXN2 RNAi agent described herein into the cell and incubating the cell for a time sufficient for the degradation of ATXN2 mRNA, thereby reducing ATXN2 expression in the cell.

[0022] In another aspect, provided herein is an ATXN2 RNAi agent, or a pharmaceutical composition comprising an ATXN2 RNAi agent, for use in reducing ATXN2 expression. Also provided herein is an ATXN2 RNAi agent, or a pharmaceutical composition comprising an ATXN2 RNAi agent, for use in therapy. Also provided is an ATXN2 RNAi agent, or a pharmaceutical composition comprising an ATXN2 RNAi agent, for use in the treatment of an ATXN2-related neurological disorder. Also provided herein is the use of an ATXN2 RNAi agent in the manufacture of a medicament for the treatment of an ATXN2-related neurological disorder.

DETAILED DESCRIPTION OF THE INVENTION

[0023] Provided herein are an ATXN2 RNAi agent and a composition comprising an ATXN2 RNAi agent. Also provided herein is a method of using an ATXN2 RNAi agent, or a composition comprising an ATXN2 RNAi agent, to reduce ATXN2 expression and / or to treat an ATXN2-related neurological disorder in a subject.

[0024] In some embodiments, an ATXN2 RNAi agent comprising a sense strand and an antisense strand is provided herein, and the sense strand and the antisense strand form a duplex. The antisense strand is complementary to a region of the ATXN2 mRNA. In further embodiments, the sense strand and the antisense strand are each 15-30 nucleotides in length, for example, 20-25 nucleotides in length. In some embodiments, an ATXN2 RNAi agent comprising a 21-nucleotide sense strand and a 23-nucleotide antisense strand is provided herein. In some embodiments, the sense strand and the antisense strand of the ATXN2 RNAi agent may have an overhang (i.e., a 5' overhang or a 3' overhang) at either the 5' end or the 3' end. For example, the sense strand and the antisense strand may have a 5' overhang or a 3' overhang of 1-5 nucleotides or 1-3 nucleotides. In some embodiments, the antisense strand comprises a 3' overhang of two nucleotides. In some embodiments, the sense strand sequence and the antisense strand sequence of the ATXN2 RNAi agent are provided in Table 1.

[0025] An ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, and the sense strand and the antisense strand are (a) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 2; (b) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: ; (c) a sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 5, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 6; (d) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 7, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 8, (e) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 9, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 10, (f) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 12, (g) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 14, (h) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 16, (i) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 18, (j) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 20, (k) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 22, (l) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 24, (m) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 26, (n) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 28, (o) A sense strand comprising a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 30, and a pair of nucleic acid sequences selected from the group consisting of Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, and an ATXN2 RNAi agent comprising the sense strand and the antisense strand is provided herein.

[0026] An ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double strand, and the sense strand and the antisense strand are (a) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 1, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 2, (b) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 3, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 4, (c) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 5, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 6, (d) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 7, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8, (e) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10, (f) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12, (g) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 13, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 14, (h) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16, (i) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 18, (j) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 19, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 20, (k) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 21, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 22, (l) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 23, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 24, (m) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 25, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 26, (n) A sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 27, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 28, (o) 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 to SEQ ID NO: 29, and an antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 30, Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. An ATXN2 RNAi agent comprising the sense strand and the antisense strand is provided herein.

[0027] [Table 1]

[0028] In some embodiments, the sense strand and the antisense strand of the ATXN2 RNAi agent described herein are (a) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2, (b) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4, (c) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6, (d) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7, and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8, (e) A sense strand 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 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, (g) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 14, (h) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 16, (i) 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: 18, (j) 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: 20, (k) 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: 22, (l) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 24, (m) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 25 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 26, (n) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 27 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 28, (o) A sense strand containing the first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand containing the second nucleic acid sequence of SEQ ID NO: 30, and comprising a pair of nucleic acid sequences selected from the group consisting of Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[0029] The ATXN2 RNAi agent described in this specification may include a modifying agent. The modification can be performed on one or more nucleotides of the sense strand and / or the antisense strand, or on the internucleotide linkage that is the bond between two nucleotides in the sense strand or the antisense strand. For example, some 2'-modifications of ribose or deoxyribose can increase RNA or DNA stability and half-life. Such 2'-modifications can be 2'-fluoro, 2'-O-methyl (i.e., 2'-methoxy), 2'-O-alkyl, or 2'-O-methoxyethyl (2'-O-MOE).

[0030] In some embodiments, one or more nucleotides of the sense strand and / or the antisense strand are independently modified nucleotides, which means that the sense strand and the antisense strand can have different modified nucleotides. In some embodiments, one or more nucleotides of the sense strand are modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, one or more nucleotides of the antisense strand are modified nucleotides. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide. In some embodiments, each nucleotide of the sense strand and the antisense strand is independently a modified nucleotide, for example, a 2'-fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide.

[0031] In some embodiments, the sense strand has four 2'-fluoro modified nucleotides at positions 7, 9, 10, and 11, for example, from the 5' end of the sense strand. In some embodiments, the nucleotides at positions other than 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro modified nucleotides at positions 2, 6, 14, and 16, for example, from the 5' end of the antisense strand. In some embodiments, the nucleotides at positions other than 2, 6, 14, and 16 of the antisense strand are 2'-O-methyl modified nucleotides.

[0032] In some embodiments, the modified nucleotide is a 2'-O-alkyl modified nucleotide, which can function as a delivery moiety. In some embodiments, the 2'-O-alkyl modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine. In some embodiments, 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine is the modified nucleotide in the sense strand.

[0033] 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).

[0034] In some embodiments, the sense strand contains a abasic moiety or an inverted abasic moiety, such as the moiety shown in Table 3, at positions 9, 10, or 11, for example.

[0035] In some embodiments, the sense strand and the antisense strand have one or more modified nucleotide linkages. In some embodiments, the modified nucleotide linkage is a phosphorothioate linkage. In some embodiments, the sense strand has four or five phosphorothioate linkages. In some embodiments, the antisense strand has four or five phosphorothioate linkages. In some embodiments, the sense strand and the antisense strand each have four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has four phosphorothioate linkages.

[0036] In a further aspect, an ATXN2 RNAi agent comprising 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: 31 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 32; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 34; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 36; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 38; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 40; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 42; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 44; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 46; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 48; (j) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 50, (k) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 52, (l) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 54, (m) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 56, (n) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 58, (o) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 60, provided herein is an ATXN2 RNAi agent comprising a pair of nucleic acid sequences selected from the group consisting of a sense strand and an antisense strand.

[0037] In some embodiments, an ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double strand, and the sense strand and the antisense strand are (a) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 31 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 32, (b) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 34, (c) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 36, (d) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 38, (e) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 40, (f) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 42, (g) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 44, (h) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 46, (i) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 48, (j) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 50, (k) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 52, (l) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 54, (m) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 56, (n) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 58, (o) An ATXN2 RNAi agent comprising a sense strand and an antisense strand having a pair of nucleic acid sequences selected from the group consisting of a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 60, is provided herein.

[0038] [Table 2-1]

[0039] [Table 2-2] Abbreviations - "m" represents 2'-OMe, "f" represents 2'-fluoro, " * " represents a phosphorothioate linkage, "P" represents a 5'-phosphate, "S" means a sense strand, and "AS" means an antisense strand.

[0040] [Table 3]

[0041] In some embodiments, the sense strand of the ATXN2 RNAi agent has a delivery moiety conjugated to the 3'-end of the sense strand. In some embodiments, the sense strand of the ATXN2 RNAi agent has a delivery moiety conjugated to the nucleotides of the sense strand. The delivery moiety can facilitate the entry of the RNAi agent into cells. In some embodiments, the delivery moiety is α-tocopherol, cholesterol, or palmitic acid (see Table 4). In some aspects, the delivery moiety is a known delivery moiety for delivering the RNAi agent into cells. The placement of the delivery moiety on the RNAi agent needs to overcome a possible inefficient loading of AGO2 (Argonaute-2), or other obstacles to the activity of the RNA-induced silencing complex (RISC) complex.

[0042] In some embodiments, the delivery moiety is conjugated to the 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 of Table 5. Other suitable linkers are known in the art. Exemplary linker-delivery moiety pairs are shown in Table 6. In some embodiments, the ATXN2 RNAi agent has the linker-delivery moiety pair of Table 6.

[0043] In some embodiments, the delivery moiety is conjugated to the nucleotides of the sense strand. In that case, the delivery moiety is a modified nucleotide located on the sense strand. In some embodiments, the modified nucleotide is 2'-O-hexadecyluridine, 2'-O-hexadecylcytidine, 2'-O-hexadecylguanine, or 2'-O-hexadecyladenosine (Table 4).

[0044] [Table 4-1]

[0045]

Table 4-2

[0046]

Table 5

[0047]

Table 6-1

[0048]

Table 6-2

[0049]

Table 6-3

[0050] In a further aspect, there is provided an ATXN2 RNAi agent of formula (I): R-L-D, wherein R is a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the sense strand and the antisense strand form a duplex, D is a delivery means for delivering the dsRNA into a cell, L is a linking means for linking the dsRNA to the delivery means or is optionally absent, and the sense strand and the antisense strand are (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2, and (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4, and (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6, and (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8, and (e) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10, (f) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12, (g) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14, (h) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16, (i) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18, (j) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20, (k) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22, (l) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24, (m) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 25 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 26, (n) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 27 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 28, (o) A pair of nucleic acid sequences selected from the group consisting of a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30, Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, a formula (I): R-L-D ATXN2 RNAi agent is provided herein.

[0051] In some embodiments, an ATXN2 RNAi agent of formula (I): R-L-D, wherein R is a dsRNA comprising a sense strand and an antisense strand, the sense strand and the antisense strand form a double strand, D is a delivery moiety, L is a linker or is optionally absent, and the sense strand and the antisense strand are (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 3 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 4; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18; (j) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20; (k) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22; (l) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24; (m) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 25 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 26; (n) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 27 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 28; (o) a pair of nucleic acid sequences selected from the group consisting of a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 29 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30; Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages. The ATXN2 RNAi agent of formula (I): R-L-D is provided herein.

[0052] In some embodiments, the sense strand and the antisense strand of the RNAi agent of formula (I) are (a) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 31 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 32; (b) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 34; (c) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 36; (d) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 38; (e) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 40; (f) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 42; (g) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 44; (h) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 46; (i) a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 48; (j) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 50, (k) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 52, (l) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 54, (m) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 56, (n) A sense strand comprising the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 58, (o) A pair of nucleic acid sequences selected from the group consisting of a sense strand comprising the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 60.

[0053] In some embodiments, the sense and antisense strands of the RNAi agent of formula (I) are (a) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 31 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 32, (b) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 33 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 34, (c) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 35 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 36, (d) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 37 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 38, (e) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 39 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 40, (f) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 41 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 42, (g) A sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 43 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 44, (h) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 45 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 46, (i) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 47 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 48, (j) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 49 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 50, (k) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 51 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 52, (l) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 53 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 54, (m) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 55 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 56, (n) a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 57 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 58, (o) It has a pair of nucleic acid sequences selected from the group consisting of a sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 59 and an antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 60.

[0054] In some embodiments, the delivery means or delivery moiety is conjugated to the 3' end of the sense strand. In some embodiments, the delivery means or delivery moiety is conjugated to the nucleotides of the sense strand. In some embodiments, the delivery means is palmitic acid, cholesterol, or α-tocopherol. In some embodiments, the linking means or linker is selected from the group consisting of linker 1, linker 2, linker 3, and linker 4 in Table 5.

[0055] The sense and antisense strands of the ATXN2 RNAi agent can be synthesized using any nucleic acid polymerization method known in the art, for example, solid-phase synthesis (e.g., Current Protocols in Nucleic Acid Chemistry, Beaucage, S.L. et al. (Eds.), John Wiley & Sons, Inc., New York, NY, USA) by using phosphoramidite chemistry methodology, H-phosphonate method, phosphotriester chemistry, or enzymatic synthesis. Automated commercially available synthesizers, such as the MerMade™ 12 from LGC Biosearch Technologies, or other synthesizers from BioAutomation or Applied Biosystems can be used. Phosphorothioate linkages can be introduced using sulfurization reagents such as phenylacetyl disulfide or DDTT (((dimethylaminomethylene)amino)-3H-1,2,4-dithiazoline-3-thione). It is well known to use similar techniques and commercially available modified amidites and controlled-pore glass (CPG) products to synthesize modified oligonucleotides and conjugated oligonucleotides.

[0056] Using a purification method, unwanted impurities can be removed from the final oligonucleotide product. Commonly used purification techniques for single-stranded oligonucleotides include reverse-phase ion pair high performance liquid chromatography (RP-IP-HPLC), capillary gel electrophoresis (CGE), anion exchange HPLC (AX-HPLC), and size exclusion chromatography (SEC). After purification, the oligonucleotide can be analyzed by mass spectrometry and quantified by spectrophotometry at a wavelength of 260 nm. Next, the sense strand and the antisense strand can be annealed to form a double strand.

[0057] In another aspect, provided herein is a pharmaceutical composition comprising an ATXN2 RNAi agent described herein and a pharmaceutically acceptable carrier. Also provided herein is a pharmaceutical composition comprising a means for reducing ATXN2 expression in a cell and a pharmaceutically acceptable carrier. Such pharmaceutical compositions may also contain one or more pharmaceutically acceptable excipients, diluents, or carriers. The pharmaceutical composition can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 23rd edition (2020), A. Loyd et al., Academic Press).

