ArticleMolecular therapy. Nucleic acids2020
Splice-Switching Antisense Oligonucleotides Reduce LRRK2 Kinase Activity in Human LRRK2 Transgenic Mice.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Citron kinase activity controls alternative splicing events that drive prostate cancer growth.Science advances · 2026Article
- Antisense Oligonucleotide Therapeutics Targeting Age-Related Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Expansion of Splice-Switching Therapy with Antisense Oligonucleotides.International journal of molecular sciences · 2025Review
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- ASO-mediated knockdown or kinase inhibition ofMolecular therapy. Nucleic acids · 2023Article
- Review
- Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain.Scientific reports · 2023Article
- Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE-mediated mRNA decay in Parkinson's disease.The EMBO journal · 2023Article
- Structural Insights and Development of LRRK2 Inhibitors for Parkinson's Disease in the Last Decade.Genes · 2022Review
- Exploring the focal role of LRRK2 kinase in Parkinson's disease.Environmental science and pollution research international · 2022Review
- Nanobodies as allosteric modulators of Parkinson's disease-associated LRRK2.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Targeting Alternative Splicing for Therapeutic Interventions.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Modelling the functional genomics of Parkinson's disease in Caenorhabditis elegans: LRRK2 and beyond.Bioscience reports · 2021Review
- LRRK2 Targeting Strategies as Potential Treatment of Parkinson's Disease.Biomolecules · 2021Review
- Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy.JMA journal · 2021Review
- Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies.Translational neurodegeneration · 2021Review
- Advancing Personalized Medicine in Common Forms of Parkinson's Disease through Genetics: Current Therapeutics and the Future of Individualized Management.Journal of personalized medicine · 2021Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease (PD) is a progressive neurological disorder estimated to affect 7-10 million people worldwide. There is no treatment available that cures or slows the progression of PD. Elevated leucine-rich repeat kinase 2 (LRRK2) activity has been associated with genetic and sporadic forms of PD and, thus, reducing LRRK2 function is a promising therapeutic strategy. We have previously reported that an antisense oligonucleotide (ASO) that blocks splicing of LRRK2 exon 41, which encodes part of the kinase domain, reverses aberrant endoplasmic reticulum (ER) calcium levels and mitophagy defects in PD patient-derived cell lines harboring the LRRK2 G2019S mutation. In this study, we show that treating transgenic mice expressing human wild-type or G2019S LRRK2 with a single intracerebroventricular injection of ASO induces exon 41 skipping and results in a decrease in phosphorylation of the LRRK2 kinase substrate RAB10. Exon 41 skipping also reverses LRRK2 kinase-dependent changes in LC3B II/I ratios, a marker for the autophagic process. These results demonstrate the potential of LRRK2 exon 41 skipping as a possible therapeutic strategy to modulate pathogenic LRRK2 kinase activity associated with PD development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.