ATXN2 RNA interference agents

Abstract

Provided herein are ATXN2 RNAi agents and compositions comprising an ATXN2 RNAi agent. Also provided herein are methods of using the ATXN2 RNAi agents or compositions comprising an ATXN2 RNAi agent for reducing ATXN2 expression, and / or treating ATXN2-associated neurological disease in a subject.

Description

SEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “30344v2” created 7-Jun-2023 and is 412 kilobytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety. BACKGROUND

[0002] Ataxin-2 is encoded by the gene ATXN2 (also known as ATX2, SCA2, TNRC13). The ATXN2 gene includes CAG trinucleotide repeats, which result 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 expansion of 31 repeats or more in ATXN-2. The most common SCA2-associated ATXN2 alleles have 37-39 CAG repeats; the 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, brain stem, and / or spinal cord. Patients with SCA2 show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, likely due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. Moderate CAG expansion (23 or more repeats but below the threshold for SCA2) in the ATXN2 gene is 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 suppression of gene expression by double-stranded RNA molecules (dsRNA) (Fire et al., Nature 391:806-811, 1998).

[0005] There remains a need for therapeutic agents that can inhibit or adjust the expression of ATXN2 for treating ATXN2-associated neurological diseases such as SCA2 or ALS, e.g., by utilizing RNAi. 2023287741   30 Jun 2026 SUMMARY OF INVENTION [0005a] In a first aspect, the present invention provides an ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises SEQ ID NO: 13, and the antisense strand comprises SEQ ID NO: 14. [0005b] In a second aspect, the present invention provides an ATXN2 RNAi agent of Formula (I): R-L-D, wherein R is a double stranded RNA (dsRNA) comprising a sense stand and an antisense strand, wherein the sense strand and the antisense strand form a duplex; wherein D is a delivery moiety; and wherein L is a linker, or absent, wherein the sense strand comprises SEQ ID NO: 13, and the antisense strand comprises SEQ ID NO: 14. [0005c] In a third aspect, the present invention provides a pharmaceutical composition comprising the ATXN2 RNAi agent of the first or second aspect and a pharmaceutically acceptable carrier. [0005d] In a fourth aspect, the present invention provides a method of reducing ATXN2 expression in a patient in need thereof, the method comprising administering to the patient an effective amount of the ATXN2 RNAi agent of the first or second aspect, or the pharmaceutical composition of the third aspect. [0005e] In a fifth aspect, the present invention provides a method of treating an ATXN2-associated neurological disease in a patient in need thereof, the method comprising administering to the patient an effective amount of the ATXN2 RNAi agent of the first or second aspect, or the pharmaceutical composition of the third aspect. [0005f] In a sixth aspect, the present invention provides a method of reducing ATXN2 expression in a cell, the method comprising: introducing the ATXN2 RNAi agent of the first or second aspect into the cell; and incubating the cell for a time sufficient for degradation of ATXN2 mRNA, thereby reducing ATXN2 expression in the cell. 2023287741   30 Jun 2026 [0005g] In a seventh aspect, the present invention provides use of the ATXN2 RNAi agent of the first or second aspect, in the manufacture of a medicament for the treatment of an ATXN2-associated neurological disease.

[0006] Also provided herein are ATXN2 RNAi agents and compositions comprising an ATXN2 RNAi agent. Also provided herein are methods of using the ATXN2 RNAi agents or compositions comprising an ATXN2 RNAi agent for reducing ATXN2 expression, and / or treating ATXN2-associated neurological diseases in a subject.

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

[0008] In some embodiments, the sense strand and the antisense strand of the ATXN2 RNAi agent described herein comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified intemucleotide linkages.

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

[00010] 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 antisense strand or to the intemucleotide linkages. In some embodiments, one or more nucleotides of the sense strand are modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, one or more nucleotides of the antisense strand are modified nucleotides. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro modified nucleotide, 2'-O-methyl modified nucleotide, or 2'-O-alkyl modified nucleotide. In some embodiments, the sense strand has four 2'-fluoro modified nucleotides at positions 7, 9, 10, and 11 from the 5’ end of the sense strand. In some embodiments, nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro modified nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand. In some embodiments, nucleotides at positions other than positions 2, 6, 14 and 16 of the antisense strand are 2'-O-methyl modified nucleotides. In some embodiments, the first nucleotide from the 5’ end of the antisense strand is a modified nucleotide that has a phosphate analog, e.g., a 5’-vinylphosphonate. In some embodiments, the sense strand has an abasic moiety or inverted abasic moiety, e.g., at position 9, 10 or 11. In some embodiments, the sense strand and the antisense strand have one or more modified intemucleotide linkages, e.g., 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 has four phosphorothioate linkages and the antisense strand has four phosphorothioate linkages.

[00011] In some embodiments, provided herein are ATXN2 RNAi agents comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60.

[00012] In some embodiments, the ATXN2 RNAi agent described herein can comprise a sense strand that comprises a sequence that has 1, 2, or 3 differences from SEQ ID NO: 31,33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59. In some embodiments, the ATXN2 RNAi agent described herein can comprise a antisense strand that comprises a sequence that has 1, 2, or 3 differences from SEQ ID NO: 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60.

[00013] In some embodiments, provided herein are ATXN2 RNAi agents comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand have a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 44, (h) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 56, (n) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 58; and (o) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 60

[00014] 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 a-tocopherol, cholesterol, or palmitic acid. In some embodiments, the delivery moiety is conjugated to the 3’ end of the sense stand via a linker, e g., a linker of Table 5.

[00015] In a further aspect, provided herein are ATXN2 RNAi agents of Formula (I): R-L-D, wherein Risa double stranded RNA (dsRNA) comprising a sense stand and an antisense strand, wherein the sense strand and the antisense strand form a duplex; wherein D is a delivery means for delivering the dsRNA into a cell; and wherein Lisa linking means for linking the dsRNA to the delivery means, or optionally absent, wherein the sense strand and the antisense strand comprises a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified intemucleotide linkages.

[00016] In some embodiments, provided herein are ATXN2 RNAi agents of Formula (I): R-L-D, wherein Risa dsRNA comprising a sense stand and an antisense strand, wherein the sense strand and the antisense strand form a duplex; wherein D is a delivery moiety; and wherein Lisa linker or optionally absent, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[00017] In some embodiments, the sense strand and the antisense strand in RNAi agents of Formula (I) comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58; (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60.

[00018] In another aspect, provided herein are pharmaceutical compositions comprising an ATXN2 RNAi agent described herein and a pharmaceutically acceptable carrier. Also provided herein are pharmaceutical compositions comprising a means for reducing ATXN2 expression in a cell and a pharmaceutically acceptable carrier.

[00019] In another aspect, provided herein are methods of reducing ATXN2 expression in a patient in need thereof, and such method comprises administering to the patient an effective amount of an ATXN2 RNAi agent or a pharmaceutical composition described herein.

[00020] In another aspect, provided herein are methods of treating an ATXN2-associated neurological disease in a patient in need thereof, and such method comprises administering to the patient an effective amount of the ATXN2 RNAi agent or a pharmaceutical composition described herein.

[00021] Also provided herein are methods of reducing ATXN2 expression in a cell (e.g., a neuron), and such methods can 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.

[00022] In another aspect, provided herein are ATXN2 RNAi agents or pharmaceutical compositions comprising an ATXN2 RNAi agent for use in reducing ATXN2 expression. Also provided herein are ATXN2 RNAi agents or the pharmaceutical composition comprising an ATXN2 RNAi agent for use in a therapy. Also provided are ATXN2 RNAi agents or pharmaceutical compositions comprising an ATXN2 RNAi agent for use in the treatment of an ATXN2-associated neurological disease. Also provided herein are uses of ATXN2 RNAi agents in the manufacture of a medicament for the treatment of an ATXN2-associated neurological disease. DETAILED DESCRIPTION

[00023] Provided herein are ATXN2 RNAi agents and compositions comprising an ATXN2 RNAi agent. Also provided herein are methods of using the ATXN2 RNAi agents or compositions comprising an ATXN2 RNAi agent for reducing ATXN2 expression, and / or treating ATXN2-associated neurological disease in a subject.

[00024] In some embodiments, provided herein are ATXN2 RNAi agents comprising a sense strand and an antisense strand, and the sense strand and the antisense strand form a duplex. The antisense strand is complementary to a region of ATXN2 mRNA. In a further embodiment, the sense strand and the antisense strand are each 15-30 nucleotides in length, e.g., 20-25 nucleotides in length. In some embodiments, provided herein are ATXN2 RNAi agents comprising a sense strand of 21 nucleotides and an antisense strand of 23 nucleotides. In some embodiments, the sense strand and antisense strand of the ATXN2 RNAi agent may have overhangs at either the 5’ end or the 3’ end (i.e., 5’ overhang or 3’ overhang). For example, the sense strand and the antisense strand may have 5’ or 3’ overhangs of 1 to 5 nucleotides or 1 to 3 nucleotides. In some embodiments, the antisense strand comprises a 3’ overhang of two nucleotides. In some embodiments, the sense strand and antisense strand sequences of the ATXN2 RNAi agents are provided in Table 1.

[00025] Provided herein are ATXN2 RNAi agents comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 24; (m) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence having at least 90% sequence identity to SEQ ID NO: 30; wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more internucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[00026] Provided herein are ATXN2 RNAi agents comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 24; (m) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 30; wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified intemucleotide linkages. Table 1. Nucleic Acid Sequences of ATXN2 RNAi Agents ATXN 2 RNAi Agent No. Sense Strand (5' to 3') SEQ ID NO Antisense Strand (5' to 3') SEQ ID NO Start position of antisense strand target region of human ATXN2 transcript ENST00000 608853.5 1 CGAAACGUGAAG AAAUAAUGA 1 UCAUUAUUUCUUCAC GUUUCGGC 2 793 2 CCUAAACGCAUGU CUUCAGAA 3 UUCUGAAGACAUGCG UUUAGGCA 4 1671 3 GAGAUGCUUUUA CUGACUCUA 5 UAGAGUCAGUAAAA GCAUCUCUU 6 886 4 AAACGUGAAGAA AUAAUGGAA 7 UUCCAUUAUUUCUUC ACGUUUCG 8 795 5 GCUCCUGUCUCUA CUAUGCCA 9 UGGCAUAGUAGAGAC AGGAGCUG 10 1653 6 UGGUUCUCCAGCU CCUGUCUA 11 UAGACAGGAGCUGGA GAACCAUG 12 1643 7 GCCUAAACGCAUG UCUUCAGA 13 UCUGAAGACAUGCGU UUAGGCAU 14 1670 8 UUAUCAGUCUCAG CAUCCUCA 15 UGAGGAUGCUGAGAC UGAUAAUG 16 3008 9 UCUCCAGCUCCUG UCUCUACA 17 UGUAGAGACAGGAGC UGGAGAAC 18 1674 10 GCUCAUGGUUCUC CAGCUCCA 19 UGGAGCUGGAGAACC AUGAGCAG 20 1638 11 CAGUCAGGUCCCA ACUCUCUA 21 UAGAGAGUUGGGACC UGACUGGU 22 1539 12 GAGUAGUUAAUG GAGGUGUUA 23 UAACACCUCCAUUAA CUACUCUU 24 1468 13 AGUCAGGUCCCAA CUCUCUUA 25 UAAGAGAGUUGGGA CCUGACUGG 26 1540 14 CCCACCUUCUCGC UACCAGUA 27 UACUGGUAGCGAGAA GGUGGGCG 28 1523 15 CAAGACAUAUAG AGCAGUACA 29 UGUACUGCUCUAUAU GUCUUGGC 30 2819

[00027] In some embodiments, the sense strand and the antisense strand of the ATXN2 RNAi agent described herein comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified intemucleotide linkages.

[00028] 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 antisense strand or to the intemucleotide linkages, which are the bonds between two nucleotides in the sense or 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’-0-M0E).

[00029] In some embodiments, one or more nucleotides of the sense strand and / or the antisense strand are independently modified nucleotides, which means 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, 2'-O-methyl modified nucleotide, or 2'-O-alkyl modified nucleotide. In some embodiments, each nucleotide of the sense strand and the antisense strand is independently a modified nucleotide, e.g., a 2'-fluoro modified nucleotide, 2'-O-methyl modified nucleotide, or 2'-O-alkyl modified nucleotide.

[00030] In some embodiments, the sense strand has four 2'-fluoro modified nucleotides, e.g., at positions 7, 9, 10, and 11 from the 5’ end of the sense strand. In some embodiments, nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro modified nucleotides, e.g., at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand. In some embodiments, nucleotides at positions other than positions 2, 6, 14 and 16 of the antisense strand are 2'-O-methyl modified nucleotides.

[00031] In some embodiments, the modified nucleotide is a 2'-O-alkyl modified nucleotide, which can serve as a delivery moiety. In some embodiments, the 2'-O-alkyl modified nucleotide is a 2’-O-hexadecyl uridine, 2’-0-hexadecyl cytidine, 2’-O-h exadecyl guanine, or 2’-O-hexadecyl adenosine. In some embodiments, 2’-O-hexadecyl uridine, 2’-O-hexadecyl cytidine, 2’-O-hexadecyl guanine, or 2’-O-hexadecyl adenosine is a modified nucleotide in the sense strand.

[00032] In some embodiments, the first nucleotide from the 5’ end of the antisense strand is a modified nucleotide that has a phosphate analog, e.g., 5’-vinylphosphonate (5’-VP).

[00033] In some embodiments, the sense strand has an abasic moiety or inverted abasic moiety, e.g., a moiety shown in Table 3, e.g., at position 9, 10 or 11.

[00034] In some embodiments, the sense strand and the antisense strand have one or more modified internucleotide linkages. In some embodiments, the modified internucleotide linkage is 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 has four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has four phosphorothioate linkages.

[00035] In a further aspect, provided herein are ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 40; (I) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60.