[0058] In a further aspect, provided herein is a method of reducing ATXN2 expression in a cell (e.g., a nerve cell), such method may include introducing an ATXN2 RNAi agent described herein into the cell and incubating the cell for a time sufficient for degradation of ATXN2 mRNA, thereby reducing ATXN2 expression in the cell. The ATXN2 RNAi agent can be introduced into a cell (e.g., a nerve cell) using methods known in the art, such as transfection, electroporation, microinjection, or uptake by the cell via natural transport mechanisms.

[0059] In another aspect, provided herein is a method of reducing ATXN2 expression in a patient in need thereof, such method includes administering to the patient an effective amount of an ATXN2 RNAi agent or pharmaceutical composition described herein.

[0060] In another aspect, provided herein is a method of treating an ATXN2-related neurological disorder in a patient in need thereof, such method comprising administering to the patient an effective amount of an ATXN2 RNAi agent or pharmaceutical composition described herein. Abnormal CAG trinucleotide expansions in the ATXN2 gene are associated with spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). In another aspect, ataxin-2 is known to be required for toxicity mediated by abnormal aggregation of TAR DNA-binding protein (TDP-43), which is thought to be a driver in 95% of cases of sporadic and familial amyotrophic lateral sclerosis. Exemplary ATXN2-related neurological disorders include spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Parkinson's disease, Alzheimer's disease, frontotemporal lobar degeneration (FTLD), progressive muscular atrophy (PMA), multisystem proteinopathy, Perry's disease, and TDP-43 proteinopathy, e.g., neurological disorders associated with abnormal TDP-43 aggregation, but are not limited thereto (de Boer et al, 2021, J Neurol. Neurosurg. Psychiatry. 2020 Nov 11;92(1):86-95).

[0061] The ATXN2 RNAi agent can be administered to the patient via intrathecal, intraventricular, or intracisternal injection. In some embodiments, the ATXN2 RNAi agent is administered intrathecally to the patient, e.g., via a catheter or by direct injection into the intrathecal space.

[0062] The RNAi dosing regimen can be adjusted to provide an optimal desired response (e.g., a therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigency of the treatment situation.

[0063] The dosage value may vary depending on the type and severity of the condition to be alleviated. It is further understood that for any given subject, the specific dosing 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.

[0064] In another aspect, provided herein is an ATXN2 RNAi agent, or a pharmaceutical composition comprising an ATXN2 RNAi agent, for use in reducing ATXN2 expression. Also provided herein is an ATXN2 RNAi agent, or a pharmaceutical composition comprising an ATXN2 RNAi agent, for use in therapy. Also provided herein is an ATXN2 RNAi agent, or a pharmaceutical composition comprising an ATXN2 RNAi agent, for use in the treatment of an ATXN2-related neurological disorder. Also provided herein is the use of an ATXN2 RNAi agent in the manufacture of a medicament for the treatment of an ATXN2-related neurological disorder.

[0065] As used herein, the terms "a", "an", "the" and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural forms unless otherwise specified herein or clearly contradicted by the context.

[0066] As used herein, the term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, "C1-C 20 alkyl" means a radical having from 1 to 20 carbon atoms in a straight-chain or branched-chain arrangement.

[0067] As used herein, "antisense strand" means a single-stranded oligonucleotide that is complementary to a region of a target sequence. Similarly, as used herein, "sense strand" means a single-stranded oligonucleotide that is complementary to a region of the antisense strand.

[0068] As used herein, "complementary" refers to the structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand, such as a hairpin) that allows 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 can base pair by forming hydrogen bonds with each other. Complementary nucleotides can form base pairs in a Watson-Crick-like manner or in any other manner that allows for the formation of a stable double-strand. Similarly, two nucleic acids can have regions of multiple nucleotides that are complementary to each other and form regions of complementarity, as described herein.

[0069] As used herein, "delivery moiety" refers to a chemical moiety that facilitates entry of an oligonucleotide or RNAi agent into a cell. The delivery moiety can be a lipid, cholesterol, vitamin E, carbohydrate, amino sugar, polypeptide, or protein. In some embodiments, the delivery moiety is α-tocopherol, cholesterol, or palmitic acid.

[0070] As used herein, "double-strand" with respect to a nucleic acid or oligonucleotide refers to a structure formed through complementary base pairing of two anti-parallel sequences of nucleotides, whether formed by two separate nucleic acid strands or by a single folded strand (e.g., via a hairpin).

[0071] "Effective amount" refers to the amount (duration and means of administration) necessary to achieve a desired therapeutic result. The effective amount of an RNAi agent can vary depending on factors such as the medical condition of the individual, age, gender, and weight of the individual, and the ability of the RNAi agent to induce a desired response in the individual. The effective amount is also an amount where the therapeutically beneficial effect exceeds any toxic or detrimental effects of the RNAi agent.

[0072] The term "knockdown" or "expression knockdown" refers to the reduction of gene mRNA or protein expression after treatment with a reagent, such as an RNAi agent.

[0073] As used herein, "modified internucleotide linkage" means an internucleotide linkage having one or more chemical modifications when compared to a reference internucleotide linkage having a phosphodiester bond. A modified internucleotide linkage can be a non-naturally occurring linkage. In some embodiments, the modified nucleotide linkage is a phosphorothioate linkage.

[0074] As used herein, "modified nucleotide" refers to a nucleotide having one or more chemical modifications when compared to the corresponding reference nucleotide selected from adenosine ribonucleotide, guanosine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenosine deoxyribonucleotide, guanosine deoxyribonucleotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide. A modified nucleotide can have one or more chemical modifications, for example, to its sugar, nucleobase, and / or phosphate group. Additionally, or alternatively, a modified nucleotide can have one or more chemical moieties conjugated to the corresponding reference nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a 2'-O-alkyl-modified nucleotide. In some embodiments, the modified nucleotide has a phosphate analog, for example, 5'-vinylphosphonate. In some embodiments, the modified nucleotide has an abasic moiety or an inverted abasic moiety, for example, the moieties shown in Table 3, at the 9th, 10th, or 11th position.

[0075] As used herein, "nucleotide" means an organic compound having a nucleoside (e.g., a nucleobase such as adenine, cytosine, guanine, thymine, or uracil, and a pentose sugar such as ribose or 2'-deoxyribose) linked to a phosphate group. "Nucleotides" can function as monomeric units of nucleic acid polymers such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0076] 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.

[0077] As used herein, "overhang" means one or more unpaired nucleotides (singular or plural) that project from the duplex structure of a double-stranded oligonucleotide. An overhang can include one or more unpaired nucleotides that extend from the duplex region at the 5' or 3' end of the double-stranded oligonucleotide. An overhang can be a 3' overhang or a 5' overhang on the antisense or sense strand of the double-stranded oligonucleotide.

[0078] As used herein, the term "patient" refers to a human patient.

[0079] As used herein, "phosphate analog" means 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 the oligonucleotide in place of the 5'-phosphate, which is often susceptible to enzymatic removal. The 5' phosphate analog can include a phosphatase-resistant linkage. Examples of phosphate analogs include 5'-methylene phosphonate (5'-MP) and 5'-(E)-vinyl phosphonate (5'-VP). In some embodiments, the phosphate analog is 5'-VP.

[0080] The term "percent sequence identity" or "percentage of sequence identity" with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical to the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence after the sequences have been optimally aligned and gaps or overhangs have been introduced, if necessary, to achieve the maximum percentage of sequence identity. Alignments for the purpose of determining nucleic acid sequence identity percentage can be achieved by a variety of methods within the skill of the art, for example, using publicly available computer software programs such as those described in Current Protocols in Molecular Biology (Ausubel et al., eds., 1987, Supp. 30, section 7.7.18, Table 7.7.1), BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), Clustal W2.0, or Clustal X2.0 computer software programs. One of ordinary skill in the art can determine appropriate parameters for measuring the alignment, including any algorithms necessary to achieve the maximum alignment over the full length of the sequences being compared. The percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, wherein the fragment of the nucleic acid sequence in the comparison window may include additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (without additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleotides, nucleosides, or nucleobases occur in both sequences, determining the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percentage of sequence identity. The output is the percentage of identity of the subject sequence to the query sequence.

[0081] As used herein, "RNAi", "RNAi agent", "iRNA", "iRNA agent", and "RNA interference agent" mean an agent that mediates sequence-specific degradation of a target mRNA by RNA interference, e.g., via the RNA-induced silencing complex (RISC) pathway. In some embodiments, the RNAi agent has a sense strand and an antisense strand, and the sense strand and the antisense strand form a duplex (e.g., double-stranded RNA). In some embodiments, the sense strand has a delivery moiety conjugated to the 5' end or 3' end of the sense strand, or to a nucleotide of the sense strand.

[0082] As used herein, "strand" refers to a single continuous sequence of nucleotides joined together by internucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). A strand can have two free ends (e.g., a 5' end and a 3' end).

