Objective: We will present the preclinical efficacy and safety data and the design of the first in human trial of an antisense oligonucleotide (ASO) for leucine-rich repeat kinase 2 (LRRK2). This is the first clinical ASO study in Parkinson’s disease (PD).

Background: We hypothesize that reducing LRRK2 will slow PD progression. Key preclinical proof of concept data have been published demonstrating that a tool LRRK2 ASO attenuates α-synuclein‑induced pathology and neuronal loss in a mouse model (Zhao et al 2017).

Method: ASOs designed to specifically target LRRK2 mRNA, resulting in RNase H1-mediated degradation of the mRNA, in turn reducing LRRK2 protein levels, were screened and potential candidates were identified & evaluated in preclinical efficacy and safety studies.

Results: The lead ASO was shown to selectively and potently reduce the levels of LRRK2 mRNA in vitro, in monkey and human cell lines. In vivo studies in rodents (i.c.v. administration) and in cynomolgus macaques (i.t. administration) demonstrated that the ASO potently reduced LRRK2 mRNA and protein levels throughout the brain. FIH-enabling toxicology studies have been successfully completed in mice and non-human primates. In the non-human primates, the lead LRRK2 ASO was well tolerated and, importantly, there was no LRRK2 mRNA reduction and no pathology in the lung, a known target organ for LRRK2.

Conclusion: The pharmacodynamic, safety and toxicology data from these studies support the initiation of the first human clinical study for the LRRK2 ASO. The primary objective of this study is to evaluate the safety and tolerability of single and multiple doses of the LRRK2 ASO administered via intrathecal (IT) injection to participants with Parkinson’s disease (PD). The secondary objective of this study is to evaluate the pharmacokinetic (PK) profile of the ASO. Exploratory endpoints will include measurement of LRRK2 levels in CSF using a novel mass-spectrometry assay.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phase-i-study-design-of-a-leucine-rich-repeat-kinase-2-lrrk2-antisense-oligonucleotide-for-parkinsons-disease/