[00036] In some embodiments, provided herein are ATXN2 RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex, wherein the sense strand and the antisense strand have a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 46, (i) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 58; and (o) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 60. Table 2: ATXN2 RNAi Agents with Modifications ATXN2 RNAi Agent No. Strand Sequence from 5’ to 3’ end SEQ ID NO 16 S mC*mG*mAmAmAmCfGmUfGfAfAmGmAmAmA mUmAmAmU*mG*mA 31 AS PmU*fC*mAmUmUfAmUmUmUmCmUmUmCfAm CfGmUmUmUmCmG*mG*mC 32 17 S mC*mC*mUmAmAmAfCmGfCfAfUmGmUmCmUm UmCmAmG*mA*mA 33 AS PmU*fU*mCmUmGfAmAmGmAmCmAmUmGfCm GfUmUmUm AmGmG* mC *m A 34 18 S mG*mA*mGmAmUmGfCmUfUfUfUmAmCmUmG mAmCmUmC *mU*mA 35 AS PmU*fA*mGmAmGfUmCmAmGmUmAmAmAfAm GfCmAmUmCmUmC *mU*mU 36 19 S mA*mA*mAmCmGmUfGmAfAfGfAmAmAmUmA mAmUmGmG*mA*mA 37 AS PmU*fU*mCmCmAfUmUmAmUmUmUmCmUfUm CfAmCmGmUmUmU*mC*mG 38 20 S mG*mC*mUmCmCmUfGmUfCfUfCmUmAmCmUm AmUmGmC*mC*mA 39 AS PmU*fG*mGmCmAfUmAmGmUm AmGm AmGfAm CfAmGmGmAmGmC*mU*mG 40 21 S mU*mG*mGmUmUmCfUmCfCfAfGmCmUmCmCm UmGmUmCWmA 41 AS PmU*fA*mGmAmCfAmGmGmAmGmCmUmGfGm AfGmAmAmCmCmA*mU*mG 42 22 S mG*mC*mCmUmAmAfAmCfGfCfAmUmGmUmCm UmUmCmA*mG*mA 43 AS PmU*fC*mUmGmAfAmGmAmCmAmUmGmCfGm UfUmUmAmGmGmC *mA*mU 44 23 S mU*mU*mAmUmCmAfGmUfCfUfCmAmGmCmAm UmCmCmU*mC*mA 45 AS PmU*fG*mAmGmGfAmUmGmCmUmGmAmGfAm CfUmGmAmUmAmA*mU*mG 46 24 S mU*mC*mUmCmCmAfGmCfUfCfCmUmGmUmCm UmCmUmA*mC*mA 47 AS PmU*fG*mUmAmGfAmGmAmCmAmGmGmAfGm CfUmGmGmAmGmA*mA*mC 48 25 S mG*mC*mUmCmAmUfGmGfUfUfCmUmCmCmAm GmCmUmC*mC*mA 49 AS PmU*fG*mGm AmGfCmUmGmGm AmGm Am AfCm CfAmUmGmAmGmC*mA*mG 50 26 S mC*mA*mGmUmCmAfGmGfUfCfCmCmAmAmCm UmCmUmCWmA 51 AS PmU*fA*mGmAmGfAmGmUmUmGmGmGmAfCm CfUmGmAmCmUmG*mG*mU 52 27 S mG*mA*mGmUmAmGfUmUfAfAfUmGmGmAmG mGmUmGmU*mU*mA 53 AS PmU*fA*mAmCmAfCmCmUmCmCmAmUmUfAm AfCmUmAmCmUmC*mU*mU 54 28 S mA*mG*mUmCmAmGfGmUfCfCfCmAmAmCmUm CmUmCmUWmA 55 AS PmU*fA*m AmGm AfGmAmGmUmUmGmGmGfAm CfCmUmGmAmCmU*mG*mG 56 29 S mC*mC*mCmAmCmCfUmUfCfUfCmGmCmUmAm CmCmAmG*mU*mA 57 AS PmU*fA*mCmUmGfGrnUmAmGmCmGmAmGfAm AfGmGmUmGmGmG*mC*mG 58 30 S mC*mA*mAmGmAmCfAmUfAfUfAmGmAmGmCm AmGmUmA*mC*mA 59 AS PmU*fG*mUmAmCfUmGmCmUmCmUmAmUfAm UfGmUmCmUmUmG*mG*mC 60 Abbreviations - “m” indicates 2’-OMe; “f” indicates 2’-fluoro; indicates phosphorothioate linkage; “P” indicates 5’-phosphate; “S” means the sense strand; “AS” means the antisense strand. Table 3. Abasic and inverted abasic (iAb) moieties

[00037] 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. The delivery moiety can facilitate the entry of RNAi agent into the cells. In some embodiments, the delivery moiety is oc-tocopherol, cholesterol or palmitic acid (see Table 4). In some embodiments, the delivery moiety is a known delivery moiety for delivering RNAi agent into a cell. Placement of a delivery moiety on the RNAi agent needs to overcome potential inefficient loading of AGO2 (Argonaute-2), or other hindrance of the RNA-induced silencing complex (RISC) complex activity.

[00038] In some embodiments, the delivery moiety is conjugated to the 3’ end of the sense stand 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 a linker -delivery moiety pair of Table 6.

[00039] In some embodiments, the delivery moiety is conjugated to a nucleotide of the sense strand. In that case, the delivery moiety is a modified nucleotide located in the sense strand. In some embodiments, the modified nucleotide is 2’-O-hexadecyl uridine, 2’-O-hexadecyl cytidine, 2’-O-hexadecyl guanine, or 2’-O-hexadecyl adenosine (Table 4). Table 4. Delivery Moieties Delivery Moiety Structure a-Tocopherol 1 v I T JV) / — Palmitic Acid 2 0 Uhd (2’-O-hexadecyl uridine) Ghd (2’-O-hexadecyl guanine) Cholesterol Table 5. Linkers Linker Structure 1 Teg (tetraethylene glycol) linker sense strand-0' OH O' 0      0 OH Piperidinol-PEG linker Teg (tetraethylene glycol) linker PS sense strand-C\ HO' OH Piperidinol-PEG linker PS Table 6. Linker Delivery Moiety Pairs (LDP) LDP Linker Delivery Moiety 1 Teg (tetraethylene glycol) linker a-Tocopherol sense strand-Ox ZOH OH v Y Y Piperidinol-PEG linker a-Tocopherol 2 ho-\           r°\__x y P OH sense strand r—Z v Y Y JV) ^N^0"V / ---7 3 Piperidinol-PEG linker Palmitic Acid HO-X / \ u p v    o-\ l ) H / /   0          V-0    / <K y P OH sense strand 0 4 None Uhd I                 r'0 Y         i o i V      o A o 1        \ z— / \ / Yz o None Ahd 5 I.                     r'0 l       v° N          L ° \ y z I 6 None Chd 1. \       v° L ° i         J z'~^ z I NJ 7 None Ghd r'0 N         L ° N / < IX o Teg (tetraethylene glycol) linker Cholesterol

[00040] In a further aspect, provided herein are ATXN2 RNAi agents of Formula (I): R-L-D, wherein Risa double stranded RNA (dsRNA) comprising a sense stand and an antisense strand, wherein the sense strand and the antisense strand form a duplex; wherein D is a delivery means for delivering the dsRNA into a cell; and wherein Lisa linking means for linking the dsRNA to the delivery means, or optionally absent, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified intemucleotide linkages.

[00041] In some embodiments, provided herein are ATXN2 RNAi agents of Formula (I): R-L-D, wherein Risa dsRNA comprising a sense stand and an antisense strand, wherein the sense strand and the antisense strand form a duplex; wherein D is a delivery moiety; and wherein Lisa linker or optionally absent, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 1, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 2; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 4; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 6; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 8; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 10; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 12; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 14; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 16; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 18; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 20; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 22; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 24; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 26; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 28; and (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 30, wherein optionally one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides, and wherein optionally one or more intemucleotide linkages of the sense strand and the antisense strand are modified internucleotide linkages.

[00042] In some embodiments, the sense strand and the antisense strand in RNAi agents of Formula (I) comprise a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 32; (b) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 44; (h) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54; (m)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58; (o) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60.

[00043] In some embodiments, the sense strand and the antisense strand in RNAi agents of Formula (I) have a pair of nucleic acid sequences selected from the group consisting of: (a) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 32, (b) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 34; (c) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 36; (d) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 38; (e) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 40; (f) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 42; (g) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 44, (h) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 46; (i) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 48; (j) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 49, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 50; (k) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 51, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 52; (1) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 53, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 54; (m) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 55, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 56; (n) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 57, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 58; and (o) the sense strand consists of a first nucleic acid sequence of SEQ ID NO: 59, and the antisense strand consists of a second nucleic acid sequence of SEQ ID NO: 60.

[00044] 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 a nucleotide of the sense strand. In some embodiments, the delivery means or delivery moiety is palmitic acid, cholesterol, or a-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 of Table 5.

[00045] The sense strand and antisense strand of ATXN2 RNAi agent can be synthesized using any nucleic acid polymerization methods known in the art, for example, solid-phase synthesis by employing phosphoramidite chemistry methodology (e.g., Current Protocols in Nucleic Acid Chemistry, Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA), H-phosphonate, phosphortriester chemistry, or enzymatic synthesis. Automated commercial synthesizers can be used, for example, MerMade™ 12 from LGC Biosearch Technologies, or other synthesizers from BioAutomation or Applied Biosystems. Phosphorothioate linkages can be introduced using a sulfurizing reagent such as phenylacetyl disulfide or DDTT (((dimethylaminomethylidene) amino)-3H-l,2,4-dithiazaoline-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 or conjugated oligonucleotides

[00046] Purification methods can be used to exclude the unwanted impurities from the final oligonucleotide product. Commonly used purification techniques for single stranded oligonucleotides include reverse-phase ion pair high performance liquid chromatography (RP-IP-HPLC), capillary gel electrophoresis (CGE), anion exchange HPLC (AX-HPLC), and size exclusion chromatography (SEC). After purification, oligonucleotides can be analyzed by mass spectrometry and quantified by spectrophotometry at a wavelength of 260 nm. The sense strand and antisense strand can then be annealed to form a duplex.

[00047] In another aspect, provided herein are pharmaceutical compositions comprising an ATXN2 RNAi agent described herein and a pharmaceutically acceptable carrier. Also provided herein are pharmaceutical compositions comprising a means for reducing ATXN2 expression in a cell and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can also comprise one or more pharmaceutically acceptable excipient, diluent, or carrier. Pharmaceutical compositions can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 23rd edition (2020), A. Loyd et al., Academic Press).

[00048] In a further aspect, provided herein are methods of reducing ATXN2 expression in a cell (e.g., a neuron), such methods can 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 the cell (e.g., a neuron) using a method known in the art, e.g., transfection, electroporation, microinjection, or uptake by the cell via natural transport mechanisms.

[00049] In another aspect, provided herein are methods of reducing ATXN2 expression in a patient in need thereof, and such method comprises administering to the patient an effective amount of an ATXN2 RNAi agent or a pharmaceutical composition described herein.

[00050] In another aspect, provided herein are methods of treating an ATXN2-associated neurological disease in a patient in need thereof, and such method comprises administering to the patient an effective amount of the ATXN2 RNAi agent or a pharmaceutical composition described herein. Abnormal CAG trinucleotide expansion in ATXN2 gene is associated with spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). In another aspect, Ataxin-2 is known to be required for the toxicity mediated by abnormal aggregation of TAR DNA binding protein (TDP-43), which is believed to be the driver in 95% of sporadic and familial amyotrophic lateral sclerosis cases. Exemplary ATXN2-associated neurological diseases, includes, but are not limited to, 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), multiple system proteinopathy, Perry disease, and TDP-43 proteinopathy, e.g., neurological disease associated with abnormal TDP-43 aggregation (de Boer et al, 2021, J Neurol. Neurosurg. Psychiatry. 2020 Nov ll;92(l):86-95).

[00051] The ATXN2 RNAi agent can be administered to the patient intrathecally, intracerebroventricularly, or via intracistemal magna injection. In some embodiments, the ATXN2 RNAi agent is administered to the patient intrathecally, e.g., via a catheter or direct injection into the intrathecal space.

[00052] RNAi dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.

[00053] Dosage values may vary with the type and severity of the condition to be alleviated. It is further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[00054] In another aspect, provided herein are ATXN2 RNAi agents or pharmaceutical compositions comprising an ATXN2 RNAi agent for use in reducing ATXN2 expression. Also provided herein are ATXN2 RNAi agents or the pharmaceutical composition comprising an ATXN2 RNAi agent for use in a therapy. Also provided herein are ATXN2 RNAi agents or pharmaceutical compositions comprising an ATXN2 RNAi agent for use in the treatment of an ATXN2-associated neurological disease. Also provided herein are uses of ATXN2 RNAi agents in the manufacture of a medicament for the treatment of an ATXN2-associated neurological disease.

[00055] 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 plural unless otherwise indicated herein or clearly contradicted by the context.

[00056] As used herein, the term “alkyl” means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms. For example, “C1-C20 alkyl” means a radical having 1-20 carbon atoms in a linear or branched arrangement.

[00057] As used herein, “antisense strand” means a single-stranded oligonucleotide that is complementary to a region of a target sequence. Likewise, and as used herein, “sense strand” means a single-stranded oligonucleotide that is complementary to a region of an antisense strand.

[00058] As used herein, “complementary” means a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand, e.g., a hairpin) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. Complementary nucleotides can base pair in the Watson-Crick manner or in any other manner that allows for the formation of stable duplexes. Likewise, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.

[00059] As used herein, a “delivery moiety” refers to a chemical moiety that facilitates the entry of an oligonucleotide or RNAi agent into a cell. The delivery moiety can be lipid, cholesterol, vitamin E, carbohydrate, amino sugar, or polypeptide. In some embodiments, the delivery moiety is oc-tocopherol, cholesterol or palmitic acid.

[00060] As used herein, “duplex,” in reference to nucleic acids or oligonucleotides, means a structure formed through complementary base pairing of two antiparallel sequences of nucleotides (i.e., in opposite directions), whether formed by two separate nucleic acid strands or by a single, folded strand (e.g., via a hairpin).

