Parkinson's disease Nervous System Diseases
Conditions
Interventions
This is a non-interventional phase 0 study, consisting of 3 arms of 8 to 12 participants each: healthy adults (HV) and patients with Parkinson’s disease (PD) with and without heterozygous GBA1 mutatio
Sponsors
Centre for Human Drug Research
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Group 1 (healthy volunteers) 1. Male or female 50-100 years of age at screening (inclusive) 2. BMI in the range of 18 – 32 kg/m2 Group 2 and 3 (patients with Parkinson’s disease with and without a GBA1 mutation) 3. Male or female 50-80 years of age at screening (inclusive) 4. BMI in the range of 18 – 32 kg/m2 5. Confirmed clinical diagnosis of Parkinson's disease by a neurologist, based on the presence of bradykinesia and either resting tremor and/or muscular rigidity in at least one limb 6. Hoehn and Yahr stage I-III, inclusive 7. GBA-PD group (2): confirmed presence of heterozygous GBA1 mutation via (historic) genotyping 8. IPD group (3): confirmed absence of GBA1 mutation via (historic) genotyping Groups 1, 2 and 3 9. Able to speak, read, and understand study procedures in Dutch sufficiently to allow completion of all study assessments 10. Must understand and provide written informed consent prior to the initiation of any protocol-specific procedures 11. Willing and able to maintain stable doses and regimens for all medications, herbal treatments, medical marijuana, dietary supplements and caffeine intake from the screening visit through the last study visit 12. Willing and able to abstain from alcohol 24 hours prior to all study procedures at study Day 1 and Day 8 13. Women of childbearing potential must use a form of birth control (e.g., oral contraceptive, condom use, IUD, abstinence of heterosexual intercourse).
Exclusion criteria
Exclusion criteria: Groups 1, 2 and 3 1. Significant haematological abnormalities during screening such as anaemia (haemoglobin level 500mL whole blood) in the past 30 days 5. Recent infection with hospital admission (<1 month) or clinical evidence of infection at screening and study visits 6. Alcohol or drugs abuse in the past 12 months (a negative test for alcohol and drugs of abuse at screening and prior to the first blood sample collection will be required for inclusion) 7. Clinically abnormal findings in the resting ECG at screening as determined by the Investigator 8. Vital sign measurements must be within the following ranges during screening: 8.1. Body temperature, =35C to =38C 8.2. Systolic blood pressure, =90 to =160 mm Hg 8.3. Diastolic blood pressure, =40 to =95 mm Hg 8.4. Pulse rate, =40 to =100 bpm 9. Positive serology for human immunodeficiency virus (HIV), hepatitis B virus (HBV) (positive hepatitis B core antibody [anti-HBc] with negative hepatitis B DNA is acceptable), or hepatitis C virus (HCV) (treated/resolved hepatitis C with negative polymerase chain reaction [PCR] RNA is allowed) 10. Any other issue that, in the opinion of the investigator, would make the participant ineligible for study participation 11. Previous exposure to gene therapy 12. For CSF sampling, any of the criteria below: 12.1. History of clinically significant hypersensitivity to local anesthetics that may be used for LP (e.g., lidocaine) 12.2. Criteria that would preclude an LP, such as a local infection at the site of the LP, <100× 103/µl platelet count at screening or clinically significant coagulation abnormality or significant active bleeding, or treatment with an anticoagulant or treatment with more than two antiplatelet agents 12.3. History of clinically significant back pathology and/or back injury (e.g., degenerative disease, spinal deformity, or spinal surgery) that may predispose to complications or technical difficulty with LP Group 1 13. Clinical evidence or history of Parkinson's disease, parkinsonism or Gaucher disease 14. First-order relative with Parkinson's disease or Gaucher disease 15. Any history of unstable or poorly controlled psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders. Well-controlled conditions are permitted if the investigator and Sponsor agree. Group 2 16. Presence of clinical features suggestive of atypical Parkinsonian syndromes 17. Presence of homozygous or compound heterozygous GBA-1 mutation or PD-related risk variant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| GCase activity and activation in healthy participants and patients with Parkinson’s disease with and without a GBA1 mutation measured in monocytes from whole blood samples using flow cytometry at multiple timepoints on day 1 and day 8 | — |
Secondary
| Measure | Time frame |
|---|---|
| The following secondary outcome measures are assessed at multiple timepoints on day 1 and day 8 unless otherwise stated: 1. Sphingolipid pathway biomarker variability in healthy participants and patients with Parkinson’s disease with and without a GBA1 mutation measured using laboratory assays. The biomarkers and the medium the biomarkers are measured in are as follows: live cell GCase activity in whole blood, GCase activity in dried blood spots, GCase activation in whole blood, GluSphing in plasma and CSF, GluCer in plasma and CSF, ceramide in plasma and CSF, sphingomyelin in plasma and CSF, bis(monoacylglycerol)phosphate (BMP) in urine and CSF and serum amyloid alpha (SAA) in plasma and CSF. 2. Variability of additional exploratory biomarkers (to be determined). Pharmacodynamic endpoints 1. GCase activity in dried blood spots (DBS) measured using fluorimetry 2. Live-cell GCase activity and GCase activation by VQ101 in whole blood measured using flow cytometry 3. GluSphing, GluCer, ceramide, sphingomyelin and SAA in plasma and CSF measured using LC-MS / MS 4. BMP in urine and CSF measured using laboratory assays at baseline 5. Variability in other exploratory biomarkers (to be determined) measured using laboratory assays | — |
Countries
Netherlands
Outcome results
None listed