[0083] As used herein, "ATXN2" (also known as ATX2, SCA2, TNRC13) refers to the human ATXN2 mRNA transcript. The nucleotide sequence of human ATXN2 mRNA isoform 1 can be found in NM_002973.4: 1 AGAGCTCGCC TCCCTCCGCC TCAGACTGTT TTGGTAGCAA CGGCAACGGC GGCGGCGCGT 61 TTCGGCCCGG CTCCCGGCGG CTCCTTGGTC TCGGCGGGCC TCCCCGCCCC TTCGTCGTCC 121 TCCTTCTCCC CCTCGCCAGC CCGGGCGCCC CTCCGGCCGC GCCAACCCGC GCCTCCCCGC 181 TCGGCGCCCG CGCGTCCCCG CCGCGTTCCG GCGTCTCCTT GGCGCGCCCG GCTCCCGGCT 241 GTCCCCGCCC GGCGTGCGAG CCGGTGTATG GGCCCCTCAC CATGTCGCTG AAGCCCCAGC 301 AGCAGCAGCA GCAGCAGCAG CAGCAGCAGC AGCAGCAACA GCAGCAGCAG CAGCAGCAGC 361 AGCAGCCGCC GCCCGCGGCT GCCAATGTCC GCAAGCCCGG CGGCAGCGGC CTTCTAGCGT 421 CGCCCGCCGC CGCGCCTTCG CCGTCCTCGT CCTCGGTCTC CTCGTCCTCG GCCACGGCTC 481 CCTCCTCGGT GGTCGCGGCG ACCTCCGGCG GCGGGAGGCC CGGCCTGGGC AGAGGTCGAA 541 ACAGTAACAA AGGACTGCCT CAGTCTACGA TTTCTTTTGA TGGAATCTAT GCAAATATGA 601 GGATGGTTCA TATACTTACA TCAGTTGTTG GCTCCAAATG TGAAGTACAA GTGAAAAATG 661 GAGGTATATA TGAAGGAGTT TTTAAAACTT ACAGTCCGAA GTGTGATTTG GTACTTGATG 721 CCGCACATGA GAAAAGTACA GAATCCAGTT CGGGGCCGAA ACGTGAAGAA ATAATGGAGA 781 GTATTTTGTT CAAATGTTCA GACTTTGTTG TGGTACAGTT TAAAGATATG GACTCCAGTT 841 ATGCAAAAAG AGATGCTTTT ACTGACTCTG CTATCAGTGC TAAAGTGAAT GGCGAACACA 901 AAGAGAAGGA CCTGGAGCCC TGGGATGCAG GTGAACTCAC AGCCAATGAG GAACTTGAGG 961 CTTTGGAAAA TGACGTATCT AATGGATGGG ATCCCAATGA TATGTTTCGA TATAATGAAG 1021 AAAATTATGG TGTAGTGTCT ACGTATGATA GCAGTTTATC TTCGTATACA GTGCCCTTAG 1081 AAAGAGATAA CTCAGAAGAA TTTTTAAAAC GGGAAGCAAG GGCAAACCAG TTAGCAGAAG 1141 AAATTGAGTC AAGTGCCCAG TACAAAGCTC GAGTGGCCCT GGAAAATGAT GATAGGAGTG 1201 AGGAAGAAAA ATACACAGCA GTTCAGAGAA ATTCCAGTGA ACGTGAGGGG CACAGCATAA 1261 ACACTAGGGA AAATAAATAT ATTCCTCCTG GACAAAGAAA TAGAGAAGTC ATATCCTGGG 1321 GAAGTGGGAG ACAGAATTCA CCGCGTATGG GCCAGCCTGG ATCGGGCTCC ATGCCATCAA 1381 GATCCACTTC TCACACTTCA GATTTCAACC CGAATTCTGG TTCAGACCAA AGAGTAGTTA 1441 ATGGAGGTGT TCCCTGGCCA TCGCCTTGCC CATCTCCTTC CTCTCGCCCA CCTTCTCGCT 1501 ACCAGTCAGG TCCCAACTCT CTTCCACCTC GGGCAGCCAC CCCTACACGG CCGCCCTCCA 1561 GGCCCCCCTC GCGGCCATCC AGACCCCCGT CTCACCCCTC TGCTCATGGT TCTCCAGCTC 1621 CTGTCTCTAC TATGCCTAAA CGCATGTCTT CAGAAGGGCC TCCAAGGATG TCCCCAAAGG 1681 CCCAGCGACA TCCTCGAAAT CACAGAGTTT CTGCTGGGAG GGGTTCCATA TCCAGTGGCC 1741 TAGAATTTGT ATCCCACAAC CCACCCAGTG AAGCAGCTAC TCCTCCAGTA GCAAGGACCA 1801 GTCCCTCGGG GGGAACGTGG TCATCAGTGG TCAGTGGGGT TCCAAGATTA TCCCCTAAAA 1861 CTCATAGACC CAGGTCTCCC AGACAGAACA GTATTGGAAA TACCCCCAGT GGGCCAGTTC 1921 TTGCTTCTCC CCAAGCTGGT ATTATTCCAA CTGAAGCTGT TGCCATGCCT ATTCCAGCTG 1981 CATCTCCTAC GCCTGCTAGT CCTGCATCGA ACAGAGCTGT TACCCCTTCT AGTGAGGCTA 2041 AAGATTCCAG GCTTCAAGAT CAGAGGCAGA ACTCTCCTGC AGGGAATAAA GAAAATATTA 2101 AACCCAATGA AACATCACCT AGCTTCTCAA AAGCTGAAAA CAAAGGTATA TCACCAGTTG 2161 TTTCTGAACA TAGAAAACAG ATTGATGATT TAAAGAAATT TAAGAATGAT TTTAGGTTAC 2221 AGCCAAGTTC TACTTCTGAA TCTATGGATC AACTACTAAA CAAAAATAGA GAGGGAGAAA 2281 AATCAAGAGA TTTGATCAAA GACAAAATTG AACCAAGTGC TAAGGATTCT TTCATTGAAA 2341 ATAGCAGCAG CAACTGTACC AGTGGCAGCA GCAAGCCGAA TAGCCCCAGC ATTTCCCCTT 2401 CAATACTTAG TAACACGGAG CACAAGAGGG GACCTGAGGT CACTTCCCAA GGGGTTCAGA 2461 CTTCCAGCCC AGCATGTAAA CAAGAGAAAG ACGATAAGGA AGAGAAGAAA GACGCAGCTG 2521 AGCAAGTTAG GAAATCAACA TTGAATCCCA ATGCAAAGGA GTTCAACCCA CGTTCCTTCT 2581 CTCAGCCAAA GCCTTCTACT ACCCCAACTT CACCTCGGCC TCAAGCACAA CCTAGCCCAT 2641 CTATGGTGGG TCATCAACAG CCAACTCCAG TTTATACTCA GCCTGTTTGT TTTGCACCAA 2701 ATATGATGTA TCCAGTCCCA GTGAGCCCAG GCGTGCAACC TTTATACCCA ATACCTATGA 2761 CGCCCATGCC AGTGAATCAA GCCAAGACAT ATAGAGCAGT ACCAAATATG CCCCAACAGC 2821 GGCAAGACCA GCATCATCAG AGTGCCATGA TGCACCCAGC GTCAGCAGCG GGCCCACCGA 2881 TTGCAGCCAC CCCACCAGCT TACTCCACGC AATATGTTGC CTACAGTCCT CAGCAGTTCC 2941 CAAATCAGCC CCTTGTTCAG CATGTGCCAC ATTATCAGTC TCAGCATCCT CATGTCTATA 3001 GTCCTGTAAT ACAGGGTAAT GCTAGAATGA TGGCACCACC AACACACGCC CAGCCTGGTT 3061 TAGTATCTTC TTCAGCAACT CAGTACGGGG CTCATGAGCA GACGCATGCG ATGTATGCAT 3121 GTCCCAAATT ACCATACAAC AAGGAGACAA GCCCTTCTTT CTACTTTGCC ATTTCCACGG 3181 GCTCCCTTGC TCAGCAGTAT GCGCACCCTA ACGCTACCCT GCACCCACAT ACTCCACACC 3241 CTCAGCCTTC AGCTACCCCC ACTGGACAGC AGCAAAGCCA ACATGGTGGA AGTCATCCTG 3301 CACCCAGTCC TGTTCAGCAC CATCAGCACC AGGCCGCCCA GGCTCTCCAT CTGGCCAGTC 3361 CACAGCAGCA GTCAGCCATT TACCACGCGG GGCTTGCGCC AACTCCACCC TCCATGACAC 3421 CTGCCTCCAA CACGCAGTCG CCACAGAATA GTTTCCCAGC AGCACAACAG ACTGTCTTTA 3481 CGATCCATCC TTCTCACGTT CAGCCGGCGT ATACCAACCC ACCCCACATG GCCCACGTAC 3541 CTCAGGCTCA TGTACAGTCA GGAATGGTTC CTTCTCATCC AACTGCCCAT GCGCCAATGA 3601 TGCTAATGAC GACACAGCCA CCCGGCGGTC CCCAGGCCGC CCTCGCTCAA AGTGCACTAC 3661 AGCCCATTCC AGTCTCGACA ACAGCGCATT TCCCCTATAT GACGCACCCT TCAGTACAAG 3721 CCCACCACCA ACAGCAGTTG TAAGGCTGCC CTGGAGGAAC CGAAAGGCCA AATTCCCTCC 3781 TCCCTTCTAC TGCTTCTACC AACTGGAAGC ACAGAAAACT AGAATTTCAT TTATTTTGTT 3841 TTTAAAATAT ATATGTTGAT TTCTTGTAAC ATCCAATAGG AATGCTAACA GTTCACTTGC 3901 AGTGGAAGAT ACTTGGACCG AGTAGAGGCA TTTAGGAACT TGGGGGCTAT TCCATAATTC 3961 CATATGCTGT TTCAGAGTCC CGCAGGTACC CCAGCTCTGC TTGCCGAAAC TGGAAGTTAT 4021 TTATTTTTTA ATAACCCTTG AAAGTCATGA ACACATCAGC TAGCAAAAGA AGTAACAAGA 4081 GTGATTCTTG CTGCTATTAC TGCTAAAAAA AAAAAAAAAA AAAAATCAAG ACTTGGAACG 4141 CCCTTTTACT AAACTTGACA AAGTTTCAGT AAATTCTTAC CGTCAAACTG ACGGATTATT 4201 ATTTATAAAT CAAGTTTGAT GAGGTGATCA CTGTCTACAG TGGTTCAACT TTTAAGTTAA 4261 GGGAAAAACT TTTACTTTGT AGATAATATA AAATAAAAAC TTAAAAAAAA TTTAAAAAAT 4321 AAAAAAAGTT TTAAAAACTG A (SEQ ID NO: 61).

[0084] The corresponding amino acid sequence of human ATXN2 protein isoform 1 can be found in NP_002964.4: 1 MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS 61 SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSVVGSKC 121 EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF 181 KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND 241 MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL 301 ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG 361 SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT 421 PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR 481 GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSVVSGV PRLSPKTHRP RSPRQNSIGN 541 TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA 601 GNKENIKPNE TSPSFSKAEN KGISPVVSEH RKQIDDLKKF KNDFRLQPSS TSESMDQLLN 661 KNREGEKSRD LIKDKIEPSA KDSFIENSSS NCTSGSSKPN SPSISPSILS NTEHKRGPEV 721 TSQGVQTSSP ACKQEKDDKE EKKDAAEQVR KSTLNPNAKE FNPRSFSQPK PSTTPTSPRP 781 QAQPSPSMVG HQQPTPVYTQ PVCFAPNMMY PVPVSPGVQP LYPIPMTPMP VNQAKTYRAV 841 PNMPQQRQDQ HHQSAMMHPA SAAGPPIAAT PPAYSTQYVA YSPQQFPNQP LVQHVPHYQS 901 QHPHVYSPVI QGNARMMAPP THAQPGLVSS SATQYGAHEQ THAMYACPKL PYNKETSPSF 961 YFAISTGSLA QQYAHPNATL HPHTPHPQPS ATPTGQQQSQ HGGSHPAPSP VQHHQHQAAQ 1021 ALHLASPQQQ SAIYHAGLAP TPPSMTPASN TQSPQNSFPA AQQTVFTIHP SHVQPAYTNP 1081 PHMAHVPQAH VQSGMVPSHP TAHAPMMLMT TQPPGGPQAA LAQSALQPIP VSTTAHFPYM 1141 THPSVQAHHQ QQL (SEQ ID NO: 62).

