# US 2023/0056569 A1 · Ataxin3 (atxn3) rnai agent compositions and methods of use thereof

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- Number: US 2023/0056569 A1
- Document ID: US20230056569A1
- Status: Published application
- Kind: A1
- Application number: 17/778,366
- Filed: 2020-11-20
- Published: 2023-02-23
- Earliest claimed: 2019-11-22
- Assignees: Alnylam Pharmaceuticals, Inc.
- Applicants: Alnylam Pharmaceuticals, Inc.
- Inventors: ADAM CASTORENO; ELANE FISHILEVICH; JASON A. GILBERT; CHARALAMBOS KAITTANIS; JAMES D. MCININCH; STUART MILSTEIN; MARK K. SCHLEGEL
- Web page: https://patentgrep.com/patent/US20230056569A1

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/3183: Diol linkers, e.g. glycols or propanediols
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/351: Conjugate
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosure relates to double-stranded ribonucleic acid (dsRNA) agents and compositions targeting the ATXN3 gene, as well as methods of inhibiting expression of an APP gene and methods of treating subjects having an ATXN3-associated disease or disorder, such as SCA3, using such dsRNA agents and compositions.

## Claims

### Claim 1

A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of ATXN3, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides, with 0 or 1 mismatches, of a portion of the nucleotide sequence of SEQ ID NO: 1 and the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides, with 0 or 1 mismatches, of the corresponding portion of nucleotide sequence of SEQ ID NO: 2 such that the sense strand is complementary to the at least 15 contiguous nucleotides in the antisense strand, wherein substitution of a thymidine base for a uridine base is not considered a mismatch.

### Claim 2 (depends on 1)

The dsRNA agent of claim 1, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides, with 0 or 1 mismatches, of a portion of the nucleotide sequence of SEQ ID NO: 1 and the antisense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides, with 0 or 1 mismatches, of the corresponding portion of nucleotide sequence of SEQ ID NO: 2 such that the sense strand is complementary to the at least 17 contiguous nucleotides in the antisense strand, wherein substitution of a thymidine base for a uridine base is not considered a mismatch.

### Claim 3 (depends on 1)

The dsRNA agent of claim 1, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising at least 19 contiguous nucleotides, with 0 or 1 mismatches, of a portion of the nucleotide sequence of SEQ ID NO: 1 and the antisense strand comprises a nucleotide sequence comprising at least 19 contiguous nucleotides, with 0 or 1 mismatches, of the corresponding portion of nucleotide sequence of SEQ ID NO:2 such that the sense strand is complementary to the at least 19 contiguous nucleotides in the antisense strand, wherein substitution of a thymidine base for a uridine base is not considered a mismatch.

### Claim 4 (depends on 1)

The dsRNA agent of claim 1, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising at least 21 contiguous nucleotides, with 0 or 1 mismatches, of a portion of the nucleotide sequence of SEQ ID NO: 1 and the antisense strand comprises a nucleotide sequence comprising at least 21 contiguous nucleotides, with 0 or 1 mismatches, of the corresponding portion of nucleotide sequence of SEQ ID NO: 2 such that the sense strand is complementary to the at least 21 contiguous nucleotides in the antisense strand, wherein substitution of a thymidine base for a uridine base is not considered a mismatch.

### Claim 5 (depends on 1, 2, 3, 4)

The dsRNA agent of any of claims 1-4, wherein the portion of the sense strand is a portion within nucleotides 76-96, 386-406, 477-497, 642-662, 897-917, 953-973, 1087-1107, 1109-1129, 1113-1133, 1114-1134, or 1200-1220 of SEQ ID NO: 1.

### Claim 6 (depends on 1, 2, 3, 4)

The dsRNA agent of any one of claims 1-4, wherein the portion of the sense strand is a portion within a sense strand from a duplex selected from
AD-368996
(GCGGUUUGCAAACAAAAUGAU (SEQ ID NO: 749)),
AD-369082
(GCAUUCAGCAAUUAAAGACAU (SEQ ID NO: 752)),
AD-414322
(UCGACCAAAACUUAUUGGAGA (SEQ ID NO: 837)),
AD-368337
(AGGAAGGUUAUUCUAUAUUUG (SEQ ID NO: 724)),
AD-368871
(UGUCUUUAGAAACUGUCAGAA (SEQ ID NO: 740)),
and
AD-368815
(GAGUGAUCUAGGUGAUGCUAU (SEQ ID NO: 735)).

