Phase 0 biomarker study: assessment of day-to-day, within-day and inter-individual variability in β-Glucocerebrosidase activity and pathway biomarkers in healthy adults and patients with Parkinson*s disease with heterozygous GBA1-mutations.

beta-Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the
glucosylceramidase beta 1 (GBA1) gene that is responsible for hydrolysis of the
sphingolipid glucosylceramide to ceramide and glucose. It has been well
established that heterozygous mutations in GBA1 are a major risk factor for
Parkinson*s disease (PD) and are present in 7-13% of PD cases. These mutations
in GCase lead to reduced enzymatic activity in the lysosome which is associated
with impaired lysosomal function. A consequence of this lysosomal dysfunction
is the accumulation of misfolded alpha synuclein which is the hallmark of PD.
PD patients with GBA1 mutations exhibit earlier onset of disease and have an
increased risk of cognitive impairment but are otherwise indistinguishable from
patients with idiopathic PD.
A significant challenge in the study of the GCase enzyme has been the
measurement of enzymatic activity. While techniques to assess GCase activity
exist, these methods assess GCase activity extracted from a cell lysate and do
not account for the physiology of the lysosomal environment that directly
affects enzymatic function. Vanqua has developed an approach to assess in situ
lysosomal GCase activity in monocytes from whole blood samples using flow
cytometry. This technique will enable a real-time assessment of GCase activity.
The primary goal of this cross-sectional phase 0 study is to verify the
performance of GCase activity assay at CHDR and assess the day-to-day,
within-day and inter-individual variability of the GCase activity assay in
healthy volunteers and Parkinson*s disease patients. The secondary goal of this
study is to assess plasma biomarkers in healthy volunteers and patients with
GBA-PD. These markers include measurements of sphingolipids, measurements of
lysosomal function, alpha synuclein, and analysis of plasma exosomes. Achieving
these goals will establish a target engagement assay at CHDR for future
clinical studies, and help guide future biomarker strategies for this program.

Primary Objectives
• Characterize day-to-day, within-day, intra-individual and inter-individual
variability of GCase activity in healthy participants and patients with
Parkinson*s disease with a GBA1 mutation.

Secondary Objectives
• Assess variability of sphingolipid pathway biomarkers in healthy participants
and patients with Parkinson*s disease with a GBA1 mutation. These biomarkers
and the medium the biomarkers are measured in, are listed in table 1 of the
protocol
• Assess variability of additional exploratory biomarkers (to be determined).

This is a non-interventional phase 0 study, consisting of 2 arms of 8 to 12
participants each: healthy adults (HV) and patients with Parkinson*s disease
(PD) with heterozygous GBA1 mutations (GBA-PD). Intra-individual and
inter-individual variability at multiple days and multiple timepoints
throughout a single day will be evaluated.

This is a non-interventional biomarker study. No investigational drug will be
administered to the participants. Sampling of the biomarkers will be done via
blood sampling and CSF sampling. All collections will be performed in a
state-of-the-art clinical research unit and will be medically supervised by
qualified medical staff. The blood sampling and CSF sampling are considered low
risk procedures and the burden for the participants related to the study
procedures will be kept to a minimum.