[0085] The human ATXN2 isoform 2 mRNA sequence can be found in NM_001310121.1 (SEQ ID NO: 63) and the corresponding protein sequence can be found in NP_001297050.1 (SEQ ID NO: 64). 1 CCCGAGAAAG CAACCCAGCG CGCCGCCCGC TCCTCACGTG TCCCTCCCGG CCCCGGGGCC 61 ACCTCACGTT CTGCTTCCGT CTGACCCCTC CGACTTCCGA GGTCGAAACA GTAACAAAGG 121 ACTGCCTCAG TCTACGATTT CTTTTGATGG AATCTATGCA AATATGAGGA TGGTTCATAT 181 ACTTACATCA GTTGTTGGCT CCAAATGTGA AGTACAAGTG AAAAATGGAG GTATATATGA 241 AGGAGTTTTT AAAACTTACA GTCCGAAGTG TGATTTGGTA CTTGATGCCG CACATGAGAA 301 AAGTACAGAA TCCAGTTCGG GGCCGAAACG TGAAGAAATA ATGGAGAGTA TTTTGTTCAA 361 ATGTTCAGAC TTTGTTGTGG TACAGTTTAA AGATATGGAC TCCAGTTATG CAAAAAGAGA 421 TGCTTTTACT GACTCTGCTA TCAGTGCTAA AGTGAATGGC GAACACAAAG AGAAGGACCT 481 GGAGCCCTGG GATGCAGGTG AACTCACAGC CAATGAGGAA CTTGAGGCTT TGGAAAATGA 541 CGTATCTAAT GGATGGGATC CCAATGATAT GTTTCGATAT AATGAAGAAA ATTATGGTGT 601 AGTGTCTACG TATGATAGCA GTTTATCTTC GTATACAGTG CCCTTAGAAA GAGATAACTC 661 AGAAGAATTT TTAAAACGGG AAGCAAGGGC AAACCAGTTA GCAGAAGAAA TTGAGTCAAG 721 TGCCCAGTAC AAAGCTCGAG TGGCCCTGGA AAATGATGAT AGGAGTGAGG AAGAAAAATA 781 CACAGCAGTT CAGAGAAATT CCAGTGAACG TGAGGGGCAC AGCATAAACA CTAGGGAAAA 841 TAAATATATT CCTCCTGGAC AAAGAAATAG AGAAGTCATA TCCTGGGGAA GTGGGAGACA 901 GAATTCACCG CGTATGGGCC AGCCTGGATC GGGCTCCATG CCATCAAGAT CCACTTCTCA 961 CACTTCAGAT TTCAACCCGA ATTCTGGTTC AGACCAAAGA GTAGTTAATG GAGGTGTTCC 1021 CTGGCCATCG CCTTGCCCAT CTCCTTCCTC TCGCCCACCT TCTCGCTACC AGTCAGGTCC 1081 CAACTCTCTT CCACCTCGGG CAGCCACCCC TACACGGCCG CCCTCCAGGC CCCCCTCGCG 1141 GCCATCCAGA CCCCCGTCTC ACCCCTCTGC TCATGGTTCT CCAGCTCCTG TCTCTACTAT 1201 GCCTAAACGC ATGTCTTCAG AAGGGCCTCC AAGGATGTCC CCAAAGGCCC AGCGACATCC 1261 TCGAAATCAC AGAGTTTCTG CTGGGAGGGG TTCCATATCC AGTGGCCTAG AATTTGTATC 1321 CCACAACCCA CCCAGTGAAG CAGCTACTCC TCCAGTAGCA AGGACCAGTC CCTCGGGGGG 1381 AACGTGGTCA TCAGTGGTCA GTGGGGTTCC AAGATTATCC CCTAAAACTC ATAGACCCAG 1441 GTCTCCCAGA CAGAACAGTA TTGGAAATAC CCCCAGTGGG CCAGTTCTTG CTTCTCCCCA 1501 AGCTGGTATT ATTCCAACTG AAGCTGTTGC CATGCCTATT CCAGCTGCAT CTCCTACGCC 1561 TGCTAGTCCT GCATCGAACA GAGCTGTTAC CCCTTCTAGT GAGGCTAAAG ATTCCAGGCT 1621 TCAAGATCAG AGGCAGAACT CTCCTGCAGG GAATAAAGAA AATATTAAAC CCAATGAAAC 1681 ATCACCTAGC TTCTCAAAAG CTGAAAACAA AGGTATATCA CCAGTTGTTT CTGAACATAG 1741 AAAACAGATT GATGATTTAA AGAAATTTAA GAATGATTTT AGGTTACAGC CAAGTTCTAC 1801 TTCTGAATCT ATGGATCAAC TACTAAACAA AAATAGAGAG GGAGAAAAAT CAAGAGATTT 1861 GATCAAAGAC AAAATTGAAC CAAGTGCTAA GGATTCTTTC ATTGAAAATA GCAGCAGCAA 1921 CTGTACCAGT GGCAGCAGCA AGCCGAATAG CCCCAGCATT TCCCCTTCAA TACTTAGTAA 1981 CACGGAGCAC AAGAGGGGAC CTGAGGTCAC TTCCCAAGGG GTTCAGACTT CCAGCCCAGC 2041 ATGTAAACAA GAGAAAGACG ATAAGGAAGA GAAGAAAGAC GCAGCTGAGC AAGTTAGGAA 2101 ATCAACATTG AATCCCAATG CAAAGGAGTT CAACCCACGT TCCTTCTCTC AGCCAAAGCC 2161 TTCTACTACC CCAACTTCAC CTCGGCCTCA AGCACAACCT AGCCCATCTA TGGTGGGTCA 2221 TCAACAGCCA ACTCCAGTTT ATACTCAGCC TGTTTGTTTT GCACCAAATA TGATGTATCC 2281 AGTCCCAGTG AGCCCAGGCG TGCAACCTTT ATACCCAATA CCTATGACGC CCATGCCAGT 2341 GAATCAAGCC AAGACATATA GAGCAGTACC AAATATGCCC CAACAGCGGC AAGACCAGCA 2401 TCATCAGAGT GCCATGATGC ACCCAGCGTC AGCAGCGGGC CCACCGATTG CAGCCACCCC 2461 ACCAGCTTAC TCCACGCAAT ATGTTGCCTA CAGTCCTCAG CAGTTCCCAA ATCAGCCCCT 2521 TGTTCAGCAT GTGCCACATT ATCAGTCTCA GCATCCTCAT GTCTATAGTC CTGTAATACA 2581 GGGTAATGCT AGAATGATGG CACCACCAAC ACACGCCCAG CCTGGTTTAG TATCTTCTTC 2641 AGCAACTCAG TACGGGGCTC ATGAGCAGAC GCATGCGATG TATGCATGTC CCAAATTACC 2701 ATACAACAAG GAGACAAGCC CTTCTTTCTA CTTTGCCATT TCCACGGGCT CCCTTGCTCA 2761 GCAGTATGCG CACCCTAACG CTACCCTGCA CCCACATACT CCACACCCTC AGCCTTCAGC 2821 TACCCCCACT GGACAGCAGC AAAGCCAACA TGGTGGAAGT CATCCTGCAC CCAGTCCTGT 2881 TCAGCACCAT CAGCACCAGG CCGCCCAGGC TCTCCATCTG GCCAGTCCAC AGCAGCAGTC 2941 AGCCATTTAC CACGCGGGGC TTGCGCCAAC TCCACCCTCC ATGACACCTG CCTCCAACAC 3001 GCAGTCGCCA CAGAATAGTT TCCCAGCAGC ACAACAGACT GTCTTTACGA TCCATCCTTC 3061 TCACGTTCAG CCGGCGTATA CCAACCCACC CCACATGGCC CACGTACCTC AGTGCGCCAG 3121 TGAGGCTCTG GCAAGGTGTG GGCTAGAGAT GCGACTCAGT TGGATCTATC TCTCAGAAGG 3181 CTACCTTGCT CATGTACAGT CAGGAATGGT TCCTTCTCAT CCAACTGCCC ATGCGCCAAT 3241 GATGCTAATG ACGACACAGC CACCCGGCGG TCCCCAGGCC GCCCTCGCTC AAAGTGCACT 3301 ACAGCCCATT CCAGTCTCGA CAACAGCGCA TTTCCCCTAT ATGACGCACC CTTCAGTACA 3361 AGCCCACCAC CAACAGCAGT TGTAAGGCTG CCCTGGAGGA ACCGAAAGGC CAAATTCCCT 3421 CCTCCCTTCT ACTGCTTCTA CCAACTGGAA GCACAGAAAA CTAGAATTTC ATTTATTTTG 3481 TTTTTAAAAT ATATATGTTG ATTTCTTGTA ACATCCAATA GGAATGCTAA CAGTTCACTT 3541 GCAGTGGAAG ATACTTGGAC CGAGTAGAGG CATTTAGGAA CTTGGGGGCT ATTCCATAAT 3601 TCCATATGCT GTTTCAGAGT CCCGCAGGTA CCCCAGCTCT GCTTGCCGAA ACTGGAAGTT 3661 ATTTATTTTT TAATAACCCT TGAAAGTCAT GAACACATCA GCTAGCAAAA GAAGTAACAA 3721 GAGTGATTCT TGCTGCTATT ACTGCTAAAA AAAAAAAAAA AAAAAAATCA AGACTTGGAA 3781 CGCCCTTTTA CTAAACTTGA CAAAGTTTCA GTAAATTCTT ACCGTCAAAC TGACGGATTA 3841 TTATTTATAA ATCAAGTTTG ATGAGGTGAT CACTGTCTAC AGTGGTTCAA CTTTTAAGTT 3901 AAGGGAAAAA CTTTTACTTT GTAGATAATA TAAAATAAAA ACTTAAAAAA AATTTAAAAA 3961 ATAAAAAAAG TTTTAAAAAC TGAAAAAAAA AAA(SEQ ID NO: 63) 1 MRMVHILTSV VGSKCEVQVK NGGIYEGVFK TYSPKCDLVL DAAHEKSTES SSGPKREEIM 61 ESILFKCSDF VVVQFKDMDS SYAKRDAFTD SAISAKVNGE HKEKDLEPWD AGELTANEEL 121 EALENDVSNG WDPNDMFRYN EENYGVVSTY DSSLSSYTVP LERDNSEEFL KREARANQLA 181 EEIESSAQYK ARVALENDDR SEEEKYTAVQ RNSSEREGHS INTRENKYIP PGQRNREVIS 241 WGSGRQNSPR MGQPGSGSMP SRSTSHTSDF NPNSGSDQRV VNGGVPWPSP CPSPSSRPPS 301 RYQSGPNSLP PRAATPTRPP SRPPSRPSRP PSHPSAHGSP APVSTMPKRM SSEGPPRMSP 361 KAQRHPRNHR VSAGRGSISS GLEFVSHNPP SEAATPPVAR TSPSGGTWSS VVSGVPRLSP 421 KTHRPRSPRQ NSIGNTPSGP VLASPQAGII PTEAVAMPIP AASPTPASPA SNRAVTPSSE 481 AKDSRLQDQR QNSPAGNKEN IKPNETSPSF SKAENKGISP VVSEHRKQID DLKKFKNDFR 541 LQPSSTSESM DQLLNKNREG EKSRDLIKDK IEPSAKDSFI ENSSSNCTSG SSKPNSPSIS 601 PSILSNTEHK RGPEVTSQGV QTSSPACKQE KDDKEEKKDA AEQVRKSTLN PNAKEFNPRS 661 FSQPKPSTTP TSPRPQAQPS PSMVGHQQPT PVYTQPVCFA PNMMYPVPVS PGVQPLYPIP 721 MTPMPVNQAK TYRAVPNMPQ QRQDQHHQSA MMHPASAAGP PIAATPPAYS TQYVAYSPQQ 781 FPNQPLVQHV PHYQSQHPHV YSPVIQGNAR MMAPPTHAQP GLVSSSATQY GAHEQTHAMY 841 ACPKLPYNKE TSPSFYFAIS TGSLAQQYAH PNATLHPHTP HPQPSATPTG QQQSQHGGSH 901 PAPSPVQHHQ HQAAQALHLA SPQQQSAIYH AGLAPTPPSM TPASNTQSPQ NSFPAAQQTV 961 FTIHPSHVQP AYTNPPHMAH VPQCASEALA RCGLEMRLSW IYLSEGYLAH VQSGMVPSHP 1021 TAHAPMMLMT TQPPGGPQAA LAQSALQPIP VSTTAHFPYM THPSVQAHHQ QQL(SEQ ID NO:64)

[0086] The human ATXN2 isoform 3 mRNA sequence can be found in NM_001310123.1 (SEQ ID NO:65), and the corresponding protein sequence can be found in NP_001297052.1 (SEQ ID NO:66). 1 CCCGAGAAAG CAACCCAGCG CGCCGCCCGC TCCTCACGTG TCCCTCCCGG CCCCGGGGCC 61 ACCTCACGTT CTGCTTCCGT CTGACCCCTC CGACTTCCGA TTTCTTTTGA TGGAATCTAT 121 GCAAATATGA GGATGGTTCA TATACTTACA TCAGTTGTTT GTGATTTGGT ACTTGATGCC 181 GCACATGAGA AAAGTACAGA ATCCAGTTCG GGGCCGAAAC GTGAAGAAAT AATGGAGAGT 241 ATTTTGTTCA AATGTTCAGA CTTTGTTGTG GTACAGTTTA AAGATATGGA CTCCAGTTAT 301 GCAAAAAGAG ATGCTTTTAC TGACTCTGCT ATCAGTGCTA AAGTGAATGG CGAACACAAA 361 GAGAAGGACC TGGAGCCCTG GGATGCAGGT GAACTCACAG CCAATGAGGA ACTTGAGGCT 421 TTGGAAAATG ACGTATCTAA TGGATGGGAT CCCAATGATA TGTTTCGATA TAATGAAGAA 481 AATTATGGTG TAGTGTCTAC GTATGATAGC AGTTTATCTT CGTATACAGT GCCCTTAGAA 541 AGAGATAACT CAGAAGAATT TTTAAAACGG GAAGCAAGGG CAAACCAGTT AGCAGAAGAA 601 ATTGAGTCAA GTGCCCAGTA CAAAGCTCGA GTGGCCCTGG AAAATGATGA TAGGAGTGAG 661 GAAGAAAAAT ACACAGCAGT TCAGAGAAAT TCCAGTGAAC GTGAGGGGCA CAGCATAAAC 721 ACTAGGGAAA ATAAATATAT TCCTCCTGGA CAAAGAAATA GAGAAGTCAT ATCCTGGGGA 781 AGTGGGAGAC AGAATTCACC GCGTATGGGC CAGCCTGGAT CGGGCTCCAT GCCATCAAGA 841 TCCACTTCTC ACACTTCAGA TTTCAACCCG AATTCTGGTT CAGACCAAAG AGTAGTTAAT 901 GGAGGTGTTC CCTGGCCATC GCCTTGCCCA TCTCCTTCCT CTCGCCCACC TTCTCGCTAC 961 CAGTCAGGTC CCAACTCTCT TCCACCTCGG GCAGCCACCC CTACACGGCC GCCCTCCAGG 1021 CCCCCCTCGC GGCCATCCAG ACCCCCGTCT CACCCCTCTG CTCATGGTTC TCCAGCTCCT 1081 GTCTCTACTA TGCCTAAACG CATGTCTTCA GAAGGGCCTC CAAGGATGTC CCCAAAGGCC 1141 CAGCGACATC CTCGAAATCA CAGAGTTTCT GCTGGGAGGG GTTCCATATC CAGTGGCCTA 1201 GAATTTGTAT CCCACAACCC ACCCAGTGAA GCAGCTACTC CTCCAGTAGC AAGGACCAGT 1261 CCCTCGGGGG GAACGTGGTC ATCAGTGGTC AGTGGGGTTC CAAGATTATC CCCTAAAACT 1321 CATAGACCCA GGTCTCCCAG ACAGAACAGT ATTGGAAATA CCCCCAGTGG GCCAGTTCTT 1381 GCTTCTCCCC AAGCTGGTAT TATTCCAACT GAAGCTGTTG CCATGCCTAT TCCAGCTGCA 1441 TCTCCTACGC CTGCTAGTCC TGCATCGAAC AGAGCTGTTA CCCCTTCTAG TGAGGCTAAA 1501 GATTCCAGGC TTCAAGATCA GAGGCAGAAC TCTCCTGCAG GGAATAAAGA AAATATTAAA 1561 CCCAATGAAA CATCACCTAG CTTCTCAAAA GCTGAAAACA AAGGTATATC ACCAGTTGTT 1621 TCTGAACATA GAAAACAGAT TGATGATTTA AAGAAATTTA AGAATGATTT TAGGTTACAG 1681 CCAAGTTCTA CTTCTGAATC TATGGATCAA CTACTAAACA AAAATAGAGA GGGAGAAAAA 1741 TCAAGAGATT TGATCAAAGA CAAAATTGAA CCAAGTGCTA AGGATTCTTT CATTGAAAAT 1801 AGCAGCAGCA ACTGTACCAG TGGCAGCAGC AAGCCGAATA GCCCCAGCAT TTCCCCTTCA 1861 ATACTTAGTA ACACGGAGCA CAAGAGGGGA CCTGAGGTCA CTTCCCAAGG GGTTCAGACT 1921 TCCAGCCCAG CATGTAAACA AGAGAAAGAC GATAAGGAAG AGAAGAAAGA CGCAGCTGAG 1981 CAAGTTAGGA AATCAACATT GAATCCCAAT GCAAAGGAGT TCAACCCACG TTCCTTCTCT 2041 CAGCCAAAGC CTTCTACTAC CCCAACTTCA CCTCGGCCTC AAGCACAACC TAGCCCATCT 2101 ATGGTGGGTC ATCAACAGCC AACTCCAGTT TATACTCAGC CTGTTTGTTT TGCACCAAAT 2161 ATGATGTATC CAGTCCCAGT GAGCCCAGGC GTGCAACCTT TATACCCAAT ACCTATGACG 2221 CCCATGCCAG TGAATCAAGC CAAGACATAT AGAGCAGTAC CAAATATGCC CCAACAGCGG 2281 CAAGACCAGC ATCATCAGAG TGCCATGATG CACCCAGCGT CAGCAGCGGG CCCACCGATT 2341 GCAGCCACCC CACCAGCTTA CTCCACGCAA TATGTTGCCT ACAGTCCTCA GCAGTTCCCA 2401 AATCAGCCCC TTGTTCAGCA TGTGCCACAT TATCAGTCTC AGCATCCTCA TGTCTATAGT 2461 CCTGTAATAC AGGGTAATGC TAGAATGATG GCACCACCAA CACACGCCCA GCCTGGTTTA 2521 GTATCTTCTT CAGCAACTCA GTACGGGGCT CATGAGCAGA CGCATGCGAT GTATGTTTCC 2581 ACGGGCTCCC TTGCTCAGCA GTATGCGCAC CCTAACGCTA CCCTGCACCC ACATACTCCA 2641 CACCCTCAGC CTTCAGCTAC CCCCACTGGA CAGCAGCAAA GCCAACATGG TGGAAGTCAT 2701 CCTGCACCCA GTCCTGTTCA GCACCATCAG CACCAGGCCG CCCAGGCTCT CCATCTGGCC 2761 AGTCCACAGC AGCAGTCAGC CATTTACCAC GCGGGGCTTG CGCCAACTCC ACCCTCCATG 2821 ACACCTGCCT CCAACACGCA GTCGCCACAG AATAGTTTCC CAGCAGCACA ACAGACTGTC 2881 TTTACGATCC ATCCTTCTCA CGTTCAGCCG GCGTATACCA ACCCACCCCA CATGGCCCAC 2941 GTACCTCAGG CTCATGTACA GTCAGGAATG GTTCCTTCTC ATCCAACTGC CCATGCGCCA 3001 ATGATGCTAA TGACGACACA GCCACCCGGC GGTCCCCAGG CCGCCCTCGC TCAAAGTGCA 3061 CTACAGCCCA TTCCAGTCTC GACAACAGCG CATTTCCCCT ATATGACGCA CCCTTCAGTA 3121 CAAGCCCACC ACCAACAGCA GTTGTAAGGC TGCCCTGGAG GAACCGAAAG GCCAAATTCC 3181 CTCCTCCCTT CTACTGCTTC TACCAACTGG AAGCACAGAA AACTAGAATT TCATTTATTT 3241 TGTTTTTAAA ATATATATGT TGATTTCTTG TAACATCCAA TAGGAATGCT AACAGTTCAC 3301 TTGCAGTGGA AGATACTTGG ACCGAGTAGA GGCATTTAGG AACTTGGGGG CTATTCCATA 3361 ATTCCATATG CTGTTTCAGA GTCCCGCAGG TACCCCAGCT CTGCTTGCCG AAACTGGAAG 3421 TTATTTATTT TTTAATAACC CTTGAAAGTC ATGAACACAT CAGCTAGCAA AAGAAGTAAC 3481 AAGAGTGATT CTTGCTGCTA TTACTGCTAA AAAAAAAAAA AAAAAAAAAT CAAGACTTGG 3541 AACGCCCTTT TACTAAACTT GACAAAGTTT CAGTAAATTC TTACCGTCAA ACTGACGGAT 3601 TATTATTTAT AAATCAAGTT TGATGAGGTG ATCACTGTCT ACAGTGGTTC AACTTTTAAG 3661 TTAAGGGAAA AACTTTTACT TTGTAGATAA TATAAAATAA AAACTTAAAA AAAATTTAAA 3721 AAATAAAAAA AGTTTTAAAA ACTGAAAAAA AAAAA(SEQ ID NO: 65) 1 MRMVHILTSV VCDLVLDAAH EKSTESSSGP KREEIMESIL FKCSDFVVVQ FKDMDSSYAK 61 RDAFTDSAIS AKVNGEHKEK DLEPWDAGEL TANEELEALE NDVSNGWDPN DMFRYNEENY 121 GVVSTYDSSL SSYTVPLERD NSEEFLKREA RANQLAEEIE SSAQYKARVA LENDDRSEEE 181 KYTAVQRNSS EREGHSINTR ENKYIPPGQR NREVISWGSG RQNSPRMGQP GSGSMPSRST 241 SHTSDFNPNS GSDQRVVNGG VPWPSPCPSP SSRPPSRYQS GPNSLPPRAA TPTRPPSRPP 301 SRPSRPPSHP SAHGSPAPVS TMPKRMSSEG PPRMSPKAQR HPRNHRVSAG RGSISSGLEF 361 VSHNPPSEAA TPPVARTSPS GGTWSSVVSG VPRLSPKTHR PRSPRQNSIG NTPSGPVLAS 421 PQAGIIPTEA VAMPIPAASP TPASPASNRA VTPSSEAKDS RLQDQRQNSP AGNKENIKPN 481 ETSPSFSKAE NKGISPVVSE HRKQIDDLKK FKNDFRLQPS STSESMDQLL NKNREGEKSR 541 DLIKDKIEPS AKDSFIENSS SNCTSGSSKP NSPSISPSIL SNTEHKRGPE VTSQGVQTSS 601 PACKQEKDDK EEKKDAAEQV RKSTLNPNAK EFNPRSFSQP KPSTTPTSPR PQAQPSPSMV 661 GHQQPTPVYT QPVCFAPNMM YPVPVSPGVQ PLYPIPMTPM PVNQAKTYRA VPNMPQQRQD 721 QHHQSAMMHP ASAAGPPIAA TPPAYSTQYV AYSPQQFPNQ PLVQHVPHYQ SQHPHVYSPV 781 IQGNARMMAP PTHAQPGLVS SSATQYGAHE QTHAMYVSTG SLAQQYAHPN ATLHPHTPHP 841 QPSATPTGQQ QSQHGGSHPA PSPVQHHQHQ AAQALHLASP QQQSAIYHAG LAPTPPSMTP 901 ASNTQSPQNS FPAAQQTVFT IHPSHVQPAY TNPPHMAHVP QAHVQSGMVP SHPTAHAPMM 961 LMTTQPPGGP QAALAQSALQ PIPVSTTAHF PYMTHPSVQA HHQQQL(SEQ ID NO:66)