### Claim 7 (depends on 6)

The dsRNA agent of claim 6, wherein the portion of the sense strand is a sense strand selected from the sense strands of
AD-368996
(GCGGUUUGCAAACAAAAUGAU (SEQ ID NO: 749)),
AD-369082
(GCAUUCAGCAAUUAAAGACAU (SEQ ID NO: 752)),
AD-414322
(UCGACCAAAACUUAUUGGAGA (SEQ ID NO: 837)),
AD-368337
(AGGAAGGUUAUUCUAUAUUUG (SEQ ID NO: 724)),
AD-368871
(UGUCUUUAGAAACUGUCAGAA (SEQ ID NO: 740)),
and
AD-368815
(GAGUGAUCUAGGUGAUGCUAU (SEQ ID NO: 735)).

### Claim 8 (depends on 1, 2, 3, 4)

The dsRNA agent of any one of claims 1-4, wherein the portion of the antisense strand is a portion within an antisense strand from a duplex selected from
AD-368996
(AUCAUUTUGUUUGCAAACCGCUA (SEQ ID NO: 885)),
AD-369082
(AUGUCUTUAAUUGCUGAAUGCCU (SEQ ID NO: 888)),
AD-414322
(UCUCCAAUAAGUUUUGGUCGAUG (SEQ ID NO: 973)),
AD-368337
(CAAAUATAGAAUAACCUUCCUGU (SEQ ID NO: 860)),
AD-368871
(UUCUGACAGUUUCUAAAGACAUG (SEQ ID NO: 876)),
and
AD-368815
(AUAGCATCACCUAGAUCACUCCC (SEQ ID NO: 871)).

### Claim 9 (depends on 1, 2, 3, 4, 5, 6)

The dsRNA agent of any one of claims 1-6, wherein the portion of antisense strand is an antisense strand selected from the antisense strands of
AD-368996
(AUCAUUTUGUUUGCAAACCGCUA (SEQ ID NO: 885)),
AD-369082
(AUGUCUTUAAUUGCUGAAUGCCU (SEQ ID NO: 888)),
AD-414322
(UCUCCAAUAAGUUUUGGUCGAUG (SEQ ID NO: 973)),
AD-368337
(CAAAUATAGAAUAACCUUCCUGU (SEQ ID NO: 860)),
AD-368871
(UUCUGACAGUUUCUAAAGACAUG (SEQ ID NO: 876)),
and
AD-368815
(AUAGCATCACCUAGAUCACUCCC (SEQ ID NO: 871)).

### Claim 10 (depends on 1, 2, 3, 4)

The dsRNA agent of any one of claims 1-4, wherein the sense strand and antisense strand comprise nucleotide sequences of the paired sense strand and antisense strand of a duplex selected from
AD-368996
(GCGGUUUGCAAACAAAAUGAU (SEQ ID NO: 749)
and
AUCAUUTUGUUUGCAAACCGCUA (SEQ ID NO: 885)),
AD-369082
(GCAUUCAGCAAUUAAAGACAU (SEQ ID NO: 752)
and
AUGUCUTUAAUUGCUGAAUGCCU (SEQ ID NO: 888)),
AD-414322
(UCGACCAAAACUUAUUGGAGA (SEQ ID NO: 837)
and
UCUCCAAUAAGUUUUGGUCGAUG (SEQ ID NO: 973)),
AD-368337
(AGGAAGGUUAUUCUAUAUUUG (SEQ ID NO: 724)
and
CAAAUATAGAAUAACCUUCCUGU (SEQ ID NO: 860)),
AD-368871
(UGUCUUUAGAAACUGUCAGAA (SEQ ID NO: 740)
and
UUCUGACAGUUUCUAAAGACAUG (SEQ ID NO: 876)),
and
AD-368815
(GAGUGAUCUAGGUGAUGCUAU (SEQ ID NO: 735)
and
AUAGCATCACCUAGAUCACUCCC (SEQ ID NO: 871)).

