# US 2021/0340546 A1 · Methods for reducing lrrk2 expression

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- Number: US 2021/0340546 A1
- Document ID: US20210340546A1
- Status: Published application
- Kind: A1
- Application number: 17/125,738
- Filed: 2020-12-17
- Published: 2021-11-04
- Earliest claimed: 2016-01-05
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Hien Thuy Zhao; Holly Kordasiewicz
- Web page: https://patentgrep.com/patent/US20210340546A1

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 31/7115: Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
- 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
- A61P 25/16: Anti-Parkinson drugs
- C12N 9/12: transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- 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 2310/346: having a combination of backbone and sugar modifications
- C12Y 207/11001: Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Y: ENZYMES

## Abstract

Provided herein are methods for decreasing LRRK2 mRNA expression. Such methods are useful to ameliorate LRRK2 associated diseases. Such LRRK2 associated diseases include Parkinson's Disease, including non-LRRK2 mediated Parkinson's Disease.

## Claims

### Claim at position 1

1-43. (canceled)

### Claim 44

A method comprising administering to an animal having Parkinson's disease an oligomeric compound comprising a modified oligonucleotide, wherein the animal has a causative LRRK2 genetic mutation for Parkinson's disease, and wherein the modified oligonucleotide:
a) consists of 12 to 30 linked nucleosides;
b) has a nucleobase sequence that is at least 90% complementary to the nucleobase sequence of SEQ ID NO: 2 or SEQ ID NO: 3; and
c) comprises at least one modified nucleoside comprising a modified sugar moiety and/or at least one modified internucleoside linkage,
wherein the administering results in an amelioration of a symptom of Parkinson's disease selected from aggregate formation or reduced motor function.

### Claim 45

A method comprising identifying an animal having Parkinson's disease wherein the animal has a causative LRRK2 genetic mutation for Parkinson's disease, and administering to the animal an oligomeric compound comprising a modified oligonucleotide, wherein the modified oligonucleotide:
a) consists of 12 to 30 linked nucleosides;
b) has a nucleobase sequence that is at least 90% complementary to the nucleobase sequence of SEQ ID NO: 2 or SEQ ID NO: 3; and
c) comprises at least one modified nucleoside comprising a modified sugar moiety and/or at least one modified internucleoside linkage,
wherein the administering results in an amelioration of a symptom of Parkinson's disease selected from aggregate formation or reduced motor function.

### Claim 46 (depends on 44)

The method of claim 44, wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to LRRK2.

### Claim 47 (depends on 44)

The method of claim 44, wherein the administering results in improved motor function.

### Claim 48 (depends on 44)

The method of claim 44, wherein the administering results in reduced aggregate formation.

### Claim 49 (depends on 44)

The method of claim 44, wherein the oligomeric compound is administered prior to the detection of the symptom.

### Claim 50 (depends on 44)

The method of claim 44, wherein the amelioration is the slowing of progression of the symptom, the delay of onset of the symptom, or the reduction in severity or frequency of the symptom.

### Claim 51 (depends on 44)

The method of claim 44, wherein expression of LRRK2 mRNA and/or LRRK2 protein is reduced in the animal.

### Claim 52 (depends on 44)

The method of claim 44, wherein the animal is a human.

### Claim 53 (depends on 44)

The method of claim 44, wherein the oligomeric compound is single-stranded.

### Claim 54 (depends on 44)

The method of claim 44, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.

### Claim 55 (depends on 54)

The method of claim 54, wherein the at least one modified nucleoside comprises a bicyclic sugar moiety.

### Claim 56 (depends on 55)

The method of claim 55, wherein the bicyclic sugar moiety has a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH2—; —O—CH2—CH2—; and —O—CH(CH3)—.

### Claim 57 (depends on 44)

The method of claim 44, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety.

### Claim 58 (depends on 57)

The method of claim 57, wherein the modified non-bicyclic sugar moiety comprises 2′-O-methoxyethyl (2′-MOE) or 2′-OMe.

### Claim 59 (depends on 44)

The method of claim 44, wherein the at least one modified nucleoside comprises a sugar surrogate.

### Claim 60 (depends on 44)

The method of claim 44, wherein the modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 1-5 linked 5′-region nucleosides;
a central region consisting of 6-10 linked central region nucleosides; and
a 3′-region consisting of 1-5 linked 3′-region nucleosides,
wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.

### Claim 61 (depends on 44)

The method of claim 44, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 62 (depends on 44)

The method of claim 44, wherein each internucleoside linkage of the modified oligonucleotide is either an unmodified phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

### Claim 63 (depends on 44)

The method of claim 44, wherein the modified oligonucleotide comprises at least one modified nucleobase, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 64 (depends on 44)

The method of claim 44, wherein the oligomeric compound comprises a conjugate group.

### Claim 65 (depends on 44)

The method of claim 44, wherein the oligomeric compound is paired with a second oligomeric compound to form a duplex.

### Claim 66 (depends on 44)

The method of claim 44, wherein the administering is intrathecal administration or intracerebroventricular administration.

### Claim 67 (depends on 44)

The method of claim 44, wherein the administering does not cause toxicity in the periphery.