Objective: Measure LRRK2 pathway activity in Parkinson’s Disease patients stratified using a genetic predictive classifier model.

Background: Extensive research has shown that overactivation of the LRRK2 pathway plays a role in PD pathogenesis and progression. The clinical presentation of LRRK2-associated PD is indistinguishable from that of idiopathic PD making the identification of patients with PD who could benefit from an investigational LRRK2 inhibitor treatment difficult. Neuron23 has developed a predictive model that uses specific single nucleotide polymorphisms (SNPs) to stratify patients according to their level of intrinsic LRRK2-pathway activity into “LRRK2-rare variant” (LRRK2-RV; PD patients with LRRK2 mutations; 1.5 ± 0.8%), “LRRK2-predicted” (LRRK2-PR; PD patients with an overactive LRRK2 pathway; 31 ± 6.7%) or “LRRK2-normal” (LRRK2-N; PD patients with LRRK2 pathway with normal LRRK2 pathway activity; 68 ± 6.6%) PD groups.

Method: In this multi-center non-interventional study, biological samples were collected from patients at 3 study visits occurring every 6 weeks. Using genotyping arrays and a diagnostic classifier, PD patients were stratified into 3 cohorts 1) LRRK2-RV PD patients 2) LRRK2-PR PD patients and 3) LRRK2-N PD patients. The correlation between the diagnostic classification and the LRRK2 pathway activity was evaluated using accepted biomarkers of LRRK2 pathway activity.

Results: 71 PD patients were enrolled from 8 clinical sites (3 in United States, 2 in Canada, 1 in France and 2 in Israel) and 14,670 samples (blood, PBMC, plasma/serum, CSF and urine) were collected. The study population was enriched for LRRK-RV patients as 28.2% (n=20) of participant were LRRK2-RV, 16.9% (n=12) were LRRK2-PR, and 54.9% (n=39) were LRRK2-N.Urine BMP, urine EV total LRRK2, urine EV pT73 Rab10, urine EV total Rab10, were significantly elevated in LRRK2-RV patients in comparison with LRRK2-N patients. A similar trend was observed in LRRK2-PR patients without reaching statistical significance.

Conclusion: Neuron23’s novel blood-based, genetic classifier identified PD patients with elevated LRRK2 pathway activity facilitating the stratification of PD patients into diagnostic groups for clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/non-interventional-phase-0-study-for-the-collection-of-biospecimens-from-patients-with-parkinsons-disease-pd-to-support-the-development-of-a-diagnostic-classifier-for-lrrk2-driven-pd/