[0087] The human ATXN2 isoform 4 mRNA sequence can be found in NM_001372574.1 (SEQ ID NO:67), and the corresponding protein sequence can be found in NP_001359503.1 (SEQ ID NO:68). 1 AGAGCTCGCC TCCCTCCGCC TCAGACTGTT TTGGTAGCAA CGGCAACGGC GGCGGCGCGT 61 TTCGGCCCGG CTCCCGGCGG CTCCTTGGTC TCGGCGGGCC TCCCCGCCCC TTCGTCGTCC 121 TCCTTCTCCC CCTCGCCAGC CCGGGCGCCC CTCCGGCCGC GCCAACCCGC GCCTCCCCGC 181 TCGGCGCCCG CGCGTCCCCG CCGCGTTCCG GCGTCTCCTT GGCGCGCCCG GCTCCCGGCT 241 GTCCCCGCCC GGCGTGCGAG CCGGTGTATG GGCCCCTCAC CATGTCGCTG AAGCCCCAGC 301 AGCAGCAGCA GCAGCAGCAG CAGCAGCAGC AGCAGCAACA GCAGCAGCAG CAGCAGCAGC 361 AGCAGCCGCC GCCCGCGGCT GCCAATGTCC GCAAGCCCGG CGGCAGCGGC CTTCTAGCGT 421 CGCCCGCCGC CGCGCCTTCG CCGTCCTCGT CCTCGGTCTC CTCGTCCTCG GCCACGGCTC 481 CCTCCTCGGT GGTCGCGGCG ACCTCCGGCG GCGGGAGGCC CGGCCTGGGC AGAGGTCGAA 541 ACAGTAACAA AGGACTGCCT CAGTCTACGA TTTCTTTTGA TGGAATCTAT GCAAATATGA 601 GGATGGTTCA TATACTTACA TCAGTTGTTG GCTCCAAATG TGAAGTACAA GTGAAAAATG 661 GAGGTATATA TGAAGGAGTT TTTAAAACTT ACAGTCCGAA GTGTGATTTG GTACTTGATG 721 CCGCACATGA GAAAAGTACA GAATCCAGTT CGGGGCCGAA ACGTGAAGAA ATAATGGAGA 781 GTATTTTGTT CAAATGTTCA GACTTTGTTG TGGTACAGTT TAAAGATATG GACTCCAGTT 841 ATGCAAAAAG AGATGCTTTT ACTGACTCTG CTATCAGTGC TAAAGTGAAT GGCGAACACA 901 AAGAGAAGGA CCTGGAGCCC TGGGATGCAG GTGAACTCAC AGCCAATGAG GAACTTGAGG 961 CTTTGGAAAA TGACGTATCT AATGGATGGG ATCCCAATGA TATGTTTCGA TATAATGAAG 1021 AAAATTATGG TGTAGTGTCT ACGTATGATA GCAGTTTATC TTCGTATACA GTGCCCTTAG 1081 AAAGAGATAA CTCAGAAGAA TTTTTAAAAC GGGAAGCAAG GGCAAACCAG TTAGCAGAAG 1141 AAATTGAGTC AAGTGCCCAG TACAAAGCTC GAGTGGCCCT GGAAAATGAT GATAGGAGTG 1201 AGGAAGAAAA ATACACAGCA GTTCAGAGAA ATTCCAGTGA ACGTGAGGGG CACAGCATAA 1261 ACACTAGGGA AAATAAATAT ATTCCTCCTG GACAAAGAAA TAGAGAAGTC ATATCCTGGG 1321 GAAGTGGGAG ACAGAATTCA CCGCGTATGG GCCAGCCTGG ATCGGGCTCC ATGCCATCAA 1381 GATCCACTTC TCACACTTCA GATTTCAACC CGAATTCTGG TTCAGACCAA AGAGTAGTTA 1441 ATGGAGGTGT TCCCTGGCCA TCGCCTTGCC CATCTCCTTC CTCTCGCCCA CCTTCTCGCT 1501 ACCAGTCAGG TCCCAACTCT CTTCCACCTC GGGCAGCCAC CCCTACACGG CCGCCCTCCA 1561 GGCCCCCCTC GCGGCCATCC AGACCCCCGT CTCACCCCTC TGCTCATGGT TCTCCAGCTC 1621 CTGTCTCTAC TATGCCTAAA CGCATGTCTT CAGAAGGGCC TCCAAGGATG TCCCCAAAGG 1681 CCCAGCGACA TCCTCGAAAT CACAGAGTTT CTGCTGGGAG GGGTTCCATA TCCAGTGGCC 1741 TAGAATTTGT ATCCCACAAC CCACCCAGTG AAGCAGCTAC TCCTCCAGTA GCAAGGACCA 1801 GTCCCTCGGG GGGAACGTGG TCATCAGTGG TCAGTGGGGT TCCAAGATTA TCCCCTAAAA 1861 CTCATAGACC CAGGTCTCCC AGACAGAACA GTATTGGAAA TACCCCCAGT GGGCCAGTTC 1921 TTGCTTCTCC CCAAGCTGGT ATTATTCCAA CTGAAGCTGT TGCCATGCCT ATTCCAGCTG 1981 CATCTCCTAC GCCTGCTAGT CCTGCATCGA ACAGAGCTGT TACCCCTTCT AGTGAGGCTA 2041 AAGATTCCAG GCTTCAAGAT CAGAGGCAGA ACTCTCCTGC AGGGAATAAA GAAAATATTA 2101 AACCCAATGA AACATCACCT AGCTTCTCAA AAGCTGAAAA CAAAGGTATA TCACCAGTTG 2161 TTTCTGAACA TAGAAAACAG ATTGATGATT TAAAGAAATT TAAGAATGAT TTTAGGTTAC 2221 AGCCAAGTTC TACTTCTGAA TCTATGGATC AACTACTAAA CAAAAATAGA GAGGGAGAAA 2281 AATCAAGAGA TTTGATCAAA GACAAAATTG AACCAAGTGC TAAGGATTCT TTCATTGAAA 2341 ATAGCAGCAG CAACTGTACC AGTGGCAGCA GCAAGCCGAA TAGCCCCAGC ATTTCCCCTT 2401 CAATACTTAG TAACACGGAG CACAAGAGGG GACCTGAGGT CACTTCCCAA GGGGTTCAGA 2461 CTTCCAGCCC AGCATGTAAA CAAGAGAAAG ACGATAAGGA AGAGAAGAAA GACGCAGCTG 2521 AGCAAGTTAG GAAATCAACA TTGAATCCCA ATGCAAAGGA GTTCAACCCA CGTTCCTTCT 2581 CTCAGCCAAA GCCTTCTACT ACCCCAACTT CACCTCGGCC TCAAGCACAA CCTAGCCCAT 2641 CTATGGTGGG TCATCAACAG CCAACTCCAG TTTATACTCA GCCTGTTTGT TTTGCACCAA 2701 ATATGATGTA TCCAGTCCCA GTGAGCCCAG GCGTGCAACC TTTATACCCA ATACCTATGA 2761 CGCCCATGCC AGTGAATCAA GCCAAGACAT ATAGAGCAGG TAAAGTACCA AATATGCCCC 2821 AACAGCGGCA AGACCAGCAT CATCAGAGTG CCATGATGCA CCCAGCGTCA GCAGCGGGCC 2881 CACCGATTGC AGCCACCCCA CCAGCTTACT CCACGCAATA TGTTGCCTAC AGTCCTCAGC 2941 AGTTCCCAAA TCAGCCCCTT GTTCAGCATG TGCCACATTA TCAGTCTCAG CATCCTCATG 3001 TCTATAGTCC TGTAATACAG GGTAATGCTA GAATGATGGC ACCACCAACA CACGCCCAGC 3061 CTGGTTTAGT ATCTTCTTCA GCAACTCAGT ACGGGGCTCA TGAGCAGACG CATGCGATGT 3121 ATGCATGTCC CAAATTACCA TACAACAAGG AGACAAGCCC TTCTTTCTAC TTTGCCATTT 3181 CCACGGGCTC CCTTGCTCAG CAGTATGCGC ACCCTAACGC TACCCTGCAC CCACATACTC 3241 CACACCCTCA GCCTTCAGCT ACCCCCACTG GACAGCAGCA AAGCCAACAT GGTGGAAGTC 3301 ATCCTGCACC CAGTCCTGTT CAGCACCATC AGCACCAGGC CGCCCAGGCT CTCCATCTGG 3361 CCAGTCCACA GCAGCAGTCA GCCATTTACC ACGCGGGGCT TGCGCCAACT CCACCCTCCA 3421 TGACACCTGC CTCCAACACG CAGTCGCCAC AGAATAGTTT CCCAGCAGCA CAACAGACTG 3481 TCTTTACGAT CCATCCTTCT CACGTTCAGC CGGCGTATAC CAACCCACCC CACATGGCCC 3541 ACGTACCTCA GGCTCATGTA CAGTCAGGAA TGGTTCCTTC TCATCCAACT GCCCATGCGC 3601 CAATGATGCT AATGACGACA CAGCCACCCG GCGGTCCCCA GGCCGCCCTC GCTCAAAGTG 3661 CACTACAGCC CATTCCAGTC TCGACAACAG CGCATTTCCC CTATATGACG CACCCTTCAG 3721 TACAAGCCCA CCACCAACAG CAGTTGTAAG GCTGCCCTGG AGGAACCGAA AGGCCAAATT 3781 CCCTCCTCCC TTCTACTGCT TCTACCAACT GGAAGCACAG AAAACTAGAA TTTCATTTAT 3841 TTTGTTTTTA AAATATATAT GTTGATTTCT TGTAACATCC AATAGGAATG CTAACAGTTC 3901 ACTTGCAGTG GAAGATACTT GGACCGAGTA GAGGCATTTA GGAACTTGGG GGCTATTCCA 3961 TAATTCCATA TGCTGTTTCA GAGTCCCGCA GGTACCCCAG CTCTGCTTGC CGAAACTGGA 4021 AGTTATTTAT TTTTTAATAA CCCTTGAAAG TCATGAACAC ATCAGCTAGC AAAAGAAGTA 4081 ACAAGAGTGA TTCTTGCTGC TATTACTGCT AAAAAAAAAA AAAAAAAAAA ATCAAGACTT 4141 GGAACGCCCT TTTACTAAAC TTGACAAAGT TTCAGTAAAT TCTTACCGTC AAACTGACGG 4201 ATTATTATTT ATAAATCAAG TTTGATGAGG TGATCACTGT CTACAGTGGT TCAACTTTTA 4261 AGTTAAGGGA AAAACTTTTA CTTTGTAGAT AATATAAAAT AAAAACTTAA AAAAAATTTA 4321 AAAAATAAAA AAAGTTTTAA AAACTGA(SEQ ID NO: 67) 1 MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS 61 SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSVVGSKC 121 EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF 181 KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND 241 MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL 301 ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG 361 SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT 421 PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR 481 GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSVVSGV PRLSPKTHRP RSPRQNSIGN 541 TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA 601 GNKENIKPNE TSPSFSKAEN KGISPVVSEH RKQIDDLKKF KNDFRLQPSS TSESMDQLLN 661 KNREGEKSRD LIKDKIEPSA KDSFIENSSS NCTSGSSKPN SPSISPSILS NTEHKRGPEV 721 TSQGVQTSSP ACKQEKDDKE EKKDAAEQVR KSTLNPNAKE FNPRSFSQPK PSTTPTSPRP 781 QAQPSPSMVG HQQPTPVYTQ PVCFAPNMMY PVPVSPGVQP LYPIPMTPMP VNQAKTYRAG 841 KVPNMPQQRQ DQHHQSAMMH PASAAGPPIA ATPPAYSTQY VAYSPQQFPN QPLVQHVPHY 901 QSQHPHVYSP VIQGNARMMA PPTHAQPGLV SSSATQYGAH EQTHAMYACP KLPYNKETSP 961 SFYFAISTGS LAQQYAHPNA TLHPHTPHPQ PSATPTGQQQ SQHGGSHPAP SPVQHHQHQA 1021 AQALHLASPQ QQSAIYHAGL APTPPSMTPA SNTQSPQNSF PAAQQTVFTI HPSHVQPAYT 1081 NPPHMAHVPQ AHVQSGMVPS HPTAHAPMML MTTQPPGGPQ AALAQSALQP IPVSTTAHFP 1141 YMTHPSVQAH HQQQL(SEQ ID NO: 68)