[00061] An “effective amount” refers to an amount necessary (for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of a RNAi agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the RNAi agent to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the RNAi agent are outweighed by the therapeutically beneficial effects.

[00062] The term “knockdown” or “expression knockdown” refers to reduced mRNA or protein expression of a gene after treatment of a reagent, e g., a RNAi agent.

[00063] As used herein, “modified internucleotide linkage” means an internucleotide linkage having one or more chemical modifications when compared with a reference internucleotide linkage having a phosphodiester bond. A modified internucleotide linkage can be a non-naturally occurring linkage. In some embodiments, the modified internucleotide linkage is phosphorothioate linkage.

[00064] As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide. A modified nucleotide can have, for example, one or more chemical modification in its sugar, nucleobase, and / or phosphate group. Additionally, or alternatively, a modified nucleotide can have one or more chemical moieties conjugated to a corresponding reference nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro modified nucleotide, 2'-O-methyl modified nucleotide, or 2'-O-alkyl modified nucleotide. In some embodiments, the modified nucleotide has a phosphate analog, e.g., 5’-vinylphosphonate. In some embodiments, the modified nucleotide has an abasic moiety or inverted abasic moiety, e.g., a moiety shown in Table 3, e.g., at position 9, 10 or 11.

[00065] As used herein, “nucleotide” means an organic compound having a nucleoside (a nucleobase, e.g., adenine, cytosine, guanine, thymine, or uracil, and a pentose sugar, e g., ribose or 2'-deoxyribose) linked to a phosphate group. A “nucleotide” can serve as a monomeric unit of nucleic acid polymers such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[00066] As used herein, “oligonucleotide” means a polymer of linked nucleotides, each of which can be modified or unmodified. An oligonucleotide is typically less than about 100 nucleotides in length.

[00067] As used herein, “overhang” means the unpaired nucleotide or nucleotides that protrude from the duplex structure of a double stranded oligonucleotide. An overhang may include one or more unpaired nucleotides extending from a duplex region at the 5’ terminus or 3’ terminus of a double stranded oligonucleotide. The overhang can be a 3’ or 5’ overhang on the antisense strand or sense strand of a double stranded oligonucleotide.

[00068] The term “patient”, as used herein, refers to a human patient.

[00069] As used herein, “phosphate analog” means a chemical moiety that mimics the electrostatic and / or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5’ terminal nucleotide of an oligonucleotide in place of a 5’-phosphate, which is often susceptible to enzymatic removal. A 5’ phosphate analog can include a phosphatase-resistant linkage. Examples of phosphate analogs include 5’ methylene phosphonate (5’-MP) and 5’-(E)-vinylphosphonate (5’-VP). In some embodiments, the phosphate analog is 5’-VP.

[00070] The term “% sequence identity” or “percentage sequence identity” with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical with the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs, for example, those described in Current Protocols in Molecular Biology (Ausubel et al., eds., 1987, Supp. 30, section 7.7.18, Table 7.7.1), and including BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), Clustal W2.0 or Clustal X2.0 software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the nucleic acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical nucleotide, nucleoside, or nucleobase occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence.

[00071] As used herein, “RNAi,” “RNAi agent,” “iRNA,” “iRNA agent,” and “RNA interference agent” means an agent that mediates sequence-specific degradation of a target mRNAby RNA interference, e g., via 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., a double stranded RNA). In some embodiments, the sense strand has a delivery moiety conjugated to the 3’ end of the sense strand or a nucleotide of the sense strand.

[00072] As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through 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).

[00073] As used herein, “ATXN2” (also known as ATX2, SCA2, TNRC13) refers to a human ATXN2 mRNA transcript. The nucleotide sequence of human ATXN2 mRNA isoform 1 can be found at NM 002973.4: 1 AGAGCTCGCC TCCCTCCGCC TCAGACTGTT 61 TTCGGCCCGG CTCCCGGCGG CTCCTTGGTC 121 TCCTTCTCCC CCTCGCCAGC CCGGGCGCCC 181 TCGGCGCCCG CGCGTCCCCG CCGCGTTCCG 241 GTCCCCGCCC GGCGTGCGAG CCGGTGTATG 301 AGCAGCAGCA GCAGCAGCAG CAGCAGCAGC 361 AGCAGCCGCC GCCCGCGGCT GCCAATGTCC 421 CGCCCGCCGC CGCGCCTTCG CCGTCCTCGT 481 CCTCCTCGGT GGTCGCGGCG ACCTCCGGCG 541 ACAGTAACAA AGGACTGCCT CAGTCTACGA 601 GGATGGTTCA TATACTTACA TCAGTTGTTG 661 GAGGTATATA TGAAGGAGTT TTTAAAACTT 721 CCGCACATGA GAAAAGTACA GAATCCAGTT 781 GTATTTTGTT CAAATGTTCA GACTTTGTTG 841 ATGCAAAAAG AGATGCTTTT ACTGACTCTG 901 AAGAGAAGGA CCTGGAGCCC TGGGATGCAG TTGGTAGCAA CGGCAACGGC GGCGGCGCGT TCGGCGGGCC TCCCCGCCCC TTCGTCGTCC CTCCGGCCGC GCCAACCCGC GCCTCCCCGC GCGTCTCCTT GGCGCGCCCG GCTCCCGGCT GGCCCCTCAC CATGTCGCTG AAGCCCCAGC AGCAGCAACA GCAGCAGCAG CAGCAGCAGC GCAAGCCCGG CGGCAGCGGC CTTCTAGCGT CCTCGGTCTC CTCGTCCTCG GCCACGGCTC GCGGGAGGCC CGGCCTGGGC AGAGGTCGAA TTTCTTTTGA TGGAATCTAT GCAAATATGA GCTCCAAATG TGAAGTACAA GTGAAAAATG ACAGTCCGAA GTGTGATTTG GTACTTGATG CGGGGCCGAA ACGTGAAGAA ATAATGGAGA TGGTACAGTT TAAAGATATG GACTCCAGTT CTATCAGTGC TAAAGTGAAT GGCGAACACA GTGAACTCAC AGCCAATGAG GAACTTGAGG CTTTGGAAAA TGACGTATCT AATGGATGGG ATCCCAATGA TATGTTTCGA TATAATGAAG AAAATTATGG TGTAGTGTCT ACGTATGATA GCAGTTTATC TTCGTATACA GTGCCCTTAG AAAGAGATAA CTCAGAAGAA TTTTTAAAAC GGGAAGCAAG GGCAAACCAG TTAGCAGAAG AAATTGAGTC AAGTGCCCAG TACAAAGCTC GAGTGGCCCT GGAAAATGAT GATAGGAGTG AGGAAGAAAA ATACACAGCA GTTCAGAGAA ATTCCAGTGA ACGTGAGGGG CACAGCATAA ACACTAGGGA AAATAAATAT ATTCCTCCTG GACAAAGAAA TAGAGAAGTC ATATCCTGGG GAAGTGGGAG ACAGAATTCA CCGCGTATGG GCCAGCCTGG ATCGGGCTCC ATGCCATCAA GATCCACTTC TCACACTTCA GATTTCAACC CGAATTCTGG TTCAGACCAA AGAGTAGTTA ATGGAGGTGT TCCCTGGCCA TCGCCTTGCC CATCTCCTTC CTCTCGCCCA CCTTCTCGCT ACCAGTCAGG TCCCAACTCT CTTCCACCTC GGGCAGCCAC CCCTACACGG CCGCCCTCCA GGCCCCCCTC GCGGCCATCC AGACCCCCGT CTCACCCCTC TGCTCATGGT TCTCCAGCTC CTGTCTCTAC TATGCCTAAA CGCATGTCTT CAGAAGGGCC TCCAAGGATG TCCCCAAAGG CCCAGCGACA TCCTCGAAAT CACAGAGTTT CTGCTGGGAG GGGTTCCATA TCCAGTGGCC TAGAATTTGT ATCCCACAAC CCACCCAGTG AAGCAGCTAC TCCTCCAGTA GCAAGGACCA GTCCCTCGGG GGGAACGTGG TCATCAGTGG TCAGTGGGGT TCCAAGATTA TCCCCTAAAA CTCATAGACC CAGGTCTCCC AGACAGAACA GTATTGGAAA TACCCCCAGT GGGCCAGTTC TTGCTTCTCC CCAAGCTGGT ATTATTCCAA CTGAAGCTGT TGCCATGCCT ATTCCAGCTG CATCTCCTAC GCCTGCTAGT CCTGCATCGA ACAGAGCTGT TACCCCTTCT AGTGAGGCTA AAGATTCCAG GCTTCAAGAT CAGAGGCAGA ACTCTCCTGC AGGGAATAAA GAAAATATTA AACCCAATGA AACATCACCT AGCTTCTCAA AAGCTGAAAA CAAAGGTATA TCACCAGTTG TTTCTGAACA TAGAAAACAG ATTGATGATT TAAAGAAATT TAAGAATGAT TTTAGGTTAC AGCCAAGTTC TACTTCTGAA TCTATGGATC AACTACTAAA CAAAAATAGA GAGGGAGAAA AATCAAGAGA TTTGATCAAA GACAAAATTG AACCAAGTGC TAAGGATTCT TTCATTGAAA ATAGCAGCAG CAACTGTACC AGTGGCAGCA GCAAGCCGAA TAGCCCCAGC ATTTCCCCTT CAATACTTAG TAACACGGAG CACAAGAGGG GACCTGAGGT CACTTCCCAA GGGGTTCAGA CTTCCAGCCC AGCATGTAAA CAAGAGAAAG ACGATAAGGA AGAGAAGAAA GACGCAGCTG AGCAAGTTAG GAAATCAACA TTGAATCCCA ATGCAAAGGA GTTCAACCCA CGTTCCTTCT CTCAGCCAAA GCCTTCTACT ACCCCAACTT CACCTCGGCC TCAAGCACAA CCTAGCCCAT CTATGGTGGG TCATCAACAG CCAACTCCAG TTTATACTCA GCCTGTTTGT TTTGCACCAA ATATGATGTA TCCAGTCCCA GTGAGCCCAG GCGTGCAACC TTTATACCCA ATACCTATGA CGCCCATGCC AGTGAATCAA GCCAAGACAT ATAGAGCAGT ACCAAATATG CCCCAACAGC GGCAAGACCA GCATCATCAG AGTGCCATGA TGCACCCAGC GTCAGCAGCG GGCCCACCGA TTGCAGCCAC CCCACCAGCT TACTCCACGC AATATGTTGC CTACAGTCCT CAGCAGTTCC CAAATCAGCC CCTTGTTCAG CATGTGCCAC ATTATCAGTC TCAGCATCCT CATGTCTATA GTCCTGTAAT ACAGGGTAAT GCTAGAATGA TGGCACCACC AACACACGCC CAGCCTGGTT TAGTATCTTC TTCAGCAACT CAGTACGGGG CTCATGAGCA GACGCATGCG ATGTATGCAT GTCCCAAATT ACCATACAAC AAGGAGACAA GCCCTTCTTT CTACTTTGCC ATTTCCACGG GCTCCCTTGC TCAGCAGTAT GCGCACCCTA ACGCTACCCT GCACCCACAT ACTCCACACC CTCAGCCTTC AGCTACCCCC ACTGGACAGC AGCAAAGCCA ACATGGTGGA AGTCATCCTG CACCCAGTCC TGTTCAGCAC CATCAGCACC AGGCCGCCCA GGCTCTCCAT CTGGCCAGTC CACAGCAGCA GTCAGCCATT TACCACGCGG GGCTTGCGCC AACTCCACCC TCCATGACAC CTGCCTCCAA CACGCAGTCG CCACAGAATA GTTTCCCAGC AGCACAACAG ACTGTCTTTA CGATCCATCC TTCTCACGTT CAGCCGGCGT ATACCAACCC ACCCCACATG GCCCACGTAC CTCAGGCTCA TGTACAGTCA GGAATGGTTC CTTCTCATCC AACTGCCCAT GCGCCAATGA TGCTAATGAC GACACAGCCA CCCGGCGGTC CCCAGGCCGC CCTCGCTCAA AGTGCACTAC AGCCCATTCC AGTCTCGACA ACAGCGCATT TCCCCTATAT GACGCACCCT TCAGTACAAG CCCACCACCA ACAGCAGTTG TAAGGCTGCC CTGGAGGAAC CGAAAGGCCA AATTCCCTCC TCCCTTCTAC TGCTTCTACC AACTGGAAGC ACAGAAAACT AGAATTTCAT TTATTTTGTT TTTAAAATAT ATATGTTGAT TTCTTGTAAC ATCCAATAGG AATGCTAACA GTTCACTTGC AGTGGAAGAT ACTTGGACCG AGTAGAGGCA TTTAGGAACT TGGGGGCTAT TCCATAATTC CATATGCTGT TTCAGAGTCC CGCAGGTACC CCAGCTCTGC TTGCCGAAAC TGGAAGTTAT TTATTTTTTA ATAACCCTTG AAAGTCATGA ACACATCAGC TAGCAAAAGA AGTAACAAGA GTGATTCTTG CTGCTATTAC TGCTAAAAAA AAAAAAAAAA AAAAATCAAG ACTTGGAACG CCCTTTTACT AAACTTGACA AAGTTTCAGT AAATTCTTAC CGTCAAACTG ACGGATTATT ATTTATAAAT CAAGTTTGAT GAGGTGATCA CTGTCTACAG TGGTTCAACT TTTAAGTTAA GGGAAAAACT TTTACTTTGT AGATAATATA AAATAAAAAC TTAAAAAAAA TTTAAAAAAT 4321 AAAAAAAGTT TTAAAAACTG A (SEQ ID NO: 61).

[00074] The corresponding amino acid sequence of human ATXN2 protein isoform 1 can be found at NP_002964.4: 1 MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS 61 SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSWGSKC 121 EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVWQF 181 KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND 241 MFRYNEENYG WSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL 301 ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG 361 SGSMPSRSTS HTSDFNPNSG SDQRWNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT 421 PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR 481 GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSWSGV PRLSPKTHRP RSPRQNSIGN 541 TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA 601 GNKENIKPNE TSPSFSKAEN KGISPWSEH 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).

