# US 2018/0023077 A1 · Compositions for modulating expression of c9orf72 antisense transcript

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- Number: US 2018/0023077 A1
- Document ID: US20180023077A1
- Status: Published application
- Kind: A1
- Application number: 15/540,251
- Filed: 2016-01-06
- Published: 2018-01-25
- Earliest claimed: 2015-01-06
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Frank Rigo
- Web page: https://patentgrep.com/patent/US20180023077A1

## 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)}
- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/31: of the backbone
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/33: of the base
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/351: Conjugate
- C12N 2320/31: Combination therapy
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Disclosed herein are compositions and methods for reducing expression of C9ORF72 antisense transcript in an animal with C9ORF72 antisense transcript specific inhibitors. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Such C9ORF72 antisense transcript specific inhibitors include antisense compounds.

## Claims

### Claim 1

A compound comprising a C9ORF72 antisense transcript specific inhibitor.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the C9ORF72 antisense transcript specific inhibitor is an antisense compound.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the C9ORF72 antisense transcript specific antisense compound is an antisense oligonucleotide.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the antisense oligonucleotide consists of 12-30 linked nucleosides.

### Claim 5 (depends on 3)

The compound of claim 3, wherein the antisense oligonucleotide consists of 16-25 linked nucleosides.

### Claim 6 (depends on 3)

The compound of claim 3, wherein the antisense oligonucleotide consists of 18-22 linked nucleosides.

### Claim 7 (depends on 3, 4, 5, 6)

The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 antisense transcript.

### Claim 8 (depends on 3, 4, 5, 6)

The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is at least 90% complementary to a C9ORF72 antisense transcript.

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

The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is at least 95% complementary to a C9ORF72 antisense transcript.

### Claim 10 (depends on 3, 4, 5, 6)

The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is 100% complementary to a C9ORF72 antisense transcript.

### Claim 11 (depends on 7, 8, 9, 10)

The compound of any of claims 7-10, wherein the C9ORF72 antisense transcript has the nucleobase sequence of SEQ ID NO: 13.

### Claim 12 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11)

The compound of any of claims 3-11, wherein the antisense oligonucleotide has a nucleobase sequence comprising least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of a sequence selected from among SEQ ID NO: 30-84.

### Claim 13 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The compound of claim 3-12, wherein the antisense oligonucleotide is a modified antisense oligonucleotide.

### Claim 14 (depends on 13)

The compound of claim 13, wherein the modified antisense oligonucleotide comprises at least one modified internucleoside linkage.

### Claim 15 (depends on 14)

The compound of claim 14, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 16 (depends on 14)

The compound of claim 14, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 17 (depends on 13, 14, 15)

The compound of any of claims 13-15 wherein the modified antisense oligonucleotide comprises at least one phosphodiester internucleoside linkage.

### Claim 18 (depends on 13, 14, 15, 16, 17)

The compound of claims 13-17, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified nucleobase.

### Claim 19 (depends on 13, 14, 15, 16, 17, 18)

The compound of claim 13-18, wherein at least one modified nucleobase is a hypoxanthine.

### Claim 20 (depends on 19)

The compound of claim 19, wherein at least one modified nucleobase is a 5-methylcytosine.

### Claim 21 (depends on 13, 14, 15, 16, 17, 18, 19, 20)

The compound of claims 13-20, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

### Claim 22 (depends on 21)

The compound of claim 21, wherein the at least one modified sugar is a bicyclic sugar.

### Claim 23 (depends on 22)

The compound of claim 22, wherein the bicyclic sugar comprises a chemical bridge between the 2′ and 4′ position of the sugar, wherein the chemical bridge is selected from: 4′-CH2—O-2′; 4′-CH(CH3)—O-2′; 4′-(CH2)2—O-2′; and 4′-CH2—N(R)—O-2′ wherein R is, independently, H, C1-C12 alkyl, or a protecting group.

### Claim 24 (depends on 21)

The compound of claim 21, wherein at least one modified sugar comprises a 2′-O-methoxyethyl group.

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

The compound of any of claims 3-24, wherein the antisense oligonucleotide is a gapmer.

### Claim 26 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The compound of any of claims 3-25, wherein the antisense oligonucleotide is 20 nucleosides in length.

### Claim 27 (depends on 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)

The compound of any of claims 2-26, wherein the compound comprises at least one conjugate.

### Claim 28 (depends on 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)

The compound of any of claims 2-27, wherein the C9ORF72 antisense transcript specific antisense compound consists of an antisense oligonucleotide.