### Claim 11 (depends on 1, 2, 3, 4)

The dsRNA agent of any one of claims 1-4, wherein the portion of the sense strand is a portion within a sense strand from a duplex selected from
AD-368995
(AGCGGUUUGCAAACAAAAUGA (SEQ ID NO: 748)),
AD-368996
(GCGGUUUGCAAACAAAAUGAU (SEQ ID NO: 749)),
AD-1041266
(GAGGCAUUCAGCAAUUAAAGA (SEQ ID NO: 1806)),
AD-414356
(AUGCAUCGACCAAAACUUAUA (SEQ ID NO: 1026)),
AD-1103843
(GAGUGAUCUAGGUGAUGCUAA (SEQ ID NO: 1852)),
AD-1069823
(AGGAAGGUUAUUCUAUAUUUA (SEQ ID NO: 1835)),
AD-1069828
(UGUCUUUAGAAACUGUCAGAA (SEQ ID NO: 1840)),
AD-1069829
(UUUUAGCGGUUUGCAAACAAA (SEQ ID NO: 1841)),
and
AD-1069830
(GCGGUUUGCAAACAAAAUGAA (SEQ ID NO: 1842)).

### Claim 12 (depends on 11)

The dsRNA agent of claim 11, wherein the portion of the sense strand is a sense strand selected from the sense strands of
AD-368995
(AGCGGUUUGCAAACAAAAUGA (SEQ ID NO: 748)),
AD-368996
(GCGGUUUGCAAACAAAAUGAU (SEQ ID NO: 749)),
AD-1041266
(GAGGCAUUCAGCAAUUAAAGA (SEQ ID NO: 1806)),
AD-414356
(AUGCAUCGACCAAAACUUAUA (SEQ ID NO: 1026)),
AD-1103843
(GAGUGAUCUAGGUGAUGCUAA (SEQ ID NO: 1852)),
AD-1069823
(AGGAAGGUUAUUCUAUAUUUA (SEQ ID NO: 1835)),
AD-1069828
(UGUCUUUAGAAACUGUCAGAA (SEQ ID NO: 1840)),
AD-1069829
(UUUUAGCGGUUUGCAAACAAA (SEQ ID NO: 1841)),
and
AD-1069830
(GCGGUUUGCAAACAAAAUGAA (SEQ ID NO: 1842)).

### Claim 13 (depends on 1, 2, 3, 4)

The dsRNA agent of any one of claims 1-4, wherein the portion of the antisense strand is a portion within an antisense strand from a duplex selected from AD-368995
AD-368995
(UCAUUUTGUUUGCAAACCGCUAA (SEQ ID NO: 884)),
AD-368996
(AUCAUUTUGUUUGCAAACCGCUA (SEQ ID NO: 885)),
AD-1041266
(UCUUUAAUUGCUGAAUGCCUCUU (SEQ ID NO: 1865)),
AD-414356
(UAUAAGUUUUGGUCGAUGCAUCU (SEQ ID NO: 1120)),
AD-1103843
(UUAGCATCACCUAGAUCACUCCC (SEQ ID NO: 1911)),
AD-1069823
(UAAAUAUAGAAUAACCUUCCUGU (SEQ ID NO: 1894)),
AD-1069828
(UUCUGACAGUUUCUAAAGACAUG (SEQ ID NO: 1899)),
AD-1069829
(UUUGUUUGCAAACCGCUAAAAGU (SEQ ID NO: 1900)),
and
AD-1069830
(UUCAUUUUGUUUGCAAACCGCUA (SEQ ID NO: 1901)).