[0088] Another human ATXN2 isoform (including UTR) mRNA sequence (SEQ ID NO: 69) and the corresponding protein sequence (SEQ ID NO: 70) can be found in ENST00000608853.5.

[0089] As used herein, "ATXN2-related neurological disorder" means a neurological disorder associated with abnormal ATXN2 expression, activity, or function, CAG repeat or polyglutamine expansion in the ATXN2 gene, or abnormal TDP-43 aggregation.

[0090] As used herein, "subject" means a mammal, including cats, dogs, mice, rats, chimpanzees, apes, monkeys, and humans. Preferably, the subject is a human.

[0091] As used herein, "treatment" or "treating" refers to any process by which the progression of a disorder or disease disclosed herein can be slowed, controlled, delayed, or stopped, or the symptoms of the disorder or disease can be improved, but does not necessarily indicate complete elimination of all symptoms of the disorder or disease. Treatment includes the administration of a protein, nucleic acid, vector, or composition for the treatment of a disease or condition in a patient, particularly a human.

Examples

[0092] Example 1. Synthesis of linker-delivery moiety pairs Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AEX" refers to anion exchange, "C / D" refers to cleavage and deprotection, "CPG" refers to controlled pore glass, "DCM" refers to dichloromethane, "DEA" refers to diethylamine, "DIEA" refers to N,N-diisopropylethylamine, "DMAP" refers to 4-dimethylaminopyridine, "DMF" refers to dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "DMTCl" refers to 4,4'-dimethoxytrityl chloride, "ES / MS" refers to electrospray mass spectrometry, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol and ethyl alcohol, "HBTU" refers to 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate, "HOBt" refers to 1-hydroxybenzotriazole, "IP-RP" refers to ion-pair reverse phase, "LCAA CPG" refers to long chain alkylamine controlled pore glass, "LC / MS" refers to liquid chromatography-mass"spectrometry" refers to spectrometry, "MeOH" refers to methanol and methyl alcohol, "MPA" refers to mobile phase A, "MPB" refers to mobile phase B, "MWCO" refers to molecular weight cut-off, "NMR" refers to nuclear magnetic resonance, "PBS" refers to phosphate-buffered saline, "PEG" refers to polyethylene glycol, "PVDF" refers to polyvinylidene fluoride, "RP" refers to reverse phase, "RPM" refers to revolutions per minute, "siRNA" refers to small interfering ribonucleic acid, "TEA" refers to triethylamine, "THF" refers to tetrahydrofuran, "TLC" refers to thin line chromatography, "TMP" refers to 2,2,6,6-tetramethylpiperidine, "UPLC" refers to ultra-performance liquid chromatography, and "UV" refers to ultraviolet.

[0093] Scheme 1

[0094] [Chemical formula]

[0095] Step A of Scheme 1 depicts coupling compound (1) and (2) using a suitable base such as DMAP in a suitable solvent such as DCM to obtain compound (3). Step B shows coupling compound (3) and 1-amino-3,6,9,12-tetraoxapentadecane-15-carboxylic acid in a solvent system such as water and THF in the presence of a base such as potassium carbonate to obtain compound (4).

[0096] Scheme 2

[0097] [Chemical formula]

[0098] Step A of Scheme 2 depicts performing a Mitsunobu reaction on compound (5) and tert-butyl 1-hydroxy-3,6,9,12-tetraoxapentadecane-15-oate using triphenylphosphine and diisopropyl azodicarboxylate in a solvent such as THF to obtain compound (6). Step B shows acid-deprotecting compound (6) using an acid such as HCl (hydrochloric acid) in a solvent such as 1,4-dioxane to obtain compound (7).

[0099] Scheme 3

[0100] [Chemical formula]

[0101] Step A of Scheme 3 depicts protecting compound (8) using DMTCl with a suitable base such as DIEA in a solvent such as DCM to obtain compound (9). Step B shows amide-coupling compound (9) and piperidin-4-ylmethanol using HBTU and HOBt with TMP in a solvent such as DCM to obtain compound (10). Step C shows deprotecting compound (10) with 20% piperidine in DMF to obtain compound (11).

[0102] Scheme 4

[0103] [ka]

[0104] Step A of Scheme 4 depicts the amide coupling between compound 11 and either compound 4 or compound 7 using standard coupling reagents such as HBTU and HOBt with a base such as DIEA in a solvent such as DMF to give compound 12. Those skilled in the art will recognize the various conditions that can be used to effect this amide coupling. Step B depicts the coupling of compound 12 with succinic anhydride using a base such as TEA and catalytic DMAP in a solvent such as DCM to give compound 13. Step C depicts the amide coupling of compound 13 to amino LCAA CPG using HBTU with a base such as DIEA in a solvent such as ACN, followed by a multistep workup to give compound 14.

[0105] Preparation 1 2,5-Dioxopyrrolidin-1-ylpalmitic acid

[0106] [ka]

[0107] Palmitic acid (2.00 g, 7.80 mmol) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.79 g, 9.36 mmol) and DMAP (0.19 g, 1.56 mmol) in DCM (31 mL). The mixture was stirred at ambient temperature for 5 minutes, and then N-hydroxysuccinimide (0.99 g, 8.58 mmol) was added and stirred at ambient temperature for 18 hours. The resulting crude material was concentrated in vacuo and purified by silica gel flash chromatography, eluting with a gradient of 0 to 80% EtOAc in hexanes, to afford the title compound as a white solid (2.65 g, 96%). 11H 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).

[0108] Preparation 2 3-[2-[2-[2-[2-(Hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid

[0109]

Chem.

[0110] 1-Amino-3,6,9,12-tetraoxapentadecan-15-oic acid (0.14 g, 0.53 mmol) was added to a solution of potassium carbonate (0.14 g, 1.00 mmol) in THF (1 mL) and water (2 mL). 2,5-Dioxopyrrolidin-1-yl palmitic acid (0.18 g, 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 1 N aqueous hydrochloric acid. A precipitate formed which was collected by vacuum filtration to give the title compound as a white solid (0.19 g, 74%). ES / MS m / z 504 (M+H).

[0111] 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

[0112]

Chem.

[0113] (2R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-ol (3.00 g, 6.90 mmol), tert-butyl 1-hydroxy-3,6,9,12-tetraoxapentadecane-15-oate (2.50 g, 7.60 mmol), and triphenylphosphine (2.00 g, 7.60 mmol) were mixed in THF (28.0 mL), and diisopropyl azodicarboxylate (1.50 mL, 7.60 mmol) was added dropwise over 5 minutes. The mixture was heated at 60 °C for 16 hours. The mixture was cooled to ambient temperature, silica gel was added, and the mixture was concentrated in vacuo to afford an off-white solid. The mixture was purified by silica gel flash chromatography, eluting with 0 - 40% EtOAc / hexane to give the title compound as an oil (3.33 g, 66%). 1 1H NMR (CDCl3): 3.84 (s, 4H), 3.77 - 3.71 (m, 13H), 2.59 (t, J = 6.8 Hz, 2H), 2.52 (t, J = 6.6 Hz, 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).

[0114] 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

[0115]

Chem.

[0116] tert-Butyl 3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoate (3.33 g, 4.53 mmol) was dissolved in 4 M HCl in dioxane (22.6 mL, 90.6 mmol) and stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure to afford the title compound as an off-white solid (3.08 g, 100%). ES / MS m / z 678.0 (M-H).

[0117] Preparation 5 (2S)-3-[Bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[0118] [Chemical formula]

[0119] 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-hydroxy-propanoic acid (40 g, 0.122 mol) in dry DCM (400 mL). A solution of DMTCl (49.6 g, 0.146 mol) in DCM (200 mL) was slowly added to this mixture. The mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was then diluted with water and extracted with DCM. The organic matter was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was washed with 10% EtOAc / hexane and dried under vacuum to afford the crude title compound as a light brown solid (62 g, crude). TLC: 5% MeOH / CH2Cl2 (R f : 0.5) UV, 254 nM.

[0120] Preparation 6 9H-Fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate

[0121] [Chemical formula]

[0122] To a stirred solution of (2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (62 g, 0.103 mol) in DCM (750 mL) was slowly added HBTU (78.3 g, 0.206 mol), HOBt (27.9 g, 0.206 mol), and piperidin-4-ylmethanol (15.4 g, 0.134 mol), followed by TMP (15 mL, 0.113 mol) at 0 °C under an inert atmosphere. The resulting reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was then diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with 20 - 40% EtOAc / hexane and 1% MeOH / DCM to give the title compound (40 g, 52% over two steps). 1 H NMR (DMSO-d6) δ 7.88 (br d, J = 7.5 Hz, 2H), 7.79 - 7.59 (m, 3H), 7.45 - 7.12 (m, 13H), 6.92 - 6.76 (m, 4H), 4.79 - 4.44 (m, 2H), 4.32 (br d, J = 11.4 Hz, 2H), 4.20 (br s, 2H), 3.71 (s, 6H), 3.21 (br s, 4H), 2.99 - 2.79 (m, 1H), 2.69 (br s, 2H), 1.81 - 1.43 (m, 3H), 1.08 - 0.73 (m, 2H).

[0123] Preparation 7 (2S)-2-Amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one

[0124]

Chem.

[0125] A solution of 20% piperidine in DMF (400 mL) was slowly added to 9H-fluoren-9-ylmethyl N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate (40 g, 0.055 mol) at 0 °C under an inert atmosphere. The mixture was warmed to ambient temperature and stirred for 1 h. Thereafter, the mixture was diluted with water and extracted with EtOAc. The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with 1 - 8% MeOH / DCM to afford the title compound as an off-white solid (13 g, 47%). ES / MS m / z 1009.5 (2M + H). ..

[0126] Preparation 8 N-[2-[2-[2-[2-[3-[[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]amino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethyl]hexadecanamide

[0127]

Chem.

[0128] 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 EtOAc and saturated aqueous sodium chloride solution. The layers were separated and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with 0 - 10% MeOH / DCM to afford the title compound as an oil (327 mg, 34%). 1H NMR (DMSO-d6) δ 8.21 (d, J = 8.5 Hz, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.37 - 7.28 (m, 4H), 7.23 - 7.20 (m, 5H), 6.88 (d, J = 8.3 Hz, 4H), 5.06 - 5.02 (m, 1H), 4.51 - 4.49 (m, 1H), 4.45 - 4.40 (m, 1H), 3.97 - 3.93 (m, 1H), 3.74 (s, 5H), 3.63 - 3.56 (m, 2H), 3.49 - 3.48 (m, 4H), 3.47 - 3.45 (m, 7H), 3.40 - 3.35 (m, 2H), 3.30 (s, 1H), 3.23 - 3.13 (m, 7H), 2.41 - 2.33 (m, 2H), 2.04 (t, J = 7.4 Hz, 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).