### Claim 29 (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)

A pharmaceutical composition comprising the compound of any of claims 1-28 and a pharmaceutically acceptable diluent or carrier.

### Claim 30 (depends on 29)

The pharmaceutical composition of claim 29 comprising a C9ORF72 sense transcript specific inhibitor.

### Claim 31 (depends on 30)

The pharmaceutical composition of claim 30, wherein the C9ORF72 sense transcript specific inhibitor is a C9ORF72 sense transcript specific antisense compound.

### Claim 32 (depends on 31)

The pharmaceutical composition of claim 31, wherein the C9ORF72 sense transcript specific antisense compound is an antisense oligonucleotide.

### Claim 33

A pharmaceutical composition comprising a C9ORF72 antisense transcript specific inhibitor and a C9ORF sense transcript specific inhibitor.

### Claim 34 (depends on 33)

The pharmaceutical composition of claim 33, wherein the C9ORF72 sense transcript specific inhibitor is a C9ORF72 sense transcript specific antisense compound.

### Claim 35 (depends on 33, 34)

The pharmaceutical composition of claim 33 or 34, wherein the C9ORF72 antisense transcript specific inhibitor is a C9ORF72 antisense transcript specific antisense compound.

### Claim 36 (depends on 33, 34, 35)

The pharmaceutical composition of claim 33-35, wherein the C9ORF72 sense transcript specific antisense compound is an antisense oligonucleotide.

### Claim 37 (depends on 33, 34, 35, 36)

The pharmaceutical composition of claim 33-36, wherein the C9ORF72 antisense transcript specific antisense compound is an antisense oligonucleotide.

### Claim 38 (depends on 29, 30, 31, 32, 33, 34, 35, 36, 37)

The pharmaceutical composition of claims 29-37, wherein the C9ORF72 antisense transcript is SEQ ID NO: 13.

### Claim 39 (depends on 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)

The pharmaceutical composition of claims 29-38, wherein the C9ORF72 sense transcript is any of SEQ ID NOs: 1-10.

### Claim 40

Use of the compound of any preceding claim for the manufacture of a medicament for treating a neurodegenerative disease.

### Claim 41

A method comprising contacting a cell with an antisense oligonucleotide having the nucleobases sequence of any of SEQ ID NOs: 30-84.

### Claim 42

A method comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor.

### Claim 43

A method comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor and a C9ORF72 sense transcript specific inhibitor.

### Claim 44

A method comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor; and thereby reducing the level or expression of C9ORF72 antisense transcript in the cell.

### Claim 45

A method comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor and a C9ORF72 sense transcript specific inhibitor; and thereby reducing the level or expression of both C9ORF72 antisense transcript and C9ORF72 sense transcript in the cell.

### Claim 46 (depends on 42, 43, 44, 45)

The method of any of claim 42-45, wherein the C9ORF72 antisense specific inhibitor is an antisense compound.

### Claim 47 (depends on 41, 42, 43, 44, 45, 46)

The method of any of claims 41-46, wherein the cell is in vitro.

### Claim 48 (depends on 41, 42, 43, 44, 45, 46)

The method of any of claims 41-46, wherein the cell is in an animal.

### Claim 49

A method, comprising administering to an animal in need thereof a therapeutically effective amount of a C9ORF72 antisense transcript specific inhibitor.

### Claim 50 (depends on 49)

The method of claim 49, wherein said amount is effective to reduce the level or expression of the C9ORF72 antisense transcript.

### Claim 51

A method, comprising co-administering to an animal in need thereof a therapeutically effective amount of a C9ORF72 antisense transcript inhibitor and a therapeutically effective amount of a C9ORF72 sense transcript inhibitor.

### Claim 52 (depends on 51)

The method of claim 51, wherein said therapeutically effective amount is effective to reduce the level or expression of the C9ORF72 antisense transcript and the C9ORF72 sense transcript.

### Claim 53 (depends on 49, 50, 51, 52)

The method of claim 49-52, wherein the C9ORF72 antisense transcript inhibitor is a C9ORF72 antisense transcript specific antisense compound.

### Claim 54 (depends on 51, 52, 53)

The method of claims 51-53, wherein the C9ORF72 sense transcript inhibitor is a C9ORF72 sense transcript specific antisense compound.

### Claim 55

A method, comprising:
identifying an animal having a C9ORF72 associated disease; and
administering to the animal a therapeutically effective amount of a C9ORF72 antisense transcript specific inhibitor.

### Claim 56 (depends on 55)

The method of claim 55, wherein the amount is effective to reduce the level or expression of the C9OR72 antisense transcript.