### Claim 14 (depends on 1, 2, 3, 4, 11, 12, 13)

The dsRNA agent of any one of claim 1-4 or 11-13, wherein the portion of antisense strand is an antisense strand selected from the antisense strands of
AD-368995
(UCAUUUTGUUUGCAAACCGCUAA (SEQ ID NO: 884)),
AD-368996
(AUCAUUTUGUUUGCAAACCGCUA (SEQ ID NO: 885)),
AD-1041266
(UCUUUAAUUGCUGAAUGCCUCUU (SEQ ID NO: 1865)),
AD-414356 (UAUAAGUUUUGGUCGAUGCA
UCU (SEQ ID NO: 1120)),
AD-1103843
(UUAGCATCACCUAGAUCACUCCC (SEQ ID NO: 1911)),
AD-1069823
(UAAAUAUAGAAUAACCUUCCUGU (SEQ ID NO: 1894)),
AD-1069828
(UUCUGACAGUUUCUAAAGACAUG (SEQ ID NO: 1899)),
AD-1069829
(UUUGUUUGCAAACCGCUAAAAGU (SEQ ID NO: 1900)),
and
AD-1069830
(UUCAUUUUGUUUGCAAACCGCUA (SEQ ID NO: 1901)).

### Claim 15 (depends on 1, 2, 3, 4, 11, 12, 13, 14)

The dsRNA agent of any one of claim 1-4 or 11-14, wherein the sense strand and antisense strand comprise nucleotide sequences of the paired sense strand and antisense strand of a duplex selected from
AD-368995
(UCAUUUTGUUUGCAAACCGCUAA (SEQ ID NO: 884)),
AD-368996
(AUCAUUTUGUUUGCAAACCGCUA (SEQ ID NO: 885)),
AD-1041266
(UCUUUAAUUGCUGAAUGCCUCUU (SEQ ID NO: 1865)),
AD-414356
(UAUAAGUUUUGGUCGAUGCAUCU (SEQ ID NO: 1120)),
AD-1103843
(UUAGCATCACCUAGAUCACUCCC (SEQ ID NO: 1911)),
AD-1069823
(UAAAUAUAGAAUAACCUUCCUGU (SEQ ID NO: 1894)),
AD-1069828
(UUCUGACAGUUUCUAAAGACAUG (SEQ ID NO: 1899)),
AD-1069829
(UUUGUUUGCAAACCGCUAAAAGU (SEQ ID NO: 1900)),
and
AD-1069830
(UUCAUUUUGUUUGCAAACCGCUA (SEQ ID NO: 1901)).

### Claim 16

A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of ATXN3, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a nucleotide sequence of an antisense sequence listed in any one of Tables 2, 5, 7A, 10, 11, or 14, and the sense strand comprises a nucleotide sequence of a sense sequence listed in any one of Tables 2, 5, 7A, 10, 11, or 14 that corresponds to the antisense sequence.

### Claim 17 (depends on 16)

The dsRNA agent of claim 16, wherein the antisense strand comprises a nucleotide sequence of an antisense sequence listed in Table 10, and the sense strand comprises a nucleotide sequence of a sense sequence listed in Table 10 that corresponds to the antisense sequence.

### Claim 18 (depends on 16)

The dsRNA agent of claim 16, wherein the antisense strand comprises a nucleotide sequence of an antisense sequence listed in Table 11, and the sense strand comprises a nucleotide sequence of a sense sequence listed in Table 11 that corresponds to the antisense sequence.

### Claim 19 (depends on 16)

The dsRNA agent of claim 16, wherein the dsRNA agent is AD-368995, AD-368996, AD-414356, AD-1041266, AD-1069823, AD-1069828, AD-1069829, AD-1069830, or AD-1103843.

### Claim 20 (depends on 16)

The dsRNA agent of any one of claim 16, comprising:
(i) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1208 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 1438;
(ii) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1209 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 1439;
(iii) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1350 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 1580;
(iv) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1931 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 1989;
(v) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1960 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 2018;
(vi) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1965 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 2023;
(vii) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1966 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 2024;
(viii) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1967 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 2025; or
(ix) the sense strand comprises the sequence and all of the modifications of SEQ ID NO: 1977 and the antisense strand comprises the sequence and all of the modifications of SEQ ID NO: 2035.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The dsRNA agent of any one of claims 1-20, wherein at least one of the sense strand and the antisense strand is conjugated to one or more lipophilic moieties.