[00075] The human ATXN2 isoform 2 mRNA sequence can be found at NM_001310121.1 (SEQ ID NO: 63); and the corresponding protein sequence can be found atNP_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 C ACC ACC A AC 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 VWQFKDMDS SYAKRDAFTD SAISAKVNGE HKEKDLEPWD AGELTANEEL 121 EALENDVSNG WDPNDMFRYN EENYGWSTY 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 WSGVPRLSP 421 KTHRPRSPRQ NSIGNTPSGP VLASPQAGII PTEAVAMPIP AASPTPASPA SNRAVTPSSE 481 AKDSRLQDQR QNSPAGNKEN IKPNETSPSF SKAENKGISP WSEHRKQID 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)

[00076] The human ATXN2 isoform 3 mRNA sequence can be found at NM_001310123.1 (SEQ ID NO: 65); and the corresponding protein sequence can be found at 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 TMPKRMSSEGPPRMSPKAQRHPRNHRVSAGRGSISSGLEF 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 1QGNARMMAP PTHAQPGLVS SSATQYGAHE QTHAMYVSTG SLAQQYAHPN ATLHPHTPHP 841 QPSATPTGQQ QSQHGGSHPA PSPVQHHQHQ AAQALHLASP QQQSAIYHAG LAPTPPSMTP 901 ASNTQSPQNS FPAAQQTVFT IHPSHVQPAY TNPPHMAHVP QAHVQSGMVP SHPTAHAPMM 961 LMTTQPPGGP QAALAQSALQ PIPVSTTAHF PYMTHPSVQAHHQQQL (SEQ ID NO: 66)

[00077] The human ATXN2 isoform 4 mRNA sequence can be found at NM_001372574.1 (SEQ ID NO: 67); the corresponding protein sequence can be found at 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 GIYANMRMVHILTSWGSKC 121 EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF 181 KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND 241 MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEE1ES SAQYKARVAL 301 ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVIS WGSGR QNSPRMGQPG 361 SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT 421 PTRPPSRPPS RPSRPPSHPS AHGSPAPVSTMPKRMSSEGPPRMSPKAQRHPRNHRVSAGR 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 PAAQQTVFTIHPSHVQPAYT 1081 NPPHMAHVPQ AHVQSGMVPS HPTAHAPMML MTTQPPGGPQ AALAQSALQP IPVSTTAHFP 1141 YMTHPSVQAH HQQQL (SEQ ID NO: 68)

[00078] Another human ATXN2 isoform (that includes UTRs) mRNA sequence (SEQ ID NO: 69) and the corresponding protein sequence (SEQ ID NO: 70) can be found at ENST00000608853.5. ATGTCGCTGAAGCCCCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAGCAGCAGC AGCAGCAGCAGCAGCAGCCGCCGCCCGCGGCTGCCAATGTCCGCAAGCCCGGCGGCAGCGGCCTTCT AGCGTCGCCCGCCGCCGCGCCTTCGCCGTCCTCGTCCTCGGTCTCCTCGTCCTCGGCCACGGCTCCCTC CTCGGTGGTCGCGGCGACCTCCGGCGGCGGGAGGCCCGGCCTGGGCAGAGGTCGAAACAGTAACAAA GGACTGCCTCAGTCTACGATTTCTTTTGATGGAATCTATGCAAATATGAGGATGGTTCATATACTTACA TCAGTTGTTGGCTCCAAATGTGAAGTACAAGTGAAAAATGGAGGTATATATGAAGGAGTTTTTAAAAC TTACAGTCCGAAGTGTGATTTGGTACTTGATGCCGCACATGAGAAAAGTACAGAATCCAGTTCGGGGC CGAAACGTGAAGAAATAATGGAGAGTATTTTGTTCAAATGTTCAGACTTTGTTGTGGTACAGTTTAAA GATATGGACTCCAGTTATGCAAAAAGAGATGCTTT1ACTGACTCTGCTATCAGTGCTAAAGTGAATGG CGAACACAAAGAGAAGGACCTGGAGCCCTGGGATGCAGGTGAACTCACAGCCAATGAGGAACTTGAG GCTTTGGAAAATGACGTATCTAATGGATGGGATCCCAATGATATGTTTCGATATAATGAAGAAAATTA TGGTGTAGTGTCTACGTATGATAGCAGITTATCTTCGTATACAGTGCCCTTAGAAAGAGATAACTCAGA AGAATTTTTAAAACGGGAAGCAAGGGCAAACCAGTTAGCAGAAGAAATTGAGTCAAGTGCCCAGTAC AAAGCTCGAGTGGCCCTGGAAAATGATGATAGGAGTGAGGAAGAAAAATACACAGCAGTTCAGAGAA ATTCCAGTGAACGTGAGGGGCACAGCATAAACACTAGGGAAAATAAATATATTCCTCCTGGACAAAG AAATAGAGAAGTCATATCCTGGGGAAGTGGGAGACAGAATTCACCGCGTATGGGCCAGCCTGGATCG GGCTCCATGCCATCAAGATCCACTTCTCACACTTCAGATTTCAACCCGAATTCTGGTTCAGACCAAAGA GTAGTTAATGGAGGTGTTCCCTGGCCATCGC.CTTGCCCATCTCCTTCCTCTCGCCCACCTTCTCGCTACC AGTCAGGTCCCAACTCTCTTCCACCTCGGGCAGCC.ACCCCTACACGGCCGC.CCTCCAGGCCCCCCTCGC GGCCATCCAGACCCCCGTCTCACCCCTCTGCTCATGGTTCTCCAGCTCCTGTCTCTACTATGCCTAAAC GC.ATGTCTTCAGAAGGGCCTCCAAGGATGTCCCCAAAGGCCCAGCGACATCCTCGAAATCACAGAGTT TCTGCTGGGAGGGGTTCCATATCCAGTGGCCTAGAATTTGTATCC.CACAACCCACCCAGTGAAGC.AGC. TACTCCTCCAGTAGCAAGGACCAGTCCCTCGGGGGGAACGTGGTCATCAGTGGTCAGTGGGGTTCCAA GATTATCCCCTAAAACTCATAGACCCAGGTCTCCCAGACAGAACAGTATTGGAAATACCCCCAGTGGG CCAGTTCTTGCTTCTCCCCAAGCTGGTATTATTCCAACTGAAGCTGTTGCCATGCCTATTCCAGCTGCAT CTCCTACGCCTGCTAGTCCTGCATCGAACAGAGCTGTTACCCCTTCTAGTGAGGCTAAAGATTCCAGGC TTCAAGATCAGAGGCAGAACTCTCCTGCAGGGAATAAAGAAAATATTAAACCCAATGAAACATCACC TAGCTTCTCAAAAGCTGAAAACAAAGGTATATCACCAGTTGTTTCTGAACATAGAAAACAGATTGATG ATTTAAAGAAATTTAAGAATGATTTTAGGTTACAGCCAAGTTCTACTTCTGAATCTATGGATCAACTAC TAAACAAAAATAGAGAGGGAGAAAAATCAAGAGATTTGATCAAAGACAAAATTGAACCAAGTGCTAA GGATTCTTTCATTGAAAATAGCAGCAGCAACTGTACCAGTGGCAGCAGCAAGCCGAATAGCCCCAGCA TTTCCCCTTCAATACTTAGTAACACGGAGCACAAGAGGGGACCTGAGGTCACTTCCCAAGGGGTTCAG ACTTCCAGCCCAGCATGTAAACAAGAGAAAGACGATAAGGAAGAGAAGAAAGACGCAGCTGAGCAA GTTAGGAAATCAACATTGAATCCCAATGCAAAGGAGTTCAACCCACGTTCCTTCTCTCAGCCAAAGCC TTCTACTACCCCAACTTCACCTCGGCCTCAAGCACAACCTAGCCCATCTATGGTGGGTCATCAACAGCC AACTCCAGTTTATACTCAGCCTGTTTGTTTTGCACCAAATATGATGTATCCAGTCCCAGTGAGCCCAGG CGTGCAACCTTTATACrC.AATACCTATGACGCCCATGCCAGTGAATCAAGCCAAGACATATAGAGCAG TACCAAATATGCCCCAACAGCGGCAAGACCAGCATCATCAGAGTGCCATGATGCACCCAGCGTCAGC AGCGGGCCCACCGATTGCAGCCACCCCACCAGCTTACTCCACGCAATATGTTGCCTACAGTCCTCAGC AGTTCCCAAATCAGCCCCTTGTTCAGCATGTGCCACATTATCAGTCTCAGCATCCTCATGTCTATAGTC CTGTAATACAGGGTAATGCTAGAATGATGGCACCACCAACACACGCCCAGCCTGGTTTAGTATCTTCT TCAGCAACTCAGTACGGGGCTCATGAGCAGACGCATGCGATGTATGCATGTCCCAAATTACCATACAA CAAGGAGACAAGCCCTTCTTTCTACTTTGCCA'nTCCACGGGCTCCCTTGCTCAGCAGTATGCGCACCC TAACGCTACCCTGCACCCACATACTCCACACCCTCAGCCTTCAGCTACCCCCACTGGACAGCAGCAAA GCCAACATGGTGGAAGTCATCCTGCACCCAGTCCTGTTCAGCACCATCAGCACCAGGCCGCCCAGGCT CTCCATCrGGCCAGTCCACAGCAGCAGTCAGCCATTTACCACGCGGGGCTTGCGCCAACTCCACCCTC CATGACACCTGCCTCCAACACGCAGTCGCCACAGAATAGTTTCCCAGCAGCACAACAGACTGTCTTTA CGATCCATCCTTCTCACGTTCAGCCGGCGTATACCAACCCACCCCACATGGCCCACGTACCTCAGGCTC ATGTACAGTCAGGAATGGTTCCTTCTCATCCAACTGCCCATGCGCCAATGATGCTAATGACGACACAG CCACCCGGCGGTCCCCAGGCCGCCCTCGCTCAAAGTGCACTACAGCCCATTCCAGTCTCGACAACAGC GCATTTCCCCTATATGACGCACCCTTCAGTACAAGCCCACCACCAACAGCAGTTGTAA (SEQ ID NO: 69) MSLKPQQQQQQQQQQQQQQQQQQQQQQQPPPAAANVRKPGGSGLLASPAAAPSPSSSSVSSSSATAPSSV VAATSGGGRPGLGRGRNSNKGLPQSTISFDGIYANMRMVHILTSVVGSKCEVQVKNGGIYEGVFKTYSPKC DLVLDAAHEKSTESSSGPKREE1MESILFKCSDFWVQFKDMDSSYAKRDAFTDSAISAKVNGEHKEKDLEP WDAGELTANEELEALENDVSNGWDPNDMFRYNEENYGWSTYDSSLSSYTVPLERDNSEEFLKREARAN QLAEE1ESSAQYKARVALENDDRSEEEKYTAVQRNSSEREGHSINTRENKYIPPGQRNREVISWGSGRQNSP RMGQPGSGSMPSRSTSHTSDFNPNSGSDQRWNGGVPWPSPCPSPSSRPPSRYQSGPNSLPPRAATPTRPPSR PPSRPSRPPSHPSAHGSPAPVSTMPKRMSSEGPPRMSPKAQRHPRNHRVSAGRGSISSGLEFVSHNPPSEAAT PPVARTSPSGGTWSSVVSGVPRLSPKTHRPRSPRQNSIGNTPSGPVLASPQAGI1PTEAVAMPIPAASPTPASP ASNRAVTPSSEAKDSRLQDQRQNSPAGNKENTKPNETSPSFSKAENKGISPVVSEHRKQTODLKKFKNDFRL QPSSTSESMDQLLNKNREGEKSRDLKDKIEPSAKDSFIENSSSNCTSGSSKPNSPSISPSILSNTHIKRGPEVT SQGVQTSSPACKQEKDDKEEKKDAAEQVRKSTLNPNAKEFNPRSFSQPKPSTTPTSPRPQAQPSPSMVGHQ QPTPVYTQPVCFAPNMMYPWVSPGVQPLYPIPMTPMPVNQAKTYRAVPNMPQQRQDQHHQSAMMHPAS AAGPPIAATPPAYSTQYVAYSPQQFPNQPLVQHVPHYQSQHPHVYSPVIQGNARMMAPP'niAQPGLVSSSA TQYGAHEQTHAMYACPKLPYNKETSPSFYFAISTGSLAQQYAHPNATLHPHTPHPQPSATPTGQQQSQHGG SHPAPSPVQHHQHQAAQALHLASKXJQSAIYHAGLAPTPPSMTPASNTQSPQNSFPAAQQTVFnHPSHVQP AYTNPPHMAHVPQAIWQSGMVPSHPTAHAPMMLMTTQPPGGPQAALAQSALQPIPVSTTAHFPYMTHPS VQAHHQQQL (SEQ ID NO: 70).

[00079] As used herein, “ATXN2-associated neurological disease” means a neurological disease associated with abnormal ATXN2 expression, activity, or function, CAG repeat or polyglutamine expansion in ATXN2 gene, or abnormal TDP-43 aggregation.

[00080] As used herein, “subject” means a mammal, including cat, dog, mouse, rat, chimpanzee, ape, monkey, and human. Preferably the subject is a human.

