LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model
Hien Tran Zhao1, Neena John2, Vedad Delic2
1Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Abstract:
No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain. Administration of LRRK2 ASOs to the brain reduces LRRK2 protein levels and fibril-induced α-syn inclusions. Mice exposed to α-syn fibrils treated with LRRK2 ASOs show more tyrosine hydroxylase (TH)-positive neurons compared to control mice. Furthermore, intracerebral injection of LRRK2 ASOs avoids unwanted phenotypes associated with loss of LRRK2 expression in the periphery. This study further demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of α-syn inclusions. Importantly, this study points toward LRRK2 ASOs as a potential therapeutic strategy for preventing PD-associated pathology and phenotypes without causing potential adverse side effects in peripheral tissues associated with LRRK2 inhibition.
Insights
Antisense oligonucleotides (ASOs) targeting leucine-rich repeat kinase 2 (LRRK2) reduce Parkinson's disease pathology in the brain. This approach avoids peripheral side effects seen with LRRK2 inhibitors, offering a promising therapeutic strategy.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Parkinson's disease (PD) lacks disease-modifying treatments.
- Inhibiting leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic avenue.
- Current LRRK2 inhibitors can cause systemic side effects in peripheral tissues.
Purpose of the Study:
- To investigate antisense oligonucleotides (ASOs) as a CNS-restricted LRRK2 inhibition strategy.
- To evaluate the efficacy of LRRK2 ASOs in reducing Parkinson's disease pathology.
- To assess the safety profile of LRRK2 ASOs compared to systemic inhibitors.
Main Methods:
- Administration of LRRK2-targeting antisense oligonucleotides (ASOs) directly into the brain.
- Assessment of LRRK2 protein levels and alpha-synuclein (α-syn) pathology in mouse models.
- Evaluation of neuronal survival, specifically tyrosine hydroxylase (TH)-positive neurons.
- Monitoring for peripheral phenotypes associated with LRRK2 inhibition.
Main Results:
- Central administration of LRRK2 ASOs effectively reduced LRRK2 protein levels in the brain.
- LRRK2 ASOs significantly decreased α-synuclein inclusions induced by α-syn fibrils.
- Mice treated with LRRK2 ASOs exhibited increased numbers of TH-positive neurons.
- Intracerebral LRRK2 ASO treatment did not induce adverse peripheral phenotypes.
Conclusions:
- LRRK2 ASOs represent a viable strategy for CNS-targeted Parkinson's disease therapy.
- Reducing endogenous LRRK2 levels effectively mitigates α-syn pathology.
- This approach offers a potential treatment for PD without peripheral side effects.
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