### Claim 22 (depends on 21)

The dsRNA agent of claim 21, wherein the lipophilic moiety is conjugated to one or more positions in the double-stranded region of the dsRNA agent.

### Claim 23 (depends on 21, 22)

The dsRNA agent of claim 21 or 22, wherein the lipophilic moiety is conjugated via a linker or carrier.

### Claim 24 (depends on 21, 22, 23)

The dsRNA agent of any one of claims 21-23, wherein lipophilicity of the lipophilic moiety, measured by log Kow, exceeds 0.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The dsRNA agent of any one of claims 1-24, wherein the hydrophobicity of the double-stranded RNAi agent, measured by the unbound fraction in a plasma protein binding assay of the double-stranded RNAi agent, exceeds 0.2.

### Claim 26 (depends on 25)

The dsRNA agent of claim 25, wherein the plasma protein binding assay is an electrophoretic mobility shift assay using human serum albumin protein.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26)

The dsRNA agent of any one of claim 1-19 or 21-26, wherein the dsRNA agent comprises at least one modified nucleotide.

### Claim 28 (depends on 27)

The dsRNA agent of claim 27, wherein no more than five of the sense strand nucleotides and not more than five of the nucleotides of the antisense strand are unmodified nucleotides.

### Claim 29 (depends on 27)

The dsRNA agent of claim 27, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification.

### Claim 30 (depends on 27, 28, 29)

The dsRNA agent of any one of claims 27-29, wherein at least one of the modified nucleotides is selected from the group a deoxy-nucleotide, a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a nucleotide comprising a 5′-methylphosphonate group, a nucleotide comprising a 5′-phosphate or 5′-phosphate mimic, a nucleotide comprising vinyl phosphonate, a nucleotide comprising adenosine-glycol nucleic acid (GNA), a nucleotide comprising thymidine-glycol nucleic acid (GNA) S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2′-deoxythymidine-3′phosphate, a nucleotide comprising 2′-deoxyguanosine-3′-phosphate, and a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group; and combinations thereof.

### Claim 31 (depends on 30)

The dsRNA agent of claim 30, wherein said modified nucleotide is selected from the group consisting of a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, 3′-terminal deoxy-thymine nucleotides (dT), a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.

### Claim 32 (depends on 30)

The dsRNA agent of claim 30, wherein said modified nucleotide comprises a short sequence of 3′-terminal deoxy-thymine nucleotides (dT).

### Claim 33 (depends on 30)

The dsRNA agent of claim 30, wherein the modifications on the nucleotides are 2′-O-methyl, GNA, and 2′-fluoro modifications.

### Claim 34 (depends on 30, 33)

The dsRNA agent of claim 30 or 33, further comprising at least one phosphorothioate internucleotide linkage.

### Claim 35 (depends on 34)

The dsRNA agent of claim 34, wherein the dsRNA agent comprises 6-8 phosphorothioate internucleotide linkages.

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The dsRNA agent of any one of claims 1-35, wherein each strand is no more than 30 nucleotides in length.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)

The dsRNA agent of any one of claims 1-36, wherein at least one strand comprises a 3′-overhang of at least 1 nucleotide.

### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)

The dsRNA agent of any one of claims 1-36, wherein at least one strand comprises a 3′-overhang of at least 2 nucleotides.

### Claim 39 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)

The dsRNA agent of any one of claim 1-19 or 21-38, wherein the double-stranded region is 15-30 nucleotide pairs in length.

### Claim 40 (depends on 39)

The dsRNA agent of claim 39, wherein the double-stranded region is 17-23 nucleotide pairs in length.

### Claim 41 (depends on 39)

The dsRNA agent of claim 39, wherein the double-stranded region is 17-25 nucleotide pairs in length.

### Claim 42 (depends on 39)

The dsRNA agent of claim 39, wherein the double-stranded region is 23-27 nucleotide pairs in length.

### Claim 43 (depends on 39)

The dsRNA agent of claim 39, wherein the double-stranded region is 19-21 nucleotide pairs in length.

### Claim 44 (depends on 39)

The dsRNA agent of claim 39, wherein the double-stranded region is 21-23 nucleotide pairs in length.

