# US 10,308,934 B2 · Compositions for modulating Ataxin 2 expression

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- Number: US 10,308,934 B2
- Document ID: US10308934B2
- Status: Granted
- Kind: B2
- Application number: 15/127,358
- Filed: 2015-03-19
- Published: 2017-06-22
- Granted: 2019-06-04
- Earliest claimed: 2014-03-19
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Susan M. Freier
- Web page: https://patentgrep.com/patent/US10308934B2

## CPC

- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/345: having at least two different backbone modifications
- C12N 2310/346: having a combination of backbone and sugar modifications
- 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

Disclosed herein are antisense compounds and methods for decreasing Ataxin 2 mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate Ataxin 2 associated diseases, disorders, and conditions. Such Ataxin 2 associated diseases include spinocerebellar ataxia type 2 (SCA2), amyotropic sclerosis (ALS), and parkinsonism.

## Claims

### Claim 1

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising a region of at least 12 contiguous nucleobases which is 90% complementary to an equal length region of nucleobases 606-656 of SEQ ID NO:1, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified sugar.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90%, at least 95% or 100% complementary to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

### Claim 3 (depends on 2)

The compound of claim 2, consisting of a single-stranded modified oligonucleotide.

### Claim 4 (depends on 2)

The compound of claim 2, wherein at least one internucleoside linkage is a modified internucleoside linkage.

### Claim 5 (depends on 4)

The compound of claim 4, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 6 (depends on 4)

The compound of claim 4, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 7 (depends on 5)

The compound of claim 5, wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage.

### Claim 8 (depends on 5)

The compound of claim 5, wherein at least one internucleoside linkage is a phosphorothioate linkage and at least one internucleoside linkage is a phosphodiester linkage.

### Claim 9 (depends on 2)

The compound of claim 2, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 10 (depends on 9)

The compound of claim 9, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 11 (depends on 2)

The compound of claim 2, wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

### Claim 12 (depends on 11)

The compound of claim 11, wherein the at least one modified sugar is a bicyclic sugar.

### Claim 13 (depends on 12)

The compound of claim 12, wherein the bicyclic sugar comprises a 4′-CH(R)—O-2′ bridge wherein R is, independently, H, C1-C12 alkyl, or a protecting group.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R is methyl.

### Claim 15 (depends on 13)

The compound of claim 13, wherein R is H.

### Claim 16 (depends on 11)

The compound of claim 11, wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group.

### Claim 17 (depends on 2)

The compound of claim 2, wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

### Claim 18 (depends on 2)

The compound of claim 2, wherein the modified oligonucleotide consists of 20 linked nucleosides.

### Claim 19 (depends on 1)

A composition comprising the compound of claim 1 and at least one of a pharmaceutically acceptable carrier or diluent.

### Claim 20 (depends on 19)

The composition of claim 19, wherein the modified oligonucleotide of the compound is a sodium salt.

### Claim 21

A compound comprising a modified oligonucleotide consisting of 12 to 30 nucleosides and having a nucleobase sequence comprising at least 12 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11, 12, 13, 92, and 93, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified sugar.

### Claim 22 (depends on 21)

The compound of claim 21, consisting of a single-stranded modified oligonucleotide.

### Claim 23 (depends on 21)

The compound of claim 21, wherein at least one internucleoside linkage is a modified internucleoside linkage.

### Claim 24 (depends on 23)

The compound of claim 23, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 25 (depends on 23)

The compound of claim 23, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 26 (depends on 24)

The compound of claim 24, wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage.

### Claim 27 (depends on 24)

The compound of claim 24, wherein at least one internucleoside linkage is a phosphorothioate linkage and at least one internucleoside linkage is a phosphodiester linkage.

### Claim 28 (depends on 21)

The compound of claim 21, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 29 (depends on 28)

The compound of claim 28, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 30 (depends on 21)

The compound of claim 21, wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

### Claim 31 (depends on 30)

The compound of claim 30, wherein the at least one modified sugar is a bicyclic sugar.

### Claim 32 (depends on 31)

The compound of claim 31, wherein the bicyclic sugar comprises a 4′-CH(R)—O-2′ bridge wherein R is, independently, H, C1-C12 alkyl, or a protecting group.

### Claim 33 (depends on 32)

The compound of claim 32, wherein R is methyl.

### Claim 34 (depends on 32)

The compound of claim 32, wherein R is H.

### Claim 35 (depends on 30)

The compound of claim 30, wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group.

### Claim 36 (depends on 21)

The compound of claim 21, wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

### Claim 37 (depends on 21)

The compound of claim 21, wherein the modified oligonucleotide consists of 20 linked nucleosides.

### Claim 38 (depends on 21)

A composition comprising the compound of claim 21 and at least one of a pharmaceutically acceptable carrier or diluent.

### Claim 39 (depends on 38)

The composition of claim 38, wherein the modified oligonucleotide of the compound is a sodium salt.