### Claim 57

A method, comprising:
identifying an animal having a C9ORF72 associated disease; and
coadministering to the animal a therapeutically effective amount of a C9ORF72 antisense transcript specific inhibitor and a therapeutically effective amount of a C9ORF72 sense transcript inhibitor.

### Claim 58 (depends on 57)

The method of claim 57, wherein said amount is effective to reduce the level or expression of the C9ORF72 antisense transcript and the C9ORF72 sense transcript.

### Claim 59 (depends on 55, 56, 57, 58)

The method of claims 55-58, wherein the C9ORF72 antisense transcript specific inhibitor is a C9ORF72 antisense transcript specific antisense compound.

### Claim 60 (depends on 57, 58, 59)

The method of claims 57-59, wherein the C9ORF72 sense transcript inhibitor is a C9ORF72 sense transcript specific antisense compound.

### Claim 61

The method of any preceding claim, wherein the C9ORF72 antisense transcript specific antisense compound is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 antisense transcript.

### Claim 62

The method of any preceding claim, wherein the C9ORF72 sense transcript specific antisense compound is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 sense transcript.

### Claim 63

The method of any preceding claim, wherein the C9ORF72 antisense transcript is SEQ ID NO: 13.

### Claim 64

The method of any preceding claim, wherein the C9ORF72 sense transcript is any of SEQ ID NO: 1-10.

### Claim 65 (depends on 55, 56, 57, 58, 59, 60, 61, 62, 63, 64)

The method of claims 55-64, wherein the C9ORF72 associated disease is a C9ORF72 hexanucleotide repeat expansion associated disease.

### Claim 66 (depends on 59, 60, 61, 62, 63, 64, 65)

The method of claims 59-65, wherein the C9ORF72 associated disease or C9ORF72 hexanucleotide repeat expansion associated disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), corticobasal degeneration syndrome (CBD), atypical Parkinsonian syndrome, and olivopontocerebellar degeneration (OPCD).

### Claim 67 (depends on 66)

The method of claim 66, wherein the amyotrophic lateral sclerosis (ALS) is familial ALS.

### Claim 68 (depends on 66)

The method of claim 66, wherein the amyotrophic lateral sclerosis (ALS) is sporadic ALS.

### Claim 69

The method of any preceding claim, wherein the contacting or administering reduces C9ORF72 antisense transcript associated RAN translation products.

### Claim 70 (depends on 69)

The method of claim 69, wherein the C9ORF72 antisense transcript associated RAN translation products are any of poly-(proline-alanine), poly-(proline-arginine), and poly-(proline-glycine).

### Claim 71 (depends on 49, 50, 51, 52, 53, 54, 55, 56, 57)

The method of claims 49-57, wherein the administering and coadminstering is parenteral administration.

### Claim 72 (depends on 71)

The method of claim 71, wherein the parental administration is any of injection or infusion.

### Claim 73 (depends on 71)

The method of claim 71, wherein the parenteral administration is any of intrathecal administration or intracerebroventricular administration.

### Claim 74 (depends on 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73)

The method of claims 55-73, wherein at least one symptom of a C9ORF72 associated disease or a C9ORF72 hexanucleotide repeat expansion associated disease is slowed, ameliorated, or prevented.

### Claim 75 (depends on 74)

The method of claim 74, wherein at least one symptom is any of motor function, respiration, muscle weakness, fasciculation and cramping of muscles, difficulty in projecting the voice, shortness of breath, difficulty in breathing and swallowing, inappropriate social behavior, lack of empathy, distractibility, changes in food preferences, agitation, blunted emotions, neglect of personal hygiene, repetitive or compulsive behavior, and decreased energy and motivation.

### Claim 76

The method of any preceding claim, wherein the C9ORF72 antisense transcript specific antisense compound is an antisense oligonucleotide.

### Claim 77

The method of any preceding claim, wherein the C9ORF72 sense transcript specific antisense compound is an antisense oligonucleotide.

### Claim 78 (depends on 76, 77)

The method of claim 76 or 77, wherein the antisense oligonucleotide is a modified antisense oligonucleotide.

### Claim 79 (depends on 78)

The method of claim 78, wherein at least one internucleoside linkage of the antisense oligonucleotide is a modified internucleoside linkage.

### Claim 80 (depends on 79)

The method of claim 79, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 81 (depends on 79)

The method of claim 79, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 82 (depends on 78)

The method of claim 78, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a hypoxanthine.

### Claim 83 (depends on 78, 79, 80, 81, 82)

The method of claims 78-82, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified nucleobase.

