# US 10,370,667 B2 · Antisense compounds targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of parkinsons disease

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- Number: US 10,370,667 B2
- Document ID: US10370667B2
- Status: Granted
- Kind: B2
- Application number: 15/837,926
- Filed: 2017-12-11
- Published: 2018-04-05
- Granted: 2019-08-06
- Earliest claimed: 2015-11-18
- Assignees: Rosalind Franklin University of Medicine and Science; The McLean Hospital Corporation
- Applicants: Rosalind Franklin University of Medicine and Science; The McLean Hospital Corporation
- Inventors: Michelle L. Hastings; Ole Isacson; Joanna A. Korecka-Roet
- Web page: https://patentgrep.com/patent/US10370667B2

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- C12Y 207/11001: Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3233: Morpholino-type ring
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2320/33: Alteration of splicing
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The present disclosure relates generally to compounds comprising oligonucleotides complementary to a Leucine-Rich-Repeat-Kinase (LRRK2) RNA transcript. Certain such compounds are useful for hybridizing to a LRRK2 RNA transcript, including but not limited to a LRRK2 RNA transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the LRRK2 transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Parkinson's disease.

## Claims

### Claim 1

A method of modulating splicing or expression of a LRRK2 transcript in a cell comprising contacting the cell with at least one compound comprising a modified oligonucleotide having 8 to 30 linked nucleosides and having a nucleobase sequence comprising a complementary region, wherein the complementary region comprises at least 8 contiguous nucleobases complementary to an equal-length portion of a target region of a Leucine-Rich-Repeat-Kinase (LRRK2) transcript, wherein the modified oligonucleotide has a nucleobase sequence as set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cell is in vitro or in vivo.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cell is in vivo in an animal and the animal is a human.

### Claim 4 (depends on 3)

The method of claim 3, wherein the modified oligonucleotide is administered to the human by intrathecal injection, intracerebroventricular injection, inhalation, parenteral injection or infusion, oral, subcutaneous or intramuscular injection, buccal, transdermal, transmucosal, or topical.

### Claim 5 (depends on 1)

The method of claim 1, wherein the target region of the modified oligonucleotide comprises at least a portion of exon 2, exon 4, exon 31, or exon 41 of the LRRK2 transcript.

### Claim 6 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide comprises a nucleobase sequence having 20-30 linked nucleoside and having the nucleobase sequence as set forth in SEQ ID NO:9.

### Claim 7 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from a modified sugar moiety, a 2′-substituted sugar moiety, a 2′OME, a 2′F, a 2′-MOE, a bicyclic sugar moiety, a LNA, a cEt, a sugar surrogate, a morpholino, or a modified morpholino.

### Claim 8 (depends on 1)

The method of claim 1, wherein the complementary region of the modified oligonucleotide comprises 10-25 contiguous nucleobases.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound further comprises a pharmaceutically acceptable carrier or diluent.

### Claim 10 (depends on 4)

The method of claim 4, wherein the modified oligonucleotide is administered by intrathecal injection or by intracerebroventricular injection.

### Claim 11 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO:7.

### Claim 12 (depends on 7)

The method of claim 7, wherein the modified nucleoside is a morpholino.

### Claim 13 (depends on 3)

The method of claim 3, wherein the human has one or more symptoms associated with Parkinson's disease.

### Claim 14 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO:6.

### Claim 15 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO:8.

### Claim 16 (depends on 6)

The method of claim 6, wherein the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO:9.