Objective: 1. To create an in vivo model system to be used to assess the effect of chronically inhibiting LRRK2 pharmacologically. 2. To confirm previous reports that chronic administration of LRRK2 inhibitors produces an increase in size and number of type II pneumocytes in the lung. 3. To identify the therapeutic index between efficacious doses and doses that produce measurable effects in lung.

Background: The LRRK2 kinase is one of the most studied potential disease modifying targets for the treatment of Parkinson’s disease (PD). Previous work demonstrated that chronic administration of the LRRK2 inhibitor, PFE-475, AAV alpha synuclein treated rats has beneficial effects on the PD symptomology, supporting the hypothesis that LRRK2 inhibitors are effective PD therapeutics (Daher et al., 2015). In mice, chronic in diet administration of the LRRK2 inhibitor MLI2 produces a mild lung phenotype (Fell et al., 2016).

Methods: Various strains of rats and mice were treated with AAV alpla synuclein. Once strains had been identified that were responsive to the treatment we assessed the effect of chronic administration of the LRRK2 inhibitor, PFE-360, which has previously been tested in animal models. In life endpoints included assessment of behavior using a fine motor kinematic analysis and imaging for DAT levels. Ex vivo endpoints included measuring DA levels by HPLC and TH by stereology. Lungs were collected for histopathological analysis.

Results: We found that there are significant strain differences in both rat and mouse, but that there are individual strains that respond to the AAV alpha synuclein treatment with reliable and robust parkinsonian effects, including a behavioral effect. Interestingly, we found no evidence that LRRK2 overexpressing rats or mice had an exaggerated phenotype relative to WT controls. We have reproduced the effect in lung following chronic dosing of MLI2 and have found a similar effect with a structurally distinct LRRK2 inhibitor, PFE-360. Using MLI2, we also demonstrate that the effect repeatedly reverses within a week of withdrawal of drug administration. To assess to potential efficacy of a LRRK2 inhibitor, C57 mice were administered AAV alpha synuclein and then chronically treated with the LRRK2 inhibitor PFE-360. Behavioral measures were taken using the fine motor kinematic assay; TH and DA were also measured.

Conclusions: There are substantial strain and species differences in the response of rodents to AAV alpha synuclien treatment. Chronic in diet administration of a LRRK2 inhibitor produces a mild effect in the mouse lung and that effect is reversible within one week of drug withdrawal. Chronic administration of a LRRK2 inhibitor protects mice against AAV alpha synuclein mediated parkinsonian deficits.

References: Daher JP, Abdelmotilib HA, Hu X, et al. Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem. 2015 Aug 7;290(32):19433-44. doi: 10.1074/jbc.M115.660001. Fell MJ, Mirescu C, Basu K et al. MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition. J Pharmacol Exp Ther. 2015 Dec;355(3):397-409. doi: 10.1124/jpet.115.227587. Epub 2015 Sep 25.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/delivery-of-aav-alpha-synuclein-to-a-mouse-and-rat-provides-a-useful-model-for-the-assessment-of-anti-parkinsonian-efficacy-of-chronic-inhibition-of-lrrk2/