[00081] As used herein, “treatment” or “treating” refers to all processes wherein there may be a slowing, controlling, delaying, or stopping of the progression of the disorders or disease disclosed herein, or ameliorating disorder or disease symptoms, but does not necessarily indicate a total elimination of all disorder or disease symptoms. Treatment includes administration of a protein or nucleic acid or vector or composition for treatment of a disease or condition in a patient, particularly in a human. EXAMPLES Example 1. Synthesis of Linker - Delivery Moiety Pairs

[00082] 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; “DMTC1” 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-l -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; “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” phosphate-buffered saline; “PEG” refers to polyethylene glycol; “PVDF” refers to poly vinylidene fluoride; “RP” refers to reverse phase; “RPM” refers to revolutions per minute; “siRNA” refers to small interfering ribonucleic acid; “TEA” refers to tri ethyl amine; “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. Scheme 1 4

[00083] Scheme 1, step A depicts the coupling of compounds (1) and (2) using an appropriate base such as DMAP in a suitable solvent such as DCM to give compound (3). Step B shows the coupling of compound (3) with l-amino-3,6,9,12-tetraoxapentadecan-15-oic acid in the presence of a base such as potassium carbonate and in a solvent system such as water and THF to give compound (4). 7

[00084] Scheme 2, step A depicts a Mitsunobu reaction between compound (5) and tert-butyl l-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate using triphenyl phosphene and diisopropyl azodicarboxylate in a solvent such as THF to give compound (6). Step B shows the acidic deprotection of compound (6) using an acid such as HC1 in a solvent such as 1,4-dioxane to give compound (7).

[00085] Scheme 3, step A depicts the protection of compound (8) using DMTC1 with a suitable base such as DIEA in a solvent such as DCM to give compound (9). Step B shows an amide coupling between compound (9) and piperidin-4-yl methanol using HBTU and HOBt with TMP in a solvent such as DCM to give compound (10). The deprotection of compound (10) with 20% piperidine in DMF to give compound (11) is shown in step C. Step C 14

[00086] Scheme 4, step A depicts an 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). One skilled in the art will recognize the variety of conditions which could be used to perform this amide coupling. Step B shows the coupling of compound (12) to succinic anhydride using a base such as TEA with catalytic DMAP in a solvent such as DCM to give compound (13). Step C shows the amide coupling of compound (13) to amino LCAA CPG using HBTU with a base such as DIEA in a solvent such as ACN followed by a multi step work up to give compound (14). Preparation 1 2,5-Dioxopyrrolidin-l-yl palmitate

[00087] Added palmitic acid (2.00 g, 7.80 mmol) to a solution of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.79 g, 9.36 mmol) and DMAP (0.19 g, 1.56 mmol) in DCM (31 mL). Stirred the mixture at ambient temperature for 5 minutes then added N-hydroxysuccinimide (0.99 g, 8.58 mmol) and stirred at ambient temperature for 18 hours. Concentrated in vacuo and purified the resulting crude material via silica gel flash chromatography eluting with a gradient of 0-80% EtOAc in hexanes to give the title compound as a white solid (2.65 g, 96%). 'H NMR (DMSO-4) 8 2.81 (s, 4H), 2.66 (t, 2H), 1.62 (m, 2H), 1.25 (br s, 24H), 0.87 (t, 3H). Preparation 2 3-[2-[2-[2-[2-(Hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid

[00088] Added l-amino-3,6,9,12-tetraoxapentadecan-15-oic acid (0.14 g, 0.53 mmol) to a solution of potassium carbonate (0.14 g, 1.00 mmol) in THF (1 mL) and water (2 mL). Added 2,5-dioxopyrrolidin-l-yl palmitate (0.18 g, 0.51 mmol) and stirred the reaction at ambient temperature for 18 hours. Quenched the reaction with water (30 mL) and adjusted the pH to ~3 with IN aqueous HC1. A precipitate formed and was collected by vacuum fdtration to give the title compound as a white solid (0.19 g, 74%). ES / MS m / z 504 (M+H). 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

[00089] Combined (2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-ol (3.00 g, 6.90 mmol), tert-butyl l-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate (2.50 g, 7.60 mmol), and triphenylphosphine (2.00 g, 7.60 mmol) in THF (28.0 mL) and added diisopropyl azodicarboxylate (1.50 mL, 7.60 mmol) dropwise over 5 minutes. Heated the mixture at 60 °C for 16 hours. Cooled the mixture to ambient temperature, added silica gel, and concentrated in vacuo to give an off-white solid. Purified the mixture via silica gel flash chromatography, eluting with 0- 40% EtOAc / hexanes, to give the title compound as an oil (3.33 g, 66%). 'H NMR (CDCh): 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). 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

[00090] Dissolved 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) in 4M HC1 in dioxane (22.6 mL, 90.6 mmol) and stirred for 16 hours at ambient temperature. Removed the solvent under reduced pressure to give the title compound as an off-white solid (3.08 g, 100%). ES / MS m / z 678.0 (M-H). Preparation 5 (2S)-3-[Bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H-fluoren-9ylmethoxy carbonylamino) propanoic acid

[00091] Added DIEA (64 mL, 0.366 mol) to a stirring solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-hydroxy-propanoic acid (40 g, 0.122 mol) in dry DCM (400 mL) at 0 °C under an inert atmosphere. To this mixture, slowly added a solution of DMTC1 (49.6 g, 0.146 mol) in DCM (200 mL). Allowed to warm to ambient temperature and stirred for 16 hours. After this time, diluted the reaction mixture with water and extracted with DCM. Dried organics over anhydrous sodium sulphate, fdtered, and concentrated in vacuo. Washed the crude residue with 10% EtOAc / hexane and dried under vacuum to give the crude title compound as a pale brown solid (62 g, crude). TLC: 5% MeOH / CH2C12 (Rf. 0.5) UV, 254 nM. Preparation 6 9H-Fluoren-9-ylmethyl N-[(lS)-l-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4 -(hydroxymethyl)-1 -piperidyl]-2-oxo-ethyl]carbamate

[00092] Slowly added HBTU (78.3 g, 0.206 mol), HOBt (27.9 g, 0.206 mol), and piperidin-4-yl methanol (15.4 g, 0.134 mol) followed by TMP (15 mL, 0.113 mol) to a stirring solution of (2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-(9H-fluoren-9-ylmethoxy carbonylamino) propanoic acid (62 g, 0.103 mol) in DCM (750 mL) at 0 °C under inert atmosphere. Allowed the resulting reaction mixture to reach ambient temperature and stirred for 4 hours. After this time, diluted the mixture with water and extracted with DCM. Dried the organics over anhydrous sodium sulphate, fdtered, and concentrated in vacuo. Purified the resulting residue via 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). *H NMR. (DMSO-de) 8 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). Preparation 7 (2S)-2-Amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-l-[4-(hydroxymethyl)-l-piperi dyl]propan-1 -one

[00093] Slowly added a solution of 20% piperidine in DMF (400 mL) to 9H-fluoren-9-ylmethyl N-[(lS)-l-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4 -(hydroxymethyl)-1-piperidyl]-2-oxo-ethyl]carbamate (40 g, 0.055 mol) at 0 °C under inert atmosphere. Allowed the mixture to warm to ambient temperature and stirred for 1 hour. After this time, diluted the mixture with water and extracted with EtOAc. Dried organics over anhydrous sodium sulphate, filtered, and concentrated in vacuo. Purified the resulting residue via silica gel flash chromatography eluting with 1-8% MeOFI / DCM to give the title compound as an off-white solid (13 g, 47%). ES / MS m / z 1009.5 (2M+H). Preparation 8 N-[2-[2-[2-[2-[3-[[(lS)-l-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-l-piperidyl]-2-oxo-ethyl]amino]-3-oxo-propoxy ]ethoxy ] ethoxy ] ethoxy ] ethyl ]hexadecanamide

[00094] Combined 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) and stirred at ambient temperature for 10 minutes. Added (2S)-2-amino-3-[bis(4- methoxyphenyl)-phenyl-methoxy]-l-[4-(hydroxymethyl)-l-piperidyl]propan-l-one (546 mg, 1.08 mmol) to the mixture and stirred at ambient temperature for 16 hours. Partitioned the mixture between EtOAc and saturated aqueous sodium chloride solution. Separated the layers and washed the organics with saturated aqueous sodium chloride solution. Dried the organics over sodium sulfate, fdtered, and concentrated in vacuo. Purified the resulting residue by silica gel flash chromatography eluting with 0-10% MeOH / DCM to give the title compound as an oil (327 mg, 34%). 1HNMR (DMSO-d6) 8.21 (d, J= 8.5 Hz, 1H), 7.80 (t, J= 5.6 Hz, 1H), 7.37-7.28 (m, 4H), 7.23-7.20 (m, 5H), 6.88 (d, J= 8.3 Hz, 4H), 5.06-5.02 (m, 1H), 4.51-4.49 (m, 1H), 4.454.40 (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), 0.880.82 (m, 5H) Preparation 9 4-[[l-[(2S)-3-[Bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid

[00095] Combined N-[2-[2-[2-[2-[3-[[(lS)-l-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-l -piperi dyl]-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 pL, 1.62 mmol), and succinic anhydride (64.7 mg, 0.646 mmol) in DCM (6.46 mL) and stirred the mixture for 16 hours at ambient temperature. Purified the mixture directly via silica gel flash chromatography, eluting with 0% to 40% MeOH / DCM, to give the title compound as a colorless oil (279 mg, 79%). LH NMR (DMSO-dg) 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). Preparation 10 4-[[l-[(2S)-3-[Bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo- butanoic acid

[00096] Combined 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) and stirred at ambient temperature for 10 minutes. Added (2S)-2-amino-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-l-[4-(hydroxymethyl)-l-piperidyl]propan-l-one (980 mg, 1.90 mmol) to the mixture and stirred at ambient temperature for 16 hours. Partitioned the mixture between EtOAc and saturated aqueous sodium chloride solution. Separated the layers and washed the organics with saturated aqueous sodium chloride solution. Dried the organic layer over sodium sulfate, filtered, and concentrated in vacuo. Purified the resulting residue by silica gel flash chromatography, eluting with 0-10% MeOH / DCM, to give N-[(1 S)-l-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-l-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.

[00097] Combined N-[(lS)-l-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-2-[4-(hydroxymethyl)-l-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 pL, 6.22 mmol), and succinic anhydride (249 mg, 2.49 mmol) in DCM (24.9 mL) and stirred for 16 hours at ambient temperature. Concentrated in vacuo and purified the resulting residue via silica gel flash chromatography, eluting with 0-40% MeOH / DCM, to give the title compound as an oil (1.36 g, 60%). ES / MS m / z 1264.4 (M-H). Preparation 11 [[4-[[l-[(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

[00098] Dissolved 4-[[l-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4- piperidyl]methoxy]-4-oxo-butanoic acid (270 mg, 0.248 mmol) in ACN (12.5 mL) and transferred the solution to a fritted glass dropping funnel. Added DIEA (150 pL, 0.860 mmol) and HBTU (190 mg, 0.500 mmol) to the solution and shook the mixture at ambient temperature for 10 minutes. Added native amino LCAA CPG 500A (1.92 g, 129 pmol / g,) to the solution and shook the mixture at 500 RPM for 16 hours at ambient temperature. Drained the CPG and dried under nitrogen for 5 minutes. Washed the CPG with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). Dried the CPG for 30 minutes under nitrogen and then resuspended in pyridine (15 mL). Added acetic anhydride (3.30 mL, 35.0 mmol) and TEA (0.50 mL) and shook the mixture at 500 RPM for 2 hours at ambient temperature. Drained the CPG and dried for 5 minutes under nitrogen. Washed the CPG with DCM (50 mL), 10% MeOH / DCM (50 mL), and then diethyl ether (50 mL). Dried the CPG for 45 minutes under nitrogen and determined the ligand loading at 505 nm to give the title compound (1.92 g, 75.5 pmol / g). Preparation 12 [[4-[[l-[(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

