Compounds and methods for reducing LRRK2 expression
Inventors
COLE, TRACY A. • Freier, Susan M.
Assignees
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Publication Number
US-12241067-B2
Publication Date
2025-03-04
Expiration Date
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.
Core Innovation
The invention relates to a modified oligonucleotide and an oligomeric compound comprising a modified oligonucleotide, wherein the modified oligonucleotide is identified by a specific formula as SEQ ID NO: 3385 or a salt thereof. The disclosed embodiments include phosphorothioate and phosphodiester internucleoside linkages, modified sugar and nucleobase features, and chemical notation defining nucleobases and linkage types. Certain embodiments specify stereorandom phosphorothioate internucleoside linkages, including mixed stereochemical configurations.
The subject matter is directed to reducing LRRK2 RNA expression and, in some embodiments, reducing LRRK2 protein. The disclosed examples connect LRRK2 reduction to neurodegenerative disease, including Parkinson’s disease, and describe amelioration of disease symptoms and hallmarks including ataxia, neuropathy, and aggregate formation.
The disclosed compositions include pharmaceutically acceptable formulations using pharmaceutically acceptable carriers and diluents, including phosphate-buffered saline and artificial cerebrospinal fluid. The subject matter further includes pharmaceutical compositions and treatment or use in connection with LRRK2-associated neurodegenerative disease.
Claims Coverage
The consolidated claim coverage centers on the modified oligonucleotide defined by SEQ ID NO: 3385 or a salt thereof, the corresponding oligomeric compound with defined chemical notation, and embodiments specifying stereorandom phosphorothioate internucleoside linkages. Dependent coverage also includes pharmaceutically acceptable diluents or carriers and functional use language directed to reducing LRRK2 expression.
Modified oligonucleotide identified by SEQ ID NO: 3385 or salt thereof
A modified oligonucleotide according to the formula SEQ ID NO: 3385 or a salt thereof.
Oligomeric compound with defined chemical notation corresponding to SEQ ID NO: 3385
An oligomeric compound comprising a modified oligonucleotide having defined 5′ to 3′ chemical notation, with nucleobases A, mC, G, T and modified sugar and linkage features defined as e for 2′-MOE modified sugar, d for 2′-deoxyribose sugar, s for phosphorothioate internucleoside linkage, and o for phosphodiester internucleoside linkage.
Stereorandom phosphorothioate internucleoside linkages
Certain embodiments specify stereorandom phosphorothioate internucleoside linkages.
Pharmaceutically acceptable diluents
Dependent claim coverage includes phosphate-buffered saline and artificial cerebrospinal fluid as pharmaceutically acceptable diluents.
Reduction of LRRK2 expression by contacting cells
A method for reducing LRRK2 expression in a cell by contacting the cell with the modified oligonucleotide.
The claims focus on the SEQ ID NO: 3385 modified oligonucleotide, the corresponding oligomeric compound defined by chemical notation, and stereorandom phosphorothioate internucleoside linkages. Dependent claim coverage further emphasizes pharmaceutically acceptable diluents including phosphate-buffered saline and artificial cerebrospinal fluid, and reducing LRRK2 expression in cells.
Stated Advantages
Reduces LRRK2 RNA expression.
Reduces LRRK2 expression in cells.
Reduces LRRK2 RNA, and in some embodiments LRRK2 protein.
Ameliorates neurodegenerative disease symptoms and hallmarks including ataxia, neuropathy, and aggregate formation.
Improves motor function in a long-term PFF α-synuclein model study.
Reduces p-α-syn aggregates in a PFF α-synuclein model.
Preserves TH-positive dopaminergic neurons in a long-term study.
Documented Applications
Treatment or use in connection with LRRK2-associated neurodegenerative disease, including Parkinson’s disease.
Reducing LRRK2 expression in a cell by contacting the cell with the modified oligonucleotide.
Administering pharmaceutical compositions comprising the modified oligonucleotide to an animal.
Pharmaceutical compositions comprising the modified oligonucleotide, including formulations with phosphate-buffered saline or artificial cerebrospinal fluid.
In vitro evaluation showing dose-dependent reduction of human LRRK2 RNA expression in SH-SY5Y cells, A431 cells, and rhesus LLC-MK2 cells.
Use in human BAC LRRK2 transgenic mice and human BAC G2019S LRRK2 transgenic rats, including ED50 calculations and tolerability assessments.
Prophylactic or therapeutic application in a PFF α-synuclein model, including reduced LRRK2 RNA, reduced p-α-syn aggregates, improved motor function, and preservation of TH-positive dopaminergic neurons.
Targeting nucleobase hotspot ranges within SEQ ID NO:2 using 20-nt 5-10-5 MOE gapmer oligonucleotides and corresponding siRNAs, with in vitro single-dose LRRK2 RNA knockdown.
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