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The dsRNA agent of any one of claim 1-19 or 21-44, wherein each strand has 19-30 nucleotides.

### Claim 46 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The dsRNA agent of any one of claim 1-19 or 21-44, wherein each strand has 19-23 nucleotides.

### Claim 47 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The dsRNA agent of any one of claim 1-19 or 21-44, wherein each strand has 21-23 nucleotides.

### Claim 48 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The dsRNA agent of any one of claims 21-47, wherein one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand.

### Claim 49 (depends on 48)

The dsRNA agent of claim 48, wherein the one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand via a linker or carrier.

### Claim 50 (depends on 49)

The dsRNA agent of claim 49, wherein the internal positions include all positions except the terminal two positions from each end of the at least one strand.

### Claim 51 (depends on 49)

The dsRNA agent of claim 49, wherein the internal positions include all positions except the terminal three positions from each end of the at least one strand.

### Claim 52 (depends on 49, 50, 51)

The dsRNA agent of claim 49-51, wherein the internal positions exclude a cleavage site region of the sense strand.

### Claim 53 (depends on 52)

The dsRNA agent of claim 52, wherein the internal positions include all positions except positions 9-12, counting from the 5′-end of the sense strand.

### Claim 54 (depends on 52)

The dsRNA agent of claim 52, wherein the internal positions include all positions except positions 11-13, counting from the 3′-end of the sense strand.

### Claim 55 (depends on 49, 50, 51)

The dsRNA agent of claim 49-51, wherein the internal positions exclude a cleavage site region of the antisense strand.

### Claim 56 (depends on 55)

The dsRNA agent of claim 55, wherein the internal positions include all positions except positions 12-14, counting from the 5′-end of the antisense strand.

### Claim 57 (depends on 49, 50, 51)

The dsRNA agent of claim 49-51, wherein the internal positions include all positions except positions 11-13 on the sense strand, counting from the 3′-end, and positions 12-14 on the antisense strand, counting from the 5′-end.

### Claim 58 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)

The dsRNA agent of any one of claims 21-57, wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strand, and positions 6-10 and 15-18 on the antisense strand, counting from the 5′end of each strand.

### Claim 59 (depends on 58)

The dsRNA agent of claim 58, wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5′-end of each strand.

### Claim 60 (depends on 22)

The dsRNA agent of claim 22, wherein the positions in the double-stranded region exclude a cleavage site region of the sense strand.

### Claim 61 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60)

The dsRNA agent of any one of claims 21-60, wherein the sense strand is 21 nucleotides in length, the antisense strand is 23 nucleotides in length, and the lipophilic moiety is conjugated to position 21, position 20, position 15, position 1, position 7, position 6, or position 2 of the sense strand or position 16 of the antisense strand.

### Claim 62 (depends on 61)

The dsRNA agent of claim 61, wherein the lipophilic moiety is conjugated to position 21, position 20, position 15, position 1, or position 7 of the sense strand.

### Claim 63 (depends on 61)

The dsRNA agent of claim 61, wherein the lipophilic moiety is conjugated to position 21, position 20, or position 15 of the sense strand.

### Claim 64 (depends on 61)

The dsRNA agent of claim 61, wherein the lipophilic moiety is conjugated to position 20 or position 15 of the sense strand.

### Claim 65 (depends on 61)

The dsRNA agent of claim 61, wherein the lipophilic moiety is conjugated to position 16 of the antisense strand.

### Claim 66 (depends on 61)

The dsRNA agent of claim 61, wherein the lipophilic moiety is conjugated to position 6, counting from the 5′-end of the sense strand.

### Claim 67 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66)

The dsRNA agent of any one of claims 21-66, wherein the lipophilic moiety is an aliphatic, alicyclic, or polyalicyclic compound.

### Claim 68 (depends on 67)

The dsRNA agent of claim 67, wherein the lipophilic moiety is selected from the group consisting of lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine.

### Claim 69 (depends on 68)

The dsRNA agent of claim 68, wherein the lipophilic moiety contains a saturated or unsaturated C4-C30 hydrocarbon chain, and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.