[00099] Prepared the title compound from 4-[[l-[(2S)-3-[bis(4-methoxyphenyl)-phenyl-methoxy]-2-[3-[2-[2-[2-[2-[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12- trimethyltridecyl]chroman-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propanoyl]-4-piperidyl]methoxy]-4-oxo-butanoic acid in a manner essentially analogous to Preparation 11. Determined the ligand loading at 505 nm to give the title compound (4.01 g, 66.9 pmol / g). Preparation 13 3-[[(2R,3R,4R,5R)-2-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-hexadecoxy-5-(2-hydroxy-4-oxo-pyrimidin-l-yl)THF-3-yl]oxy-(diisopropylamino)phosphanyl]oxypropanenitrile [000100] Prepared the title compound according to the protocols described in WO2019217459. 'H NMR (CDsCN) S 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), 1.401.14 (m, 35H), 1.08 (d, J= 6.8 Hz, 3H), 0.91 (t, J= 6.8 Hz, 3H). 31P NMR (CD3CN): 149.6, 149.2. Preparation 14 N-[9-[(2R,3R,4R,5R)-5-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cy anoethoxy -(diisopropylamino)phosphanyl]oxy-3-hexadecoxy-tetrahydrofuran-2-yl]purin-6-yl]benzamide [000101] Prepared the title compound according to the protocols described in WO2019217459. 'H-NMR (CD3CN) 5 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), 6.1 1 (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). 31P NMR (CD3CN) S 151.19, 150.78. Preparation 15 N-[l-[(2R,3R,4R,5R)-5-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cy anoethoxy -(diisopropylamino)phosphanyl]oxy-3-hexadecoxy-tetrahydrofuran-2-yl]-2-oxo-pyrimidin-4-yl]acetamide xo [000102] Prepared the title compound according to the protocols described in WO2019217459. 'H-NMR (CD3CN) 8 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). 31P NMR (CD3CN) 8 151.10, 150.19. Preparation 16 N-[9-[(2R,3R,4R,5R)-5-[[Bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[2-cy anoethoxy -(diisopropylamino)phosphanyl]oxy-3-hexadecoxy-tetrahydrofuran-2-yl]-6-oxo-lH-purin-2-yl]-2-methyl-propanamide Prepared the title compound according to the protocols described in WO2019217459. [000103] 'II-NMR. (CDCh) 8 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), 1.241.15 (m, 13H), 1.06-1.03 (m, 5H), 0.93-0.88 (m, 6H), 0.74-0.70 (m, 1H). 31P NMR (CDCh) 3 150.20, 149.92. Example 2. Synthesis of ATXN2 RNAi Agents [000104] Single strands (sense and antisense) of the RNA duplexes were synthesized on solid support via a MerMade™ 12 (LGC Biosearch Technologies). The sequences of the sense and antisense strands were shown in Table 2. The oligonucleotides were synthesized via phosphoramidite chemistry at either 5, 10, 25 or 50 pmol scales. [000105] For the sense strands, the types of solid supports were universal CPG: (3’-Piperidinol-PEG- Palmitate) and (3’-Piperidinol-PEG-Tocopherol) were synthesized in house (see Example 1) while the Universal UnyLinker (Chemgenes, Catalog No. AT273-27) and 3’Teg-Tocopherol (LGC Biosearch Technologies, Catalog No. BG7-1190) were purchased commercially. For all the antisense strands, commercially available standard support mA was utilized. Standard reagents were used in the oligo synthesis (Table 7), where 0.1M xanthane hydride in pyridine was used as the sulfurization reagent and 20% DEA in ACN was used as an auxiliary wash post synthesis. All monomers (Table 8) were made at 0.1M in ACN and contained a molecular sieves trap bag. [000106] The oligonucleotides were cleaved and deprotected (C / D) at 45 °C for 20 hours. The sense strands were C / D from the CPG using ammonia hydroxide (28-30%, cold), whereas 3% DEA in ammonia hydroxide (28-30%, cold) was used for the antisense strands. C / D was determined complete by IP-RP LCMS when the resulting mass data confirmed the identity of sequence. Dependent on scale, the CPG was filtered via 0.45 um PVDF syringeless filter, 0.22 um PVDF Steriflip® vacuum filtration or 0.22 um PVDF Stericup® Quick release. The CPG was back washed / rinsed with either 30% ACN / RNAse free water or 30% EtOH / RNAse free water then filtered through the same filtering device and combined with the first filtrate. This was repeated twice. The material was then divided evenly into 50 mL falcon tubes to remove organics via Genevac™ After concentration, the crude oligonucleotides were diluted back to synthesized scale with RNAse free water and filtered either by 0.45 pm PVDF syringeless filter, 0.22 pm PVDF Steriflip® vacuum filtration or 0.22 pm PVDF Stericup® Quick release. [000107] The crude oligonucleotides were purified via AKTA™ Pure purification system using either anion-exchange (AEX) or reverse phase (RP) a source 15Q-RP column. For AEX, an ES Industry Source™ 15Q column maintaining column temperature at 65 °C with MPA: 20mM NaH2PO4, 15% ACN, pH 7.4 and MPB: 20 mM NaH2PO4, IMNaBr, 15% ACN, pH 7.4. For RP, a Source™ 15Q-RP column with MPA: 50mMNaOAc with 10% ACN and MPB: 50mM NaOAc with 80% ACN. In all cases, fractions which contained a mass purity greater than 85% without impurities >5% where combined. [000108] The purified oligonucleotides were desalted using 15 mL 3K MWCO centrifugal spin tubes at 3500xg for ~30 min. The oligonucleotides were rinsed with RNAse free water until the eluent conductivity reached < 100 usemi / cm. After desalting was complete, 2-3 mL of RNAse free water was added then aspirated lOx, the retainment was transferred to a 50 mL falcon tube, this was repeated until complete transfer of oligo by measuring concentration of compound on filter via nanodrop. The final oligonucleotide was then nano filtered 2x via 15 mL 100K MWCO centrifugal spin tubes at 3500xg for 2 min. The final desalted oligonucleotides were analyzed for concentration (nano drop at A260), characterized by IP-RP LCMS for mass purity and UPLC for UV-purity. [000109] For the preparation of duplexes, equimolar amounts of sense and antisense strand were combined and heated at 65 °C for 10 minutes then slowly cooled to ambient temperature over 40 minutes. Integrity of the duplex was confirmed by UPLC analysis and characterized by LCMS using IP-RP. All duplexes were nano filtered then endotoxin levels measured via Charles River Endosafe® Cartridge Device to give the final compounds of conjugated RNAi (Table 9). For in vivo analysis, the appropriate amount of duplex was lyophilized then reconstituted in IX PBS for rodent studies and a CSF for non-human primate studies. Table 7 - Oligonucleotide Synthesis Reagents Reagents Activator Solution (0.5M ETT in ACN) Cap A (Acetic Anhydride, Pyridine in THF, 1:1:8) Cap B (1-Methylimidazole in THF, 16:84) Oxidation Solution (0.02M Iodine in THF / Pyridine / Water, 70:20:10) Deblock Solution, 3% TCA in DCM (w / v) Acetonitrile (Anhydrosolv, Water max. 10 ppm) Xanthane Hydride (0.1 M in Pyridine) Diethylamine (20 % in Acetonitrile) Table 8 - Phosphoramidites Phosphoramidite Abbreviation Supplier Catalog # CAS DMT-2'-F-A(Bz)-CE Phosphoamidite fA Hongene PD1-001 136834-22-5 DMT-2'-F-C(Ac)-CE Phosphoamidite fC Flongene PD3-001 159414-99-0 DMT-2'-F-G(iBu)-CE Phosphoamidite fG Hongene PD2-002 144089-97-4 DMT-2'-F-U-CE Phosphoamidite fU Flongene PD5-001 146954-75-8 DMT-2'-O-Me-A(Bz)- CE Phosphoamidite mA Hongene PR1-001 110782-31-5 DMT-2'-O-Me-C(Ac)- CE Phosphoamidite mC Hongene PR3-001 199593-09-4 DMT-2'-O-Me-G(iBu)- CE Phosphoamidite mG Hongene PR2-002 150780-67-9 DMT-2'-O-Me-U-CE Phosphoamidite mU Hongene PR5-001 110764-79-9 5'bis(POM) vinyl phosphate-2'-Ome-U3'CE phosphoroami dite POM-VPmU Hongene PR5-032 BVPMUP23B2A1 Reverse Abasic phosphoroami dite iAb Chemgenes ANP-1422 401813-16-9 Abasic phosphoroami dite Ab Chemgenes ANP-7058 129821-76-7 Uhd Uhd Lilly Chd Chd Lilly Ahd Ahd Lilly Ghd Ghd Lilly Table 9 - Conjugated ATXN2 RNAi Agents Conjugated RNAi Agent No. Strand LDP* MW Cal. (g / mol) MW Obs. (g / mol) 1 S: SEQIDNO: 31 8 7880.8 7880.8 AS: SEQIDNO: 32 7578.9 7579.2 2 S: SEQ ID NO: 33 8 7706.6 7706.5 AS: SEQIDNO: 34 7767.1 7766.5 3 S: SEQIDNO: 35 8 7701.6 7702.4 AS: SEQIDNO: 36 7735.1 7734.5 4 S: SEQ ID NO: 37 8 7904.8 7905.6 AS: SEQIDNO: 38 7539.8 7539.2 5 S: SEQ ID NO: 39 8 7612.5 7613.7 AS: SEQ ID NO: 40 7908.2 7908.7 6 S: SEQIDNO: 41 8 7629.5 7630.4 AS: SEQ ID NO: 42 7891.2 7891.2 7 S: SEQ ID NO: 43 8 7722.6 7723.1 AS: SEQ ID NO: 44 7767.1 7766.5 8 S: SEQ ID NO: 45 8 7620.5 7621.6 AS: SEQ ID NO: 46 7870.2 7870.4 9 S: SEQ ID NO: 47 8 7572.5 7572.7 AS: SEQ ID NO: 48 7931.3 7931.3 10 S: SEQ ID NO: 49 8 7651.5 7651.3 AS: SEQIDNO: 50 7907.2 7906.5 11 S: SEQIDNO: 51 8 7658.6 7658.5 AS: SEQIDNO: 52 7862.2 7862.5 12 S: SEQ ID NO: 53 8 7884.7 7885.7 AS: SEQ ID NO: 54 7552.0 7552.9 13 S: SEQ ID NO: 55 8 7659.6 7659.3 AS: SEQ ID NO: 56 7885.2 7885.8 14 S: SEQ ID NO: 57 8 7594.6 7594.5 AS: SEQ ID NO: 58 7940.4 7940.4 15 S: SEQ ID NO: 59 8 7816.8 7816.9 AS: SEQ ID NO: 60 7657.9 7658.2 “S” means the sense strand; “AS” means the antisense strand. * LDP is linked to the 3’ end of the sense strand. Example 3. Characterization of ATXN2 RNAi Agents [000110] Selected ATXN2 RNAi agents were tested in vitro for ATXN2 inhibition in cultured cells, including SH-SY5Y cells, mouse primary cortical neurons, and / or human induced pluripotent stem cells (hiPSC). Materials and Methods [000111] SH-SY5Y Cell Culture and RNAi Treatment and Analysis: SH-SY5Y cells (ATCC CRL-2266) were derived from the SK-N-SH neuroblastoma cell line (Ross, R. A., et al., 1983. J Natl Cancer Inst 71, 741-747). The base medium was composed of a 1:1 mixture of ATCC-formulated Eagle's Minimum Essential Medium, (Cat No. 30-2003), and F12 Medium. The complete growth medium was supplemented with 10% fetal bovine serum, IX amino acids, IX sodium bicarbonate, and IX penicillin-streptomycin (Gibco) and cells incubated at 37 °C in a humidified atmosphere of 5% CO2. On Day One, SH-SY5Y cells were plated in 96 well fibronectin coated tissue culture plates and allowed to attach overnight. On Day Two, complete media was removed and replaced with RNAi agent in serum free media. Cells were incubated with RNAi agent for 72 hours before analysis of gene expression. Analysis of changes in gene expression in RNAi treated SH-SY5Y cells was measured using Cells-to-CT Kits following the manufacturer’s protocol (ThermoFisher A35377). Predesigned gene expression assays (supplied as 20X mixtures) were selected from Applied Bio-systems (Foster City, CA, USA). The efficiencies of these assays (ThermoFisher Hs00240906_ml ATXN2 and ThermoFisher Hs99999905_ml GAPDH) were characterized with a dilution series of cDNA. RT-QPCR was performed in MicroAmp Optical 384-well reaction plates using QuantStudio 7 Flex system. The delta-delta CT method of normalizing to the housekeeping gene GAPDH was used to determine relative amounts of gene expression. GraphPad Prism v9.0 was used to determine IC50 with a four parameter logistic fit. [000112] Mouse Primary Cortical Neuron (MCN) Culture and RNAi Treatment and Analysis: Mouse primary cortical neurons were isolated from wild type C57BL6 mouse embryos at El 8. Cells were plated in poly-D-lysine coated 96-well plates at a density of 40k cells / well and cultured in NbActivl (BrainBits, LLC) containing 1% Antibiotic / Antimycotic (Corning) for 7 days at 37 °C in a tissue culture incubator in a humidified chamber with 5% CO2. On Day 7, half of the medium was removed from each well and 2x concentration of RNAi in culture media with 2% FBS was added for treatment as CRC and incubated with cells for additional 7, 14 or 21 days. Half media change was done every 7 days with fresh culture media. At the end of RNAi treatment, RT-qPCR was performed to quantify ATXN2 mRNA levels using TaqMan Fast Advanced Cell-to-CT kit. Specifically, cells were lysed, cDNA was generated on Mastercycler X50a (Eppendorf), and qPCR was carried out on QuantStudio 7 Flex Real-Time PCR System (Applied Biosystems). Alpha-synuclein (ThermoFisher, Mm00447333_ml) gene expression levels were normalized by P-actin (ThermoFisher, Mm02619580_gl) using respective probes. [000113] Human Induced Pluripotent Stem Cell-derived Neuron (hiPSC Neuron) Culture and RNAi Treatment and Analysis: Doxycycline-inducible Neurogenin2 (NGN2) human induced Pluripotent Stem Cells (hiPSC) were developed by Bioneer for Eli Lilly. The hiPSC were doxycycline-induced for three days (DIV3) to initiate neuronal differentiation and plated on 96-well PDL and laminin coated plates at 30k / well and grown in Neuronal Differentiation Media (NDM) consisting of DMEM / F12 (Life Technologies 11330-057), Neurobasal media (Gibco 15240062), antibiotics, supplements, growth factors and doxycycline in an incubator (37°C / 5%CO2). Cells were half-fed every seven days, and on DIV21, RNAi agent was serially diluted in NDM, and cells were treated with RNAi by aspirating 75 pL and adding 75 pL of 2x RNAi concentration for a final of lx RNAi according to dilutions. Cells were half-fed every seven days after treatment by removing half of media and adding back fresh NDM. Cell lysates were harvested at DIV35 (14 days later) or DTV42 (21 days later) and RT-qPCR was performed using TaqMan Fast Advanced Ce1ls-to-Cr Kit (ThermoFisher, A35377) and to determine mRNA knock down using ATXN2 probe as the gene of interest (ThermoFisher, Hs00240907_ml) and ACTb probe as the housekeeping gene (ThermoFisher, Hs99999903_ml). Results [000114] Table 10 summarizes the percentage knockdown of ATXN2 mRNA and IC50 of the SARM RNAi agents in human SH-SY5Y cells, mouse primary cortical neurons (MCN) and hiPSC neurons. The tested ATXN2 RNAi agents achieved ATXN2 mRNA knockdown in human SH-SY5Y cells. Table 10. In vitro activities of