### Claim 84 (depends on 82)

The method of claim 82, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 85 (depends on 78, 79, 80, 81, 82, 83, 84)

The method of claims 78-84, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

### Claim 86 (depends on 85)

The method of claim 85, wherein the at least one modified sugar is a bicyclic sugar.

### Claim 87 (depends on 86)

The method of claim 86, wherein the bicyclic sugar comprises a chemical bridge between the 2′ and 4′ position of the sugar, wherein the chemical bridge is selected from: 4′-CH2—O-2′; 4′-CH(CH3)—O-2′; 4′-(CH2)2—O-2′; and 4′-CH2—N(R)—O-2′ wherein R is, independently, H, C1-C12 alkyl, or a protecting group.

### Claim 88 (depends on 85)

The method of claim 85, wherein at least one modified sugar comprises a 2′-O-methoxyethyl group.

### Claim 89

The method of any preceding claim, wherein the antisense oligonucleotide is a gapmer.

### Claim 90

A compound comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases of any of the nucleobases sequences of SEQ ID NOs: 30-99.

### Claim 91 (depends on 90)

The compound of claim 90, wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 antisense transcript.

### Claim 92 (depends on 91)

The compound of claim 91, wherein the C9ORF72 antisense transcript has the nucleobase sequence of SEQ ID NO: 13.

### Claim 93 (depends on 90, 91, 92)

The compound of any of claims 90-92, wherein the modified oligonucleotide is a single-stranded modified oligonucleotide.

### Claim 94 (depends on 90, 91, 92, 93)

The compound of any of claims 90-93, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

### Claim 95 (depends on 94)

The compound of any of claim 94, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 96 (depends on 94, 95)

The compound of claims 94 or 95, wherein the modified oligonucleotide comprises at least one phosphodiester linkage.

### Claim 97 (depends on 95)

The compound of claim 95, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 98 (depends on 90, 91, 92, 93, 94, 95, 96, 97)

The compound of any of claims 90-97, wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.

### Claim 99 (depends on 98)

The compound of claim 98, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 100 (depends on 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)

The compound of any of claims 90-99, wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

### Claim 101 (depends on 100)

The compound of claim 100, wherein each nucleoside of the modified oligonucleotide comprises a modified sugar.

### Claim 102 (depends on 100, 101)

The compound of claims 100 or 101, wherein the modified sugar is a bicyclic sugar.

### Claim 103 (depends on 102)

The compound of claim 102, wherein the bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein the chemical bridge is selected from: 4′-CH(R)—O-2′ and 4′-(CH2)2—O-2′, wherein R is independently selected from H, C1-C6 alkyl, and C1-C6 alkoxy.

### Claim 104 (depends on 103)

The compound of claim 103, wherein the chemical bridge is 4′-CH(R)—O-2′ and wherein R is methyl.

### Claim 105 (depends on 103)

The compound of claim 103, wherein the chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.

### Claim 106 (depends on 103)

The compound of claim 103, wherein the chemical bridge is 4′-CH(R)—O-2′ and wherein R is —CH2—O—CH3.

### Claim 107 (depends on 100, 101)

The compound of claims 100 or 101, wherein the modified sugar comprises a 2′-O-methoxyethyl group.

### Claim 108 (depends on 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107)

The compound of any of claims 90-100 and 102-107, wherein the modified oligonucleotide is a gapmer.

### Claim 109 (depends on 108)

The compound of claim 108, wherein the gapmer is selected from a 5-10-5 MOE gapmer, a 5-8-5 MOE gapmer, or a 4-8-4 MOE gapmer.

### Claim 110

A pharmaceutical composition comprising the compound of any preceding claim or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.

### Claim 111 (depends on 110)

The pharmaceutical composition of claim 110 further comprising a C9ORF72 sense transcript specific inhibitor.

### Claim 112 (depends on 111)

The pharmaceutical composition of claim 111, wherein the C9ORF72 sense transcript specific inhibitor is any of a nucleic acid, aptamer, antibody, peptide, or small molecule.

### Claim 113 (depends on 112)

The pharmaceutical composition of claim 112, wherein the nucleic acid is a single-stranded nucleic acids or a double-stranded nucleic acid.

### Claim 114 (depends on 112)

The pharmaceutical composition of claim 112, wherein the nucleic acid is a siRNA.

### Claim 115 (depends on 111)

The pharmaceutical composition of claim 111, wherein the C9ORF72 sense transcript inhibitor is an antisense compound.