### Claim 70 (depends on 69)

The dsRNA agent of claim 69, wherein the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain.

### Claim 71 (depends on 69)

The dsRNA agent of claim 69, wherein the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain.

### Claim 72 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71)

The dsRNA agent of any one of claims 21-71, wherein the lipophilic moiety is conjugated via a carrier that replaces one or more nucleotide(s) in the internal position(s) or the double-stranded region.

### Claim 73 (depends on 72)

The dsRNA agent of claim 72, wherein the carrier is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, and decalinyl; or is an acyclic moiety based on a serinol backbone or a diethanolamine backbone.

### Claim 74 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71)

The dsRNA agent of any one of claims 21-71, wherein the lipophilic moiety is conjugated to the double-stranded iRNA agent via a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction, or carbamate.

### Claim 75 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)

The double-stranded iRNA agent of any one of claims 21-74, wherein the lipophilic moiety is conjugated to a nucleobase, sugar moiety, or internucleosidic linkage.

### Claim 76 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75)

The dsRNA agent of any one of claims 21-75, wherein the lipophilic moiety or targeting ligand is conjugated via a bio-clevable linker selected from the group consisting of DNA, RNA, disulfide, amide, funtionalized monosaccharides or oligosaccharides of galactosamine, glucosamine, glucose, galactose, mannose, and combinations thereof.

### Claim 77 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)

The dsRNA agent of any one of claims 21-76, wherein the 3′-end of the sense strand is protected via an end cap which is a cyclic group having an amine, said cyclic group being selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, and decalinyl.

### Claim 78 (depends on 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67)

The dsRNA agent of any one of claims 21-67, further comprising a targeting ligand that targets a liver tissue.

### Claim 79 (depends on 78)

The dsRNA agent of claim 78, wherein the targeting ligand is a GalNAc conjugate.

### Claim 80 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)

The dsRNA agent of any one of claims 1-79 further comprising
a terminal, chiral modification occurring at the first internucleotide linkage at the 3′-end of the antisense strand, having the linkage phosphorus atom in Sp configuration,
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the sense strand, having the linkage phosphorus atom in either Rp configuration or Sp configuration.

### Claim 81 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)

The dsRNA agent of any one of claims 1-79 further comprising
a terminal, chiral modification occurring at the first and second internucleotide linkages at the 3′-end of the antisense strand, having the linkage phosphorus atom in Sp configuration,
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

### Claim 82 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)

The dsRNA agent of any one of claims 1-79 further comprising
a terminal, chiral modification occurring at the first, second and third internucleotide linkages at the 3′-end of the antisense strand, having the linkage phosphorus atom in Sp configuration,
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

### Claim 83 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)

The dsRNA agent of any one of claims 1-79 further comprising
a terminal, chiral modification occurring at the first, and second internucleotide linkages at the 3′-end of the antisense strand, having the linkage phosphorus atom in Sp configuration,
a terminal, chiral modification occurring at the third internucleotide linkages at the 3′-end of the antisense strand, having the linkage phosphorus atom in Rp configuration,
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

### Claim 84 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)

The dsRNA agent of any one of claims 1-79 further comprising
a terminal, chiral modification occurring at the first, and second internucleotide linkages at the 3′-end of the antisense strand, having the linkage phosphorus atom in Sp configuration,
a terminal, chiral modification occurring at the first, and second internucleotide linkages at the 5′-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and
a terminal, chiral modification occurring at the first internucleotide linkage at the 5′-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

### Claim 85 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84)

The dsRNA agent of any one of claims 1-84, further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.

### Claim 86 (depends on 85)

The dsRNA agent of claim 85, wherein the phosphate mimic is a 5′-vinyl phosphonate (VP).

### Claim 87 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The dsRNA agent of any one of claims 1-10, wherein the base pair at the 1 position of the 5′-end of the antisense strand of the duplex is an AU base pair.

### Claim 88 (depends on 66)

The dsRNA agent of claim 66, wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.

### Claim 89 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)

A cell containing the dsRNA agent of any one of claims 1-88.