selected ATXN2 RNAi agents RNAi Agent SHSY5Y, 3d IC50 (nM) SHSY5Y, 3d % KD (knockdown) of ATXN2 at 1 uM MCN, 7d IC50 (nM) MCN, 7d % KD (knockdown) ofATXN2 at luM hiPSC Neurons, 21d IC50 (nM) hiPSC Neurons, 21d % KD (knockdown) of ATXN2 at luM Conjugated RNAi Agent NO. 1 29.34 70.66 18.2 83 17.93 67.5 Conjugated RNAi Agent NO. 2 32.26 67.74 11.4 72 62.43 75.8 Conjugated RNAi Agent NO. 3 32.42 67.58 47.4 81 25.2 62.5 Conjugated RNAi Agent NO. 4 34.53 65.47 167.9 76 50.68 72.6 Conjugated RNAi Agent NO. 5 34.67 65.33 11.8 68 45.53 80.5 Conjugated RNAi Agent NO. 6 34.80 65.20 15.2 63 51.68 68.2 Conjugated RNAi Agent NO 7 35.64 64.36 12.5 70 20.35 83.4 Conjugated RNAi Agent NO. 8 37.20 62.80 18.6 61 137.9 51 Conjugated RNAi Agent NO. 9 37.72 62.28 12.4 67 8.72 44.4 Conjugated RNAi Agent NO. 10 37.76 62.24 17.3 71 80.86 66.7 Conjugated RNAi Agent NO. 11 39.34 60.66 61.5 73 43.9 57.4 Conjugated RNAi Agent No. 12 39.59 60.41 14.3 78 97.62 56.7 Conjugated RNAi Agent No. 13 39.59 60.41 126.4 70 35.61 63.1 Conjugated RNAi Agent No. 14 39.60 60.40 108.2 7 1134 31.1 Conjugated RNAi Agent No. 15 42.28 57.72 57.3 47 61.67 65.4 Example 4. In vivo Characterization of Selected RNAi Agents in Mice [000115] The efficacy of the RNAi agents was studied in wildtype C56BL / 6N mice. Six mice received intracerebroventricular (ICV) injection of 30 pg of the RNAi agent or PBS (phosphate buffered saline), and were sacrificed on Day 21 after the injection. Mouse ATXN2 mRNA expression in spinal cord and brain were measured and analyzed by quantitative PCR (qPCR). The results are shown in Table 11. Table 11. The Percentage Knockdown (KD) of ATXN2 mRNA in Mice Conjugated RNAi Agent No. Mouse ICV, 8 d %KD Frontal Cortex Mouse ICV, 8 d %KD Brain stem Mouse ICV, 8 d %KD Lumbar Spinal Cord Mouse ICV, 8 d % KD Cerebellum 1 8 20 42 29 2 22 32 26 25 3 7 27 20 17 4 0 11 18 0 5 18 12 13 25 6 0 26 14 0 7 26 35 36 17 8 4 16 1 0 9 9 28 26 17 10 33 34 35 28 11 31 45 56 53 12 9 19 13 17 13 0 18 18 27 14 0 0 2 6 15 0 6 16 18 SEQUENCE LISTING SEQID NO Sequence 1 CGAAACGUGAAGAAAUAAUGA 2 UCAUUAUUUCUUCACGUUUCGGC 3 CCUAAACGCAUGUCUUCAGAA 4 UUCUGAAGACAUGCGUUUAGGCA 5 GAGAUGCUUUUACUGACUCUA 6 UAGAGUCAGUAAAAGCAUCUCUU 7 AAACGUGAAGAAAUAAUGGAA 8 UUCCAUUAUUUCUUCACGUUUCG 9 GCUCCUGUCUCUACUAUGCCA 10 UGGCAUAGUAGAGACAGGAGCUG 11 UGGUUCUCCAGCUCCUGUCUA 12 UAGACAGGAGCUGGAGAAC CAUG 13 GCCUAAACGCAUGUCUUCAGA 14 UCUGAAGACAUGCGUUUAGGCAU 15 UUAUCAGUCUCAGCAUCCUCA 16 UGAGGAUGCUGAGACUGAUAAUG 17 UCUCCAGCUCCUGUCUCUACA 18 UGUAGAGACAGGAGCUGGAGAAC 19 GCUCAUGGUUCUCCAGCUCCA 20 UGGAGCUGGAGAACCAUGAGCAG 21 CAGUCAGGUCCCAACUCUCUA 22 UAGAGAGUUGGGACCUGACUGGU 23 GAGUAGUUAAUGGAGGUGUUA 24 UAACACCUCCAUUAACUACUCUU 25 AGUCAGGUCCCAACUCUCUUA 26 UAAGAGAGUUGGGACCUGACUGG 27 CCCACCUUCUCGCUACCAGUA 28 UACUGGUAGCGAGAAGGUGGGCG 29 CAAGACAUAUAGAGCAGUACA 30 UGUACUGCUCUAUAUGUCUUGGC 31 mC*mG*mAmAmAmCfGmUfGfAfAmGmAmAmAmUmAmAmU*mG*mA 32 PmU*fC*mAmUmUfAmUmUmUmCmUmUmCfAmCfGmUmUmUmCmG*mG*mC 33 mC*mC*mUmAmAmAfCmGfCfAfUmGmUmCmUmUmCmAmG*mA*mA 34 PmU*fU*mCmUmGfAmAmGmAmCmAmUmGfCmGfUmUmUmAmGmG*mC*mA 35 mG*mA*mGmAmUmGfCmUfUfUfUmAmCmUmGmAmCmUmC*mU*mA 36 PmU*fA*mGmAmGfUmCmAmGmUmAmAmAfAmGfCmAmUmCmUmC*mU*mU 37 mA*mA*mAmCmGmUfGmAfAfGfAmAmAmlJmAmAmUmGmG*mA*mA 38 PmU*fU*mCmCmAfUmUmAmUmUmUmCmUfUmCfAmCmGmUmUmU*mC*mG 39 mG*mC*mUmCmCmUfGmUfCfUfCmUmAmCmUmAmUmGmC*mC*mA 40 PmU*fG*mGmCmAfUmAmGmUmAmGmAmGfAmCfAmGmGmAmGmC*mU*mG 41 mU*mG*mGmUmUmCfUmCfCfAfGmCmUmCmCmUmGmUmC*mU*mA 42 PmU*fA*mGmAmCfAmGmGmAmGmCmUmGfGmAfGmAmAmCmCmA*mU*mG 43 mG*mC*mCmUmAmAfAmCfGfCfAmUmGmUmCmUmUmCmA*mG*mA 44 PmU*fC*mUmGmAfAmGmAmCmAmUmGmCfGmUfUmUmAmGmGmC*mA*mU 45 mU*mU*mAmUmCmAfGmUfCfUfCmAmGmCmAmUmCmCmU*mC*mA 46 PmU*fG*mAmGmGfAmUmGmCmUmGmAmGfAmCfUmGmAmUmAmA*mU*mG 47 mU*mC*mUmCmCmAfGmCfUfCfCmUmGmUmCmUmCmUmA*mC*mA 48 PmU*fG*mUmAmGfAmGmAmCmAmGmGmAfGmCfUmGmGmAmGmA*mA*mC 49 mG*mC*mUmCmAmUfGmGfUfUfCmUmCmCmAmGmCmUmC*mC*mA 50 PmU*fG*mGmAmGfCmUmGmGmAmGmAmAfCmCfAmUmGmAmGmC*mA*mG 51 mC*mA*mGmUmCmAfGmGfUfCfCmCmAmAmCmUmCmUmC*mU*mA 52 PmU*fA*mGmAmGfAmGmUmUmGmGmGmAfCmCfUmGmAmCmUmG*mG*mU 53 mG*mA*mGmUmAmGfUmUfAfAfUmGmGmAmGmGmUmGmU*mU*mA 54 PmU*fA*mAmCmAfCmCmUmCmCmAmUmUfAmAfCmUmAmCmUmC*mU*mU 55 mA*mG*mUmCmAmGfGmUfCfCfCmAmAmCmUmCmUmCmU*mU*mA 56 PmU*fA*m Am Gm AfGmAmGmUmUmGmGmGfAmCfCmUmGm AmCmU*mG*mG 57 mC*mC*mCmAmCmCfUmUfCfUfCmGmCmUmAmCmCmAmG*mU*mA 58 PmU*fA*mCmUmGfGmUmAmGmCmGmAmGfAmAfGmGmUmGmGmG*niC*mG mC*mA*mAmGmAmCfAmUfAfUfAmGmAmGmCmAmGmUmA*mC*mA 60 PmU*fG*mUmAmCfUmGmCmUmCmUmAmUfAmUfGmUmCmUmUmG*mG*mC 61 1 AGAGCTCGCC TCCCTCCGCC TCAGACTGTT TTGGTAGCAA CGGCAACGGC GGCGGCGCGT 61 TTCGGCCCGG CTCCCGGCGG CTCCTTGGTC TCGGCGGGCC TCCCCGCCCC TTCGTCGTCC 121 TCCTTCTCCC CCTCGCCAGC CCGGGCGCCC CTCCGGCCGC GCCAACCCGC GCCTCCCCGC 131 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 TGZXAGTACAA 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 2 4 01 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 G CATCAT CAG AGTGCCATGA TGCACCCAGC GTCAGCAGCG GGCCCACCGA 2881 TTGCAGCCAC CCCACCAGCT TACTCCACGC AATATGTTGC CTACAGTCCT CAGCAGTTCC 2941 CAAATCAGCC CCTTGTTCAG CATGTGCCAC ATTATCAGTC TCAGCATCCT CAT GT CT AT A 3001 GTCCTGTAAT ACAGGGTAAT GCTAGAATGA TGGCACCACC AACACACGCC CAGCCTGGTT 3061 TAGTATCTTC TTCAGCAACT CAGTACGGGG CTCATGAGCA GACGCATGCG AT G TAT G CAT 3121 GTCCCAAATT ACCATACAAC AA.GGAGACAA 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 3 601 TGCTAATGAC GACACAGCCA CCCGGCGGTC CCCAGGCCGC CCTCGCTCAA AGTGCACTAC 3661 AGCCCATTCC AGTCTCGACA ACAGCGCATT TCCCCTATAT GACGCACCCT TCAGTACAAG 3 721 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 4 021 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 42 61 GGGAAAAACT TTTACTTTGT AGATAATATA AAATAAAAAC TTAAAAAAAA TTTAAAAAAT 4 321 AAAAAAAGTT TTAAAAACTG A 62 1 MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS 61 SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSWGSKC 121 EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVWQF 181 KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND 241 MFRYNEENYG WSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL 301 ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG 361 SGSMPSRSTS HTSDFNPNSG SDQRWNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT 421 PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR 481 GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSWSGV PRLSPKTHRP RSPRQNSIGN 541 TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA 601 GNKENIKPNE TSPSFSKAEN KGISPWSEH 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 63 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 64 1 MRMVHILTSV VGSKCEVQVK NGGIYEGVFK TYSPKCDLVL DAAHEKSTES SSGPKREEIM 61 ESILFKCSDF VWQFKDMDS SYAKRDAFTD SAISAKVNGE HKEKDLEPWD AGELTANEEL 121 EALENDVSNG WDPNDMFRYN EENYGWSTY 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 WSGVPRLSP 421 KTHRPRSPRQ NSIGNTPSGP VLASPQAGII PTEAVAMPIP AASPTPASPA SNRAVTPSSE 481 AKDSRLQDQR QNSPAGNKEN IKPNETSPSF SKAENKGISP WSEHRKQID 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 65 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 TAT TAT T TAT AAATCAAGTT TGATGAGGTG ATCACTGTCT ACAGTGGTTC AACTTTTAAG 3661 TTAAGGGAAA AACTTTTACT TTGTAGATAA TATAAAATAA AAACTTAAAA AAAATTTAAA 3721 AAATAAAAAA AGTTTTAAAA ACTGAAAAAA AAAAA 66 1 MRMVHILTSV VCDLVLDAAH EKSTESSSGP KREEIMESIL FKCSDFVWQ FKDMDSSYAK 61 RDAFTDSAIS AKVNGEHKEK DLEPWDAGEL TANEELEALE NDVSNGWDPN DMFRYNEENY 121 GWSTYDSSL SSYTVPLERD NSEEFLKREA RANQLAEEIE SSAQYKARVA LENDDRSEEE 181 KYTAVQRNSS EREGHSINTR ENKYIPPGQR NREVISWGSG RQNSPRMGQP GSGSMPSRST 241 SHTSDFNPNS GSDQRWNGG VPWPSPCPSP SSRPPSRYQS GPNSLPPRAA TPTRPPSRPP 301 SRPSRPPSHP SAHGSPAPVS TMPKRMSSEG PPRMSPKAQR HPRNHRVSAG RGSISSGLEF 361 VSHNPPSEAA TPPVARTSPS GGTWSSWSG VPRLSPKTHR PRSPRQNSIG NTPSGPVLAS 421 PQAGIIPTEA VAMPIPAASP TPASPASNRA VTPSSEAKDS RLQDQRQNSP AGNKENIKPN 481 ETSPSFSKAE NKGISPWSE HRKQIDDLKK FKNDFRLQPS STSESMDQLL NKNREGEKSR 541 DLIKDKIEPS AKDSFTENSS 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 67 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 12 01 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 34 81 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 4 081 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 68 1 MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS 61 SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSWGSKC 121 EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVWQF 181 KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND 241 MFRYNEENYG WSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL 301 ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG 361 SGSMPSRSTS HTSDFNPNSG SDQRWNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT 421 PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR 481 GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSWSGV PRLSPKTHRP RSPRQNSIGN 541 TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA 601 GNKENIKPNE TSPSFSKAEN KGISPWSEH 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 S S SATQYGAH 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 69 ATGTCGCTGAAGCCCCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAGCAGC AGCAGCAGCAGCAGCAGCAGCCGCCGCCCGCGGCTGCCAATGTCCGCAAGCCCGGCGGCAGCGGC CTTCTAGCGTCGCCCGCCGCCGCGCCTTCGCCGTCCTCGTCCTCGGTCTCCTCGTCCTCGGCCACGG CTCCCTCCTCGGTGGTCGCGGCGACCTCCGGCGGCGGGAGGCCCGGCCTGGGCAGAGGTCGAAAC AGTAACAAAGGACTGCCTCAGTCTACGATirCTTTTGATGGAATCTATGCAAATATGAGGA CATATACTTACATCAGTTGTTGGCTCCAAATGTGAAGTACAAGTGAAAAATGGAGGTATATATGAA GGAGTTTTTAAAACTTACAGrrCCGAAGTGTGATTTGGTACTTGATGCCGCACATGAGAAAAGTACA GAATCCAGTTCGGGGCCGAAACGTGAAGAAATAATGGAGAGTATTTTGTTCAAATGTTCAGACTTT GTTGTGGTACAGTTTAAAGATATGGACTCCAGTTATGCAAAAAGAGATGCTTTTACTGACTCTGCT ATCAGTGCTAAAGTGAATGGCGAACACAAAGAGAAGGACCTGGAGCCCTGGGATGCAGGTGAACT CACAGCCAATGAGGAACTTGAGGCTTTGGAAAATGACGTATCTAATGGATGGGATCCCAATGATA TGTTTCGATATAATGAAGAAAATTATGGTGTAGTGTCTACGTATGATAGCAGTTTATCTTCGTATAC AGTGCCCTTAGAAAGAGATAACTCAGAAGAATTTTTAAAACGGGAAGCAAGGGCAAACCAGTTAG CAGAAGAAATTGAGTCAAGTGCCCAGTACAAAGCTCGAGTGGCCCTGGAAAATGATGATAGGAGT GAGGAAGAAAAATACACAGCAGTTCAGAGAAATTCCAGTGAACGTGAGGGGCACAGCATAAACA CTAGGGAAAATAAATATATTCCTCCTGGACAAAGAAATAGAGAAGTCATATCCTGGGGAAGTGGG AGACAGAATTCACCGCGTATGGGCCAGCCTGGATCGGGCTCCATGCCATCAAGATCCACTTCTCAC ACTTCAGATTTCAACCCGAATTCTGGTTCAGACCAAAGAGTAGTTAATGGAGGTGTTCCCTGGCCA TCGCCTTGCCCATCTCCTTCCTCTCGCCCACCTTCTCGCTACCAGTCAGGTCCCAACTCTCTTCCACC TCGGGCAGCCACCCCTACACGGCCGCCCTCCAGGCCCCCCTCGCGGCCATCCAGACCCCCGTCTCA CCCCTCTGCTCATGGTTCTCCAGCTCCTGTCTCTACTATGCCTAAAC,GCATGTCTTCAGAAGGGCCT CCAAGGATGTCCCCAAAGGCCCAGCGACATCCTC,GAA.ATCACAGAGTTTCTGCTGGGAGGGGTTCC ATATCCAGTGGCCTAGAATTTGTATCCCACAACCCACCCAGTGAAGCAGCTACTCCTCCAGTAGCA AGGACCAGTCCCTCGGGGGGAACGTGGTCATCAGTGGTCAGTGGGGTTCCAAGATTATCCCCTAAA ACTCATAGACCCAGGTCTCCCAGACAGAACAGTATTGGAAATACCCCCAGTGGGCCAGTTCTTGCT TCTCCCCAAGCTGGTATTATTCCAACTGAAGCTGTTGCCATGCCTATTCCAGCTGCATCTCCTACGC CTfjCTAGTCCTGCATCGAACAGAGCTGTTACCCCTTCTAGTGAGGCTAAAGATTCCAGGCTTCAAG ATCAGAGGCAGAACTCTCCTGCAGGGAATAAAGAAAATATTAAACCCAATGAAACATCACCTAGC TTCTCAAAAGCTGAAAACAAAGGTATATCACCAGTTG'nTCTGAACATAGAAAACAGATTGATGAT TTAAAGAAATTTAAGAATGATTTTAGGTTACAGCCAAGTTCTACTTCTGAATCTATGGATCAACTA CTAAACAAAAATAGAGAGGGAGAAAAATCAAGAGATTTGATCAAAGACAAAATTGAACCAAGTG CTAAGGATTCTTTCATTGAAAATAGCAGCAGCAACTGTACCAGTGGCAGCAGCAAGCCGAATAGC CCCAGCATTTC.CCCTTCAATAC1TAGTAACACGGAGCACAAGAGGGGACCTGAGGTCACTTCCCAA GGGGITCAGACTTCCAGCCCAGCATGTAAACAAGAGAAAGACGATAAGGAAGAGAAGAAAGACG CAGCTGAGCAAGTTAGGAAATCAACATTGAATCCCAATGCAAAGGAGTTCAACCCACGTTCCTTCT CTCAGCCAAAGCCTTCTACTACCCCAACTTCACCTCGGCCTCAAGCACAACCTAGCCCATCTATGG TGGGTCATCAACAGCCAACTCCAGTTTATACTCAGCCTGTTTGTTTTGCACCAAATATGATGTATCC AGTCCCAGTGAGCCCAGGCGTGC.AACCTTTATACCCAATACCTATGACGCCCATGCCAGTGAATCA AGCCAAGACATATAGAGCAGTACCAAATATGCCCCAACAGCGGCAAGACCAGCATCATCAGAGTG CCATOATGCACCCAGCGTCAGCAGCGGGCCCACCGATTGCAGCCACCCCACCAGCTTACTCCACGC AATATGTTGCCTACAGTCCTCAGCAGTTCCCAAATCAGCCCCTTGTTCAGCATGTGCCACATTATCA GTCTCAGCATCCTCATGTCTATAGTCCTGTAATACAGGGTAATGCTAGAATGATGGCACCACCAAC ACACGCCCAGCCTGGnTAGTATCTTCTTCAGCAACTCAGTACGGGGCTCATGAGCAGACGCATGC GATGTATGCATGTCCCAAATTACCATACAACAAGGAGACAAGCCCTTCTTTCTACrTTGCCATTTCC ACGGGCTCCCTTGCTCAGCAGTATGCGCACCCTAACGCTACCCTGCACCCACATACTCCACACCCT CAGCCTrCAGCTACCCCCACTGGACAGCAGCAAAGCCAACATGGTGGAAGTCATCCTGCACCCAGT CCTGTTCAGCACCATCAGCACCAGGCCGCCCAGGCTCTCCATCTGGCCAGTCCACAGCAGCAGTCA GCCATTTACCACGCGGGGCTTGCGCCAACTCCACCCTCCATGACACCTGCCTCCAACACGCAGTCG CCACAGAATAGTTTCCCAGCAGCACAACAGACTGTCTTTACGATCCATCCTTCTCACGTTCAGCCG GCGTATACCAACCCACCCCACATGGCCCACGTACCTCAGGCTCATGTACAGTCAGGAATGGTTCCT TCTCATCCAACTGCCCATGCGCCAATGATGCTAATGACGACACAGCCACCCGGCGGTCCCCAGGCC GCCCTCGCTCAAAGTGCACTACAGCCCATTCCAGTCTCGACAACAGCGCATTTCCCCTATATGACG CACCCTTCAGTACAAGCCCACCACCAACAGCAGTTGTAA 70 MSLKPQQQQQQQQQQQQQQQQQQQQQQQPPPAAANWKPGGSGLLASPAAAPSPSSSSVSSSSATAPS SVVAATSGGGRPGLGRGRNSNKGLPQSTISFDGTYANMRMVHTLTSVVGSKCEVQVKNGGIYEGVFKT YSPKCDLVLDAAHEKSTESSSGPKREEIMESILFKCSDFVWQFKDMDSSYAKRDAF'roSAISAKVNGE HKEKDLEPWD AGELT ANEELEALEND VSNGWDPNDMFRYNEEN YGWSTYD SSL SSYTVPLERDN SE EFLKREARANQLAEEIESSAQYKARVALENDDRSEEEKYTAVQRNSSEREGHSINTRENKYIPPGQRNR EVTSWGSGRQNSPRMGQPGSGSMPSRSTSHTSDFNPNSGSDQRWNGGVPWPSPCPSPSSRPPSRYQSGP NSLPPRAATPTRPPSRPPSRPSRPPSHPSAHGSPAPVSTMPKRMSSEGPPRMSPKAQRHPRNHRVSAGRG STSSGLEFVSHNPPSEAATPPVARTSPSGGTWSSWSGVPRLSPK.THRPRSPRQNSIGNTPSGPVLASPQA GIIPTEAVAMPIPAASPTPASPASNRAVTPSSEAKDSRLQDQRQNSPAGNKEN'TKPNETSPSFSKAENKGI SPVVSEHRKQIDDLKKFKNDFRLQPSSTSESAIDQLLNKNREGEKSRDLIKDKIEPSAKDSFIENSSSNCTS GSSKPNSPS1SPSILSNTEHKRGPEVTSQGVQTSSPACKQEKDDKEEKKDAAEQVRKSTLNPNAKEFNPR SFSQPKPSTTPTSPRPQAQPSPSMVGHQQPTPVYTQPVCFAPNMMYPVPVSPGVQPLYPIPMTPMPVNQ AKTYRAVPNMPQQRQDQHHQSAMMHPASAAGPP1AATPPAYSTQYVAYSPQQFPNQPLVQHVPHYQS QHPHVYSPVIQGNARMMAPPTHAQPGLVSSSATQYGAHEQTHAMYACPKLPYNKETSPSFYFAISTGS LAQQYAHPNATLHPHTPHPQPSATPTGQQQSQHGGSHPAPSPVQHHQHQAAQALHLASPQQQSAIYHA GLAPTPPSMTPASNTQSPQNSFPAAQQTVFT1HPSHVQPAYTNPPHMAHVPQAHVQSGMVPSHPTAHAP MMLMTTQPPGGPQAALAQSALQPIPVSITAHFPYMTHPSVQAHHQQQL

