IP Library › Granted Patent US 12,241,067
Granted Patent B2
US 12,241,067 · App. 18/523,746 · Granted Mar 4, 2025

Compounds and methods for reducing LRRK2 expression

Inventors: Tracy A. Cole (Encintas, CA); Susan M. Freier (San Diego, CA)
Assignee: Ionis Pharmaceuticals, Inc.
C12N15/1137A61K31/7125A61K47/02A61K47/46A61P25/16C12N2310/11C12N2310/315C12N2310/321C12N2310/3341C12N2310/341C12N2310/346C12N2310/3525
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Quick Facts
Patent No.
US 12,241,067
App. No.
18/523,746
Granted
Mar 4, 2025
Kind
B2
Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of LRRK2 RNA in a cell or animal, and in certain instances reducing the amount of LRRK2 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include Parkinson's disease.

Claims (37)

1. A modified oligonucleotide according to the following formula:

(SEQ ID NO: 3385) or a salt thereof.

2. The modified oligonucleotide of claim 1 , which is a sodium salt or a potassium salt.

3. A modified oligonucleotide according to the following formula:

(SEQ ID NO: 3385).

4. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′):

Aes Geo mCeo Aeo Aes Tds mCds Ads Tds Tds Gds Gds Tds Ads Gds mCeo Aeo Tes Aes mCe   (SEQ TD NO: 3385);

wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

5. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

6. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent or carrier.

7. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid.

8. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid.

9. A method comprising administering to an animal a pharmaceutical composition of claim 6 .

10. A population of modified oligonucleotides of claim 3 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

11. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent or carrier.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid.

13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid.

14. A method comprising administering to an animal a pharmaceutical composition of claim 11 .

15. A population of oligomeric compounds of claim 4 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

16. A pharmaceutical composition comprising the oligomeric compound of claim 4 and a pharmaceutically acceptable diluent or carrier.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline or artificial cerebrospinal fluid.

18. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline or artificial cerebrospinal fluid.

19. A method comprising administering to an animal a pharmaceutical composition of claim 16 .

20. A method of treating Parkinson's disease comprising administering to a subject having or at risk for developing Parkinson's disease a therapeutically effective amount of a pharmaceutical composition according to claim 6 , and thereby treating the Parkinson's disease.

21. The method of claim 20 , wherein at least one symptom or hallmark of Parkinson's disease is ameliorated.

22. The method of claim 21 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.

23. The method of claim 20 , wherein the subject is human.

24. A method of reducing expression of LRRK2 in a cell comprising contacting the cell with a modified oligonucleotide of claim 1 .

25. The method of claim 24 , wherein the cell is a human cell.

Continuity (4)
Continuation 17712822 · Apr 4, 2022
Continuation 16972822
Provisional Application 62690790 · Jun 27, 2018
Related Publication 20240360453A1 · Oct 31, 2024
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Tong et al., “Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway” Mol Neurodegener (2012) 7: 1-16. [cited by applicant]
Tran et al., “Antisense oligonucleotides to LRRK2 ameliorate alpha-synuclein pathology and behavioral deficit induced by pre-formed alpha-synuclein fibrils.” Abstract from Society for Neuroscience meeting Nov. 15, 2016,… [cited by applicant]
Volpicelli-Daley et al, “LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons” J Neuroscience (2016) 36(28):7415-7427. [cited by applicant]
Volpicelli-Daley et al., “LRRK2 facilitates formation of alph-synuclein inclusions.” abstract from Society for Neuroscience meeting, Nov. 15, 2016, retreived online Aug. 21, 2018 http://www.abstractsonline.com/pp8/index… [cited by applicant]
Volta et al., “Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.” Pa… [cited by applicant]
Woolf et al., “Specificity of antisense oligonucleotides in vivo” PNAS (1992) 89: 7305-7309. [cited by applicant]
Ynigo-Mojado et al., “Efficient allele-specific targeting of LRRK2 R1441 mutations mediated by RNAi” PLoS One (2011) 6: e21352. [cited by applicant]
Zhao et al., “Antisense oligonucleotides to LRRK2 ameliorate alpha-synuclein pathology and behavioral deficit induced by pre-formed alpha-sunuclein fibrils” Abstract from American Acadamy of Neurology meeting, Oct. 16, … [cited by applicant]
Zhao et al., “Antisense oligonucleotides to LRRK2 ameliorate alpha-synuclein pathology and behavioral deficit induced by pre-formed alpha-synuclein fibrils” Presentation for Society for Neuroscience Annual Meeting (Sep.… [cited by applicant]
Zhao “Inhibitors of Leucine-rich Repeat Kinase 2 (LRRK2): Progress & Promise for the Treatment of Parkinson's Disease” Presentation for World CNS Summit (Feb. 20, 2017). [cited by applicant]
Zhao et al., “Antisense Oligonucleotides to LRRK2 Ameliorate alpha-Synuclein Pathology and Behavioral Deficit Induced by Pre-Formed alpha-Synuclein Fibrils.” Annals of Neurology (2017) 82(21):S56-S57. [cited by applicant]
Zhao et al., “Antisense Oligonucleotides to LRRK2 Ameliorate alpha-Synuclein Pathology and Behavioral Deficit Induced by Pre-Formed alpha-Synuclein Fibrils.” 13th International Conference on Alzheimer's and Parkinson's … [cited by applicant]
Zhao et al., “LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model” Mol Ther Nucleic Acids (2017) 8:508-519. [cited by applicant]
Zhao et al., “LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model” Abstract for 142nd Annual Meeting of the American Neurological Association (Oct. 15-17, 201… [cited by applicant]
Zhao et al., “LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model” Poster for 142nd Annual Meeting of the American Neurological Association (Oct. 15-17, 2017). [cited by applicant]