[0129] 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-butyric acid

[0130]

Chem.

[0131] N-[2-[2-[2-[2-[3-[[(1S)-1-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]amino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethyl]hexadecanamide (320 mg, 0.323 mmol), DMAP (120 mg, 0.969 mmol), TEA (225 μL, 1.62 mmol), and succinic anhydride (64.7 mg, 0.646 mmol) in DCM (6.46 mL) were mixed and the mixture was stirred at ambient temperature for 16 h. The mixture was purified directly by silica gel flash chromatography, eluting with 0% - 40% MeOH / DCM to afford the title compound as an oil (279 mg, 79%). 1 H NMR (DMSO-d6) 12.65 - 12.64 (m, 1H), 8.24 - 8.19 (m, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.37 - 7.28 (m, 4H), 7.24 - 7.20 (m, 5H), 6.88 (d, J = 8.6 Hz, 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 = 5.9 Hz, 3H), 3.22 - 3.14 (m, 6H), 2.48 - 2.31 (m, 7H), 2.04 (t, J = 7.4 Hz, 2H), 1.90 - 1.87 (m, 5H), 1.24 (s, 23H), 0.98 - 0.96 (m, 1H), 0.87 - 0.82 (m, 4H).

[0132] 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-butyric acid

[0133] [Chemical formula]

[0134] 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) in DMF (18.0 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 (980 mg, 1.90 mmol) was added to the mixture and stirred at ambient temperature for 16 hours. The mixture was partitioned between EtOAc and saturated aqueous sodium chloride solution. The layers were separated and the organic matter was washed with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography, eluting with 0 - 10% MeOH / DCM, to give N-[(1S)-1-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]-3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propenamide as a yellow oil.

[0135] N-[(1S)-1-[[Bis(4-methoxyphenyl)-phenyl-methoxymethyl]-2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]-3-[2-[2-[2-[2-[(2R)-2,5,7,8-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 mL) and stirred at ambient temperature for 16 h. The resulting residue was concentrated in vacuo and purified by silica gel flash chromatography, eluting with 0 - 40% MeOH / DCM to afford the title compound as an oil (1.36 g, 60%). ES / MS m / z 1264.4 (M-H).

[0136] 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

[0137]

Chemical Structure

[0138] 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-butyric acid (270 mg, 0.248 mmol) was dissolved in ACN (12.5 mL), and the solution was transferred to a fritted glass dropping funnel. DIEA (150 μL, 0.860 mmol) and HBTU (190 mg, 0.500 mmol) were added to the solution, and the mixture was shaken at ambient temperature for 10 minutes. Native amino LCAA CPG 500 Å (1.92 g, 129 μmol / g) was added to the solution, and the mixture was shaken at 500 RPM at ambient temperature for 16 hours. 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 at ambient temperature for 2 hours. The CPG was drained and dried under nitrogen for 5 minutes. The CPG was washed with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). The CPG was dried under nitrogen for 45 minutes, and the ligand loading was determined at 505 nm to give the title compound (1.92 g, 75.5 μmol / g).

[0139] Preparation 12 [4-[[1-[(2S)-3-[Bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoyl]amino] on CPG

[0140] [Chemical formula]

[0141] In a manner essentially similar to Preparation 11, 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-butyric acid. The ligand loading was determined at 505 nm to give the title compound (4.01 g, 66.9 μmol / g).

[0142] Preparation 13 3-[[(2R,3R,4R,5R)-2-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-hexadecoxy-5-(2-hydroxy-4-oxo-pyrimidin-1-yl)THF-�-yl]oxy-(diisopropylamino)phosphanyl]oxypropanenitrile z

[0143]

Chemical Structure

[0144] The title compound was prepared according to the protocol described in International Publication No. WO 2019 / 217459. 1 H NMR (CD3CN) δ 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 = 6.0 Hz, 1H), 1.66 - 1.51 (m, 2H), 1.40 - 1.14 (m, 35H), 1.08 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 6.8 Hz, 3H). 3131P NMR (CD3CN): 149.6, 149.2.

[0145] Preparation 14 N-[9-[(2R,3R,4R,5R)-5-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecyloxy-tetrahydrofuran-2-yl]purin-6-yl]benzamide

[0146] [Chemical formula]

[0147] The title compound was prepared according to the protocol described in International Publication No. WO 2019 / 217459. 1 1H-NMR (CD3CN) δ 9.37 (s, 1H), 8.57 (d, J = 9.4 Hz, 1H), 8.27 (d, J = 10.3 Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.34 - 7.16 (m, 7H), 6.85 - 6.77 (m, 4H), 6.11 (dd, J = 5.0, 2.5 Hz, 1H), 4.80 (m, 1H), 4.69 (m, 1H), 4.32 (m, 1H), 3.97 - 3.78 (m, 1H), 3.74 (d, J = 3.1 Hz, 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 = 6.0 Hz, 1H), 1.52 - 1.45 (m, 2H), 1.33 - 1.12 (m, 37H), 1.09 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H). 31 31P NMR (CD3CN) δ 151.19, 150.78.

[0148] Preparation 15 N-[1-[(2R,3R,4R,5R)-5-[[Bis(4-methoxyphenyl)phenylmethoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecyloxy-tetrahydrofuran-2-yl]-2-oxo-pyrimidin-4-yl]acetamide

[0149]

Chem.

[0150] The title compound was prepared according to the protocol described in International Publication No. WO 2019 / 217459. 1 1H-NMR (CD3CN) δ 9.15 (s, 1H), 8.46 (dd, J = 7.5 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.57 - 7.41 (m, 5H), 7.41 - 7.31 (m, 6H), 7.28 (m, 1H), 7.04 (d, J = 15.8 Hz, 1H), 6.90 (t, J = 7.9 Hz, 4H), 5.90 (d, J = 7.8 Hz, 1H), 4.51 (m, 1H), 4.20 (dd, J = 10.6, 8.1 Hz, 1H), 4.04 (dd, J = 31.3, 4.6 Hz, 1H), 3.91 - 3.81 (m, 2H), 3.79 (d, J = 3.1 Hz, 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 = 4.7 Hz, 26H), 1.21 - 1.09 (m, 10H), 1.04 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H). 31 31P NMR (CD3CN) δ 151.10, 150.19.

[0151] Preparation 16 N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-3-hexadecyloxy-tetrahydrofuran-2-yl]-6-oxo-1H-purin-2-yl]-2-methyl-propanamide

[0152]

Chem.

[0153] The title compound was prepared according to the protocol described in International Publication No. 2019217459.

[0154] 1 1H-NMR (CDCl3) δ 12.01 - 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 31P NMR (CDCl3) δ 150.20, 149.92.

[0155] Example 2. Synthesis of ATXN2 RNAi Agent Single strands (sense and antisense) of the RNA duplex were synthesized on a solid support via MerMade™ 12 (LGC Biosearch Technologies). The sequences of the sense and antisense strands are shown in Table 2. The oligonucleotides were synthesized via phosphoramidite chemistry at either 5, 10, 25, or 50 μmol scale.

[0156] For the sense strand, the type of solid support was Universal CPG: (3'-piperidinol-PEG-palmitic acid) and (3'-piperidinol-PEG-tocopherol) were synthesized in-house (see Example 1), while Universal UnyLinker (Chemgenes, catalog number AT273-27) and 3’Teg-Tocopherol (LGC Biosearch Technologies, catalog number BG7-1190) were purchased as commercial products. For all antisense strands, the commercially available standard support mA was utilized. Standard reagents were used for oligonucleotide synthesis (Table 7), where 0.1 M xanthane hydride in pyridine was used as the sulfurizing reagent and 20% DEA in ACN was used as an auxiliary wash after synthesis. All monomers (Table 8) were prepared at 0.1 M in ACN and included a molecular sieves trap bag.

[0157] The oligonucleotide was cleaved and deprotected (C / D) at 45 °C for 20 h. The sense strand was C / D from the CPG using ammonium hydroxide (28–30%, cold), while 3% DEA in ammonium hydroxide (28–30%, cold) was used for the antisense strand. When the obtained mass data confirmed the sequence identity, it was determined that C / D was complete by IP-RP LCMS. Depending on the scale, the CPG was filtered through a 0.45-μm PVDF syringe-less filter, a 0.22-μm PVDF Steriflip® vacuum filtration, or a 0.22-μm PVDF Stericup® Quick release. The CPG was backwashed / rinsed with either 30% ACN / RNAse-free water or 30% EtOH / RNAse-free water, then filtered through the same filtration device and mixed with the first filtrate. This was repeated twice. Next, the material was evenly divided into 50-mL Falcon tubes and the organics were removed via Genevac®. After concentration, it was diluted with RNAse-free water to return to the synthesis scale and the crude oligonucleotide was filtered by either a 0.45-μm PVDF syringe-less filter, a 0.22-μm PVDF Steriflip® vacuum filtration, or a 0.22-μm PVDF Stericup® Quick release.

[0158] The crude oligonucleotides were purified via an AKTA™ Pure purification system using either an anion-exchange (AEX) or reverse phase (RP) Source 15Q-RP column. For AEX, it was an ES Industry Source™ 15Q column with MPA: 20 mM NaH2PO4, 15% ACN, pH 7.4, and MPB: 20 mM NaH2PO4, 1 M NaBr, 15% ACN, pH 7.4, maintaining the column temperature at 65 °C. For RP, it was a Source™ 15Q-RP column with MPA: 50 mM NaOAc containing 10% ACN, and MPB: 50 mM NaOAc containing 80% ACN. In all cases, fractions containing >85% mass purity and <5% impurities were pooled.

[0159] The purified oligonucleotides were desalted at 3500 × g for approximately 30 min using 15 mL 3K MWCO centrifugal spin tubes. The oligonucleotides were rinsed with RNase-free water until the conductivity of the eluate reached <100 μS / cm. After desalting was complete, 2 - 3 mL of RNase-free water was added, then aspirated 10 times, and the retainment was transferred to a 50 mL Falcon tube, which was repeated until complete transfer of the oligo, by measuring the concentration of the compound on the filter via a nanodrop. Next, the final oligonucleotides were nanofiltered twice at 3500 × g for 2 min via 15 mL 100K MWCO centrifugal spin tubes. The final desalted oligonucleotides were analyzed for concentration (nanodrop at A260), characterized for mass purity by IP-RP LCMS, and for UV purity by UPLC.

[0160] For the preparation of double strands, equimolar amounts of the sense strand and the antisense strand were combined, heated at 65 °C for 10 minutes, and then slowly cooled to ambient temperature over 40 minutes. The integrity of the double strands was confirmed by UPLC analysis and characterized by LCMS using IP-RP. All double strands were nanofiltrated, and then the endotoxin levels were measured using the Charles River Endosafe® Cartridge Device to obtain the final compounds for conjugated RNAi (Table 9). For in vitro analysis, appropriate amounts of the double strands were lyophilized and then reconstituted in 1×PBS for rodent studies and in CSF for non-human primate studies.

[0161]

Table 7

[0162]

Table 8

[0163]

Table 9

[0164] Example 3. Characterization of the ATXN2 RNAi Agent The selected ATXN2 RNAi agent was tested in vitro for ATXN2 inhibition in cultured cells including SH-SY5Y cells, mouse primary cortical neurons, and / or human induced pluripotent stem cells (human iPS cells, hiPSC).

[0165] 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, R.A., et al., 1983. J Natl Cancer Inst 71, 741-747). The basal medium consisted of a 1:1 mixture of ATCC-formulated Eagle’s Minimum Essential Medium (catalog number 30-2003) and F12 medium. The 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 in a humidified atmosphere of 5% CO2. On day 1, SH-SY5Y cells were seeded onto 96-well fibronectin-coated tissue culture plates and allowed to adhere overnight. On day 2, the complete medium was removed and replaced with the RNAi agent in serum-free medium. After incubating the cells with the RNAi agent for 72 hours, gene expression was analyzed. Analysis of changes in gene expression in RNAi-treated SH-SY5Y cells was measured using Cells-to-C T Kits according to the manufacturer's protocol (ThermoFisher A35377). Pre-designed gene expression assays (supplied as 20× mixtures) were selected from Applied Bio-systems (Foster City, CA, USA). The efficiency of these assays (ThermoFisher Hs00240906_m1 ATXN2 and ThermoFisher Hs99999905_m1 GAPDH) was characterized using a dilution series of cDNA. RT-QPCR was performed in a MicroAmp Optical 384-well reaction plate using the QuantStudio 7 Flex system. The relative amount of gene expression was determined using the delta-delta CT method normalized to the housekeeping gene GAPDH. The IC50 was determined using 4-parameter logistic fitting with GraphPad Prism v9.0.