Claims

1. An ATXN2 RNAi agent comprising a sense strand and an antisense strand,wherein the sense strand and the antisense strand form a duplex, wherein the sense strand comprises SEQ ID NO: 13, and the antisense strand comprises SEQ ID NO: 14.

2. The ATXN2 RNAi agent of claim 1, wherein one or more nucleotides of the sense strand or the antisense strand are modified nucleotides.

3. The ATXN2 RNAi agent of any one of claims 1-2, wherein each nucleotide of the sense strand is a modified nucleotide.

4. The ATXN2 RNAi agent of any one of claims 1-2, wherein each nucleotide of the antisense strand is a modified nucleotide.

5. The ATXN2 RNAi agent of any one of claims 1-4, wherein the modified nucleotide is a 2'-fluoro modified nucleotide, 2'-O-methyl modified nucleotide or 2'-O-alkyl modified nucleotide.

6. The ATXN2 RNAi agent of any one of claims 1-5, wherein the sense strand has four 2'-fluoro modified nucleotides at positions 7, 9, 10, and 11 from the 5’ end of the sense strand.

7. The ATXN2 RNAi agent of claim 6, wherein nucleotides at positions other than positions 7, 9, 10, and 11 of the sense strand are 2'-O-methyl modified nucleotides.

8. The ATXN2 RNAi agent of any one of claims 1-7, wherein the antisense strand has four 2'-fluoro modified nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand.2023287741   30 Jun 20269. The ATXN2 RNAi agent of claim 8, wherein nucleotides at positions other than positions 2, 6, 14 and 16 of the antisense strand are 2'-O-methyl modified nucleotides.

10. The ATXN2 RNAi agent of any one of claims 1-9, wherein the sense strand and the antisense strand have one or more modified internucleotide linkages.

11. The ATXN2 RNAi agent of claim 10, wherein the modified internucleotide linkage is phosphorothioate linkage.

12. The ATXN2 RNAi agent of claim 11, wherein the sense strand or the antisense strand has four or five phosphorothioate linkages.

13. The ATXN2 RNAi agent of any one of claims 1-12, wherein the first nucleotide from the 5’ end of the antisense strand is a modified nucleotide that has a phosphate analog.

14. The ATXN2 RNAi agent of claim 13, wherein the phosphate analog is 5’-vinylphosphonate.

15. The ATXN2 RNAi agent of any one of claims 1-14, wherein the sense strand has an abasic moiety or inverted abasic moiety.

16. The ATXN2 RNAi agent of claim 1, wherein the sense strand comprises SEQ ID NO: 43, and the antisense strand comprises SEQ ID NO: 44.

17. The ATXN2 RNAi agent of claim 16, wherein the sense strand consists of SEQ ID NO: 43, and the antisense strand consists of SEQ ID NO: 44.2023287741   30 Jun 202618. The ATXN2 RNAi agent of any one of claims 1-17, wherein the sense strand has a delivery moiety conjugated to the 3’ end of the sense strand, or to a nucleotide of the sense strand.

19. An ATXN2 RNAi agent of Formula (I): R-L-D,wherein R is a double stranded RNA (dsRNA) comprising a sense stand and an antisense strand, wherein the sense strand and the antisense strand form a duplex;wherein D is a delivery moiety; andwherein L is a linker, or absent,wherein the sense strand comprises SEQ ID NO: 13, and the antisense strand comprises SEQ ID NO: 14.

20. The ATXN2 RNAi agent of claim 19, wherein the sense strand comprises SEQ ID NO: 43, and the antisense strand comprises SEQ ID NO: 44.

21. The ATXN2 RNAi agent of claim 19 or 20, wherein the sense strand consists of SEQ ID NO: 43, and the antisense strand consists of SEQ ID NO: 44.

22. The ATXN2 RNAi agent of any one of claims 19-21, wherein the delivery moiety is conjugated to the 3’ end of the sense strand or to a nucleotide of the sense strand.

23. A pharmaceutical composition comprising the ATXN2 RNAi agent of any one of claims 1-22 and a pharmaceutically acceptable carrier.

24. A method of reducing ATXN2 expression in a patient in need thereof, the method comprising administering to the patient an effective amount of the ATXN2 RNAi agent of any one of claims 1-22, or the pharmaceutical composition of claim 23.2023287741   30 Jun 202625. A method of treating an ATXN2-associated neurological disease in a patient in need thereof, the method comprising administering to the patient an effective amount of the ATXN2 RNAi agent of any one of claims 1-22, or the pharmaceutical composition of claim 23.

26. The method of claim 25, wherein the ATXN2-associated neurological disease 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), multiple system proteinopathy, Perry disease, or TDP-43 proteinopathy.

27. The method of any one of claims 24-26, wherein the ATXN2 RNAi agent is administered to the patient intrathecally.

28. A method of reducing ATXN2 expression in a cell, the method comprising:introducing the ATXN2 RNAi agent of any one of claims 1-22 into the cell; and incubating the cell for a time sufficient for degradation of ATXN2 mRNA, thereby reducing ATXN2 expression in the cell.

29. Use of the ATXN2 RNAi agent of any one of claims 1-22, in the manufacture of a medicament for the treatment of an ATXN2-associated neurological disease.

30. The use of claim 29, wherein the ATXN2-associated neurological disease 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), multiple system proteinopathy, Perry disease, or TDP-43 proteinopathy.