### Claim 116 (depends on 115)

The pharmaceutical composition of claim 115, wherein the antisense compound is an antisense oligonucleotide.

### Claim 117 (depends on 115)

The pharmaceutical composition of claim 115, wherein the antisense compound is a modified oligonucleotide.

### Claim 118 (depends on 115)

The pharmaceutical composition of claim 115, wherein the modified oligonucleotide is single-stranded.

### Claim 119 (depends on 115, 116)

The pharmaceutical composition of claims 115 or 116, wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 sense transcript.

### Claim 120 (depends on 119)

The pharmaceutical composition of claim 119, wherein the C9ORF72 sense transcript has the nucleobase sequence of SEQ ID NO: 1-10.

### Claim 121

Use of the compound or composition of any preceding claim for the manufacture of a medicament for treating a neurodegenerative disease.

### Claim 122

A method comprising administering to an animal the compound or composition of any preceding claim.

### Claim 123 (depends on 122)

The method of claim 122, wherein the compound prevents, treats, ameliorates, or slows progression of at least one symptom of a C9ORF72 associated disease.

### Claim 124 (depends on 123)

The method of claim 123, wherein the at least one symptom is selected from among impaired motor function, difficulty with respiration, muscle weakness, fasciculation and cramping of muscles, difficulty in projecting the voice, shortness of breath, difficulty in breathing and swallowing, inappropriate social behavior, lack of empathy, distractibility, changes in food preference, agitation, blunted emotions, neglect of personal hygiene, repetitive or compulsive behavior, and decreased energy and motivation.

### Claim 125 (depends on 123)

The method of claim 123, wherein the C9ORF72 associated disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), corticobasal degeneration syndrome (CBD), atypical Parkinsonian syndrome, or olivopontocerebellar degeneration (OPCD).

### Claim 126 (depends on 125)

The method of claim 125, wherein the amyotrophic lateral sclerosis (ALS) is familial ALS.

### Claim 127 (depends on 125)

The method of claim 125, wherein the amyotrophic lateral sclerosis (ALS) is sporadic ALS.

### Claim 128 (depends on 121, 122, 123, 124, 125, 126, 127)

The method of any of claims 121-127, wherein the administering reduces C9ORF72 antisense transcript associated RAN translation products.

### Claim 129 (depends on 128)

The method of claim 128, wherein the C9ORF72 antisense transcript associated RAN translation products are any of poly-(proline-alanine), poly-(proline-arginine), and poly-(proline-glycine).

### Claim 130 (depends on 121, 122, 123, 124, 125, 126, 127)

The method of any of claims 121-127, wherein the administering reduces C9ORF72 antisense foci.

### Claim 131 (depends on 121, 122, 123, 124, 125, 126, 127)

The method of any of claims 121-127, wherein the administering reduces C9ORF72 sense foci.

### Claim 132 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131)

The method of any of claims 121-131, wherein the administering is parenteral administration.

### Claim 133 (depends on 132)

The method of claim 132, wherein the parenteral administration is any of injection or infusion.

### Claim 134 (depends on 133)

The method of claim 133, wherein the parenteral administration is directly into the central nervous system (CNS).

### Claim 135 (depends on 132, 133, 134)

The method of any of claims 132-134, wherein the parenteral administration is any of intrathecal administration or intracerebroventricular administration.

### Claim 136 (depends on 85)

The compound of claim 85, wherein the modified oligonucleotide comprises sugar residues in any of the following patterns: eeedeeeeedeeeeedeeee or eeeeedeeeeedeeeeee, wherein,
e=a 2′-O-methoxyethylribose modified sugar, and
d=a 2′-deoxyribose sugar.

### Claim 137 (depends on 94)

The compound of claim 94, wherein the modified oligonucleotide comprises internucleoside linkages in any of the following patterns: soooossssssssssooss, sooosssssssssooss, ssososssososssososs, or ssssososssosossss, wherein,
s=a phosphorothioate linkage, and
o=a phosphodiester linkage.

### Claim 138

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 196-280 of SEQ ID NO: 13.

### Claim 139

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 286-315 of SEQ ID NO: 13.

### Claim 140

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 321-415 of SEQ ID NO: 13.

### Claim 141

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 451-516 of SEQ ID NO: 13.

### Claim 142

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 527-588 of SEQ ID NO: 13.

### Claim 143

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 608-636 of SEQ ID NO: 13.

### Claim 144

A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 704-726 of SEQ ID NO: 13.

### Claim 145 (depends on 138, 139, 140, 141, 142, 143, 144)

The compound of any of claims 138-144, wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to SEQ ID NO: 13.