[0166] Mouse primary cortical neuron (MCN) culture and RNAi treatment and analysis: Mouse primary cortical neurons were isolated from wild-type C57BL6 mouse embryos at E18. The cells were seeded at a density of 40k cells / well in poly-D-lysine-coated 96-well plates and cultured in NbActiv1 (BrainBits, LLC) containing 1% antibiotic / antifungal agent (Corning) in a tissue culture incubator in a humidified chamber with 5% CO2 at 37°C for 7 days. On day 7, half of the medium was removed from each well, and 2× concentration of RNAi in culture medium with 2% FBS was added for treatment as CRC, and the cells were incubated for an additional 7 days, 14 days, or 21 days. Half of the medium was changed every 7 days using fresh culture medium. At the end of the RNAi treatment, RT-qPCR was performed to quantify the ATXN2 mRNA level using the TaqMan Fast Advanced Cell-to-CT kit. Specifically, the cells were lysed, cDNA was generated with a Mastercycler X50a (Eppendorf), and qPCR was performed with a QuantStudio 7 Flex Real-Time PCR System (Applied Biosystems). The alpha-synuclein (ThermoFisher, Mm00447333_m1) gene expression level was normalized by beta-actin (ThermoFisher, Mm02619580_g1) using each respective probe.

[0167] Culture, RNAi treatment, and analysis of human induced pluripotent stem cell-derived neurons (hiPSC neurons): Doxycycline-inducible Neurogenin2 (NGN2) human induced pluripotent stem cells (hiPSCs) were developed by Bioneer for Eli Lilly. hiPSCs were doxycycline-induced for 3 days (DIV3) to initiate neuronal differentiation, seeded at 30k / well on 96-well PDL and laminin-coated plates, and grown in neuronal differentiation media (NDM) consisting of DMEM / F12 (Life Technologies 11330-057), Neurobasal medium (Gibco 15240062), antibiotics, supplements, growth factors, and doxycycline in an incubator (37°C / 5% CO2). Cells were fed every 7 days by half. At DIV21, RNAi agents were serially diluted in NDM, 75 μL was aspirated according to the dilution, and 75 μL of 2x RNAi concentration was added to make the final 1x RNAi, and the cells were treated with RNAi. After treatment, the cells were fed every 7 days by half by removing half of the medium and adding back fresh NDM. Cell lysates were collected at DIV35 (14 days later) or DIV42 (21 days later), and RT-qPCR was performed using the TaqMan Fast Advanced Cells-to-C T Kit (ThermoFisher, A35377), and mRNA knockdown was determined using the ATXN2 probe (ThermoFisher, Hs00240907_m1) as the target gene and the ACTb probe (ThermoFisher, Hs99999903_m1) as the housekeeping gene.

[0168] Results Table 10 summarizes the knockdown rate of ATXN2 mRNA and the IC50 of SARM RNAi agents in human SH-SY5Y cells, mouse primary neurons (MCN), and hiPSC neurons. The ATXN2 RNAi agents tested achieved strong ATXN2 mRNA knockdown in human SH-SY5Y cells.

[0169]

Table 10

[0170] Example 4. In Vivo Characterization of Selected RNAi Agents in Mice The efficacy of the RNAi agents was studied in wild-type C56BL / 6N mice. Six mice were given an intracerebroventricular (ICV) injection of 30 μg of the RNAi agent or PBS (phosphate-buffered saline) and sacrificed on day 21 after injection. Mouse ATXN2 mRNA expression in the spinal cord and brain was measured and analyzed by quantitative PCR (qPCR). The results are shown in Table 11.

[0171]

Table 11

[0172]

Table 12-1

[0173]

Table 12-2

[0174]

Table 12-3

[0175]

Table 12-4

[0176]

Table 12-5

[0177]

Table 12-6

[0178]

Table 12-7

[0179]

Table 12-8

[0180]

Table 12-9

[0181]

Table 12-10

Claims

1. An ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double strand, and the sense strand and the antisense strand are (a) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 1 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 2; (b) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 3 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 4; (c) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 5 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 6; (d) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 7 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8; (e) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; (f) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12; (g) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 13 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 14; (h) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (i) the sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17 and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 18; The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 19, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 20, The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 21, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 22, The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 23, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 24, The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 25, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 26, The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 27, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 28, The sense strand comprising a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 29, and the antisense strand comprising a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 30, and comprising a pair of nucleic acid sequences selected from the group consisting of, Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, Optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, an ATXN2 RNAi agent comprising a sense strand and an antisense strand.

2. The sense strand and the antisense strand are, The sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 2, 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, The sense strand comprising the first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6, (d) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22; (l) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24; (m) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 25 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 27 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 28; (o) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 29 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30; The ATXN2 RNAi agent according to claim 1, comprising a pair of nucleic acid sequences selected from the group consisting of (Claim 3) The ATXN2 RNAi agent according to claim 1 or 2, wherein one or more nucleotides of the sense strand are modified nucleotides. (Claim 4) The ATXN2 RNAi agent according to any one of claims 1 to 3, wherein each nucleotide of the sense strand is a modified nucleotide. (Claim 5) The ATXN2 RNAi agent according to any one of claims 1 to 4, wherein one or more nucleotides of the antisense strand are modified nucleotides. (Claim 6) The ATXN2 RNAi agent according to any one of claims 1 to 5, wherein each nucleotide of the antisense strand is a modified nucleotide. (Claim 7) The ATXN2 RNAi agent according to any one of claims 1 to 6, wherein the modified nucleotide is a 2'-fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, or a 2'-O-alkyl modified nucleotide.

8. The ATXN2 RNAi agent according to claim 7, wherein the sense strand has four 2'-fluoro modified nucleotides at the 7th, 9th, 10th, and 11th positions from the 5'-end of the sense strand.

9. The ATXN2 RNAi agent according to claim 8, wherein the nucleotides at positions other than the 7th, 9th, 10th, and 11th positions of the sense strand are 2'-O-methyl modified nucleotides.

10. The ATXN2 RNAi agent according to any one of claims 7 to 9, wherein the antisense strand has four 2'-fluoro modified nucleotides at the 2nd, 6th, 14th, and 16th positions from the 5'-end of the antisense strand.

11. The ATXN2 RNAi agent according to claim 10, wherein the nucleotides at positions other than the 2nd, 6th, 14th, and 16th positions of the antisense strand are 2'-O-methyl modified nucleotides.

12. The ATXN2 RNAi agent according to any one of claims 1 to 11, wherein the sense strand and the antisense strand have one or more modified nucleotide inter-chain linkages.

13. The ATXN2 RNAi agent according to claim 12, wherein the modified nucleotide inter-chain linkage is a phosphorothioate linkage.

14. The ATXN2 RNAi agent according to claim 13, wherein the sense strand has four or five phosphorothioate linkages.

15. The ATXN2 RNAi agent according to claim 13 or 14, wherein the antisense strand has four or five phosphorothioate linkages.

16. The ATXN2 RNAi agent according to any one of claims 1 to 15, wherein the first nucleotide from the 5'-end of the antisense strand is a modified nucleotide having a phosphate analog.

17. The ATXN2 RNAi agent according to claim 16, wherein the phosphate analog is 5'-vinylphosphonate.

18. The ATXN2 RNAi agent according to any one of claims 1 to 17, wherein the sense strand has a abasic moiety or an inverted abasic moiety.

19. An ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double strand, the sense strand and the antisense strand are (a) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 31 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 33 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 35 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 37 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 39 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 41 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 43 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 45 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 47 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 49 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 51 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 52; (l) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 53 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 55 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 57 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 58; (o) the sense strand containing the first nucleic acid sequence of SEQ ID NO: 59 and the antisense strand containing the second nucleic acid sequence of SEQ ID NO: 60, and an ATXN2 RNAi agent comprising a sense strand and an antisense strand, which pair of nucleic acid sequences is selected from the group consisting of.

20. the sense strand and the antisense strand are (a) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 31 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 33 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 35 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 37 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 39 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 41 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 43 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 45 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 47 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 49 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 51 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 52; (l) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 53 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 55 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 57 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 58; (o) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 59 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 60, the ATXN2 RNAi agent according to claim 19, having a pair of nucleic acid sequences selected from the group consisting of.

21. The ATXN2 RNAi agent according to any one of claims 1 to 20, wherein the sense strand has a delivery moiety conjugated to the 3'-end of the sense strand.

22. The ATXN2 RNAi agent according to any one of claims 1 to 20, wherein the sense strand has a delivery moiety conjugated to the nucleotides of the sense strand.

23. The ATXN2 RNAi agent according to claim 21 or 22, wherein the delivery moiety is α-tocopherol, cholesterol, or palmitic acid.

24. The delivery moiety is 【Chemical 1】 conjugated to the 3'-end of the sense strand via a linker selected from the group consisting of

25. An ATXN2 RNAi agent of formula (I): R-L-D, wherein R is double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the sense strand and the antisense strand form a double strand, D is a delivery moiety, L is a linker or is optionally absent, the sense strand and the antisense strand are (a) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1 and the antisense strand comprising 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 comprising the first nucleic acid sequence of SEQ ID NO: 5 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22; (l) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24; (m) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 25 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 27 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 28; (o) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 29 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30, and comprising a pair of nucleic acid sequences selected from the group consisting of; Optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides; Optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, an ATXN2 RNAi agent of formula (I): R-L-D.

26. An ATXN2 RNAi agent of formula (I): R-L-D, wherein R is a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the sense strand and the antisense strand forming a duplex, D is a delivery means for delivering the dsRNA to a cell, L is a linking means for linking the dsRNA to the delivery means or is optionally absent, the sense strand and the antisense strand are (a) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 1 and the antisense strand comprising 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 comprising the first nucleic acid sequence of SEQ ID NO: 5 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 7 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 9 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 10; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 11 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 12; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 13 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 14; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 15 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 16; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 17 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 18; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 19 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 20; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 21 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 22; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 23 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 24; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 25 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 26; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 27 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 28; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 29 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 30; and comprising a pair of nucleic acid sequences selected from the group consisting of, optionally, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, optionally, one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages, an ATXN2 RNAi agent of formula (I): R-L-D. [

27. ] wherein the sense strand and the antisense strand are the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 31 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 32; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 33 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 34; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 35 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 36; the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 37 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 39 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 41 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 43 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 45 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 47 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 49 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 51 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 52; (l) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 53 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 55 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 57 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 58; (o) the sense strand comprising the first nucleic acid sequence of SEQ ID NO: 59 and the antisense strand comprising the second nucleic acid sequence of SEQ ID NO: 60, the ATXN2 RNAi agent according to claim 25 or 26, comprising a pair of nucleic acid sequences selected from the group consisting of. [

28. ] The sense strand and the antisense strand are (a) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 31 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 33 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: �4; (c) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 35 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 37 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 39 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 41 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 43 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 45 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 47 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 49 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 51 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 52; (l) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 53 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 55 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 57 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 58; (o) the sense strand consisting of the first nucleic acid sequence of SEQ ID NO: 59 and the antisense strand consisting of the second nucleic acid sequence of SEQ ID NO: 60; and the ATXN2 RNAi agent according to claims 25 to 27, having a pair of nucleic acid sequences selected from the group consisting of.

29. The ATXN2 RNAi agent according to any one of claims 25 to 28, wherein the delivery means or the delivery portion is conjugated to the 3'-end of the sense strand.

30. The ATXN2 RNAi agent according to any one of claims 25 to 28, wherein the delivery means or the delivery portion is conjugated to the nucleotide of the sense strand.

31. A pharmaceutical composition comprising the ATXN2 RNAi agent according to any one of claims 1 to 30 and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising means for reducing ATXN2 expression in cells and a pharmaceutically acceptable carrier.

33. A method for reducing ATXN2 expression in a patient in need thereof, the method comprising administering to the patient an effective amount of an ATXN2 RNAi agent according to any one of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32.

34. A method for treating an ATXN2-related neurological disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of an ATXN2 RNAi agent according to any one of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32.

35. The method according to claim 34, wherein the ATXN2-related neurological disorder is selected from spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Parkinson's disease, Alzheimer's disease, frontotemporal lobar degeneration (FTLD), progressive muscular atrophy (PMA), multisystem proteinopathy, Perry disease, or TDP-43 proteinopathy.

36. The method according to claim 34, wherein the ATXN2-related neurological disorder is selected from spinocerebellar ataxia type 2 (SCA2) or amyotrophic lateral sclerosis (ALS).

37. The method according to any one of claims 33 to 36, wherein the ATXN2 RNAi agent is administered intrathecally to the patient.

38. A method for reducing ATXN2 expression in a cell, the method comprising: introducing an ATXN2 RNAi agent according to any one of claims 1 to 30 into the cell; and incubating the cell for a time sufficient for degradation of ATXN2 mRNA, thereby reducing ATXN2 expression in the cell.

39. An ATXN2 RNAi agent according to any one of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use in therapy.

40. An ATXN2 RNAi agent according to any one of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use in reducing ATXN2 expression.

41. An ATXN2 RNAi agent according to any one of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use in the treatment of an ATXN2-related neurological disorder.

42. The ATXN2-related neurological disorder is selected from spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Parkinson's disease, Alzheimer's disease, frontotemporal lobar degeneration (FTLD), progressive muscular atrophy (PMA), multisystem proteinopathy, Perry disease, or TDP-43 proteinopathy. The ATXN2 RNAi agent or pharmaceutical composition for use according to claim 41.

43. The ATXN2-related neurological disorder is selected from spinocerebellar ataxia type 2 (SCA2) or amyotrophic lateral sclerosis (ALS). The ATXN2 RNAi agent or pharmaceutical composition for use according to claim 41.

44. Use of the ATXN2 RNAi agent according to any one of claims 1 to 30 in the manufacture of a medicament for the treatment of an ATXN2-related neurological disorder.

45. The ATXN2-related neurological disorder is selected from spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Parkinson's disease, Alzheimer's disease, frontotemporal lobar degeneration (FTLD), progressive muscular atrophy (PMA), multisystem proteinopathy, Perry disease, or TDP-43 proteinopathy. The use according to claim 44.

46. The ATXN2-related neurological disorder is selected from spinocerebellar ataxia type 2 (SCA2) or amyotrophic lateral sclerosis (ALS). The use according to claim 44.

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