### Claim 90 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)

A pharmaceutical composition for inhibiting expression of a gene encoding ATXN3 comprising the dsRNA agent of any one of claims 1-88.

### Claim 91 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)

A pharmaceutical composition comprising the dsRNA agent of any one of claims 1-88 and a lipid formulation.

### Claim 92 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91)

A method of inhibiting expression of an ATXN3 gene in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent of any one of claims 1-88, or a pharmaceutical composition of claim 90 or 91; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the ATXN3 gene, thereby inhibiting expression of the ATXN3 gene in the cell.

### Claim 93 (depends on 92)

The method of claim 92, wherein the cell is within a subject.

### Claim 94 (depends on 93)

The method of claim 93, wherein the subject is a human.

### Claim 95 (depends on 92)

The method of any one of claim 92, wherein the expression of ATXN3 is inhibited by at least 50%.

### Claim 96 (depends on 93, 94)

The method of claim 93 or 94, wherein inhibiting expression of ATXN3 decreases an ATXN3 protein level in a CNS biopsy sample or a cerebrospinal fluid (CSF) sample by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

### Claim 97 (depends on 93, 94)

The method of claim 93 or 94, wherein the subject meets at least one diagnostic criterion for SCA3.

### Claim 98 (depends on 94)

The method of claim 94, wherein the subject has been diagnosed with SCA3.

### Claim 99 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91)

A method of treating a subject diagnosed with an ATXN3-associated disorder comprising administering to the subject a therapeutically effective amount of the dsRNA agent of any one of claims 1-88, or a pharmaceutical composition of claim 90 or 91, thereby treating the disorder.

### Claim 100 (depends on 99)

The method of claim 99, wherein treating comprises amelioration of at least on sign or symptom of the disorder.

### Claim 101 (depends on 100)

The method of claim 100, wherein at least one sign or symptom of SCA3 comprises ataxia, spasticity, rigidity, bradykinesia, dysarthria, spastic paraplegia, peripheral polyneuropathy, and parkinsonism-like symptoms.

### Claim 102 (depends on 99)

The method of claim 99, where treating comprises prevention of progression of the disorder.

### Claim 103 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91)

A method of preventing development of an ATXN3-associated disorder in a subject having a mutation correlated with an ATXN3-associated disorder comprising administering to the subject a therapeutically effective amount of the dsRNA agent of any one of claims 1-88, or a pharmaceutical composition of claim 90 or 91, thereby preventing the development of an ATXN3-associated disorder in the subject meeting at least one diagnostic criterion for an ATXN3-associated disorder.

### Claim 104 (depends on 99, 103)

The method of claim 99 or 103, wherein the subject is human.

### Claim 105 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method of any one of claims 93-104, wherein the dsRNA agent is administered at a dose of about 0.01 mg/kg to about 50 mg/kg.

### Claim 106 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method of any one of claims 93-104, wherein the dsRNA agent is administered to the subject intracranially or intrathecally.

### Claim 107 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method of any one of claims 93-104, wherein the dsRNA agent is administered to the subject intrathecally, intraventricularly, or intracerebrally.

### Claim 108 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method of any one of claims 93-104, further comprising measuring level of ATXN3 in the subject.

### Claim 109 (depends on 108)

The method of claim 108, where measuring the level of ATXN3 in the subject comprises measuring the level of ATXN3 protein in a subject CNS biopsy sample or a cerebrospinal fluid (CSF) sample.

### Claim 110 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method of any one of claims 93-104, further comprising performing a diagnostic assessment selected from Scale for the Assessment and Rating of Ataxia (SARA), Composite Cerebellar Functional Severity Score (CCFS), Spinocerebellar ataxia Functional Index (SCAFI), Inventory of Non-Ataxia Signs (INAS).

### Claim 111 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method of any one of claims 93-104, further comprising administering to the subject an additional agent suitable for treatment or prevention of an ATXN3-associated disorder.

### Claim 112 (depends on 111)

The method of claim 111, wherein the additional agent is selected from symptomatic treatments for Parkinsonism-like symptoms (levodopa or dopamine agonists), psychostimulants to improve daytime fatigue (modafinil), mexiletine or carbamazepine for cramps.