Parkinson’s Disease
Conditions
Interventions
None listed
Sponsors
Denali Therapeutics
Eligibility
Inclusion criteria
Inclusion criteria: Groups A and B 1. Confirmed clinical diagnosis of Parkinson’s disease by a qualified neurologist, 2. Hoehn and Yahr stage I-IV, inclusive, 3. Group A: Confirmed mutation in the Leucine-rich repeat kinase 2 (LRRK2) gene of the following types: G2019S, I2020T, R1441G, R1441C, R1441H, N1437H or Y1699C. 4. Group B: Confirmed wild type Leucine-rich repeat kinase 2 (LRRK2) gene. 5. Male or female of 30-85 years of age at screening (inclusive). Group A patients may be as young as 25 years of age with Investigatory and Sponsor agreement. 6. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive), and with a minimum weight of 50 kg at screening. 7. Able to speak, read, and understand study procedures in Dutch sufficiently to allow completion of all study assessments. 8. Mentally competent as assessed by the screening physician and –if deemed necessary- by the treating neurologist CHDR1741 Protocol Version 3 / 14-Aug-2018 Confidential Page 14 of 40 9. Must understand and provide written informed consent prior to the initiation of any protocol-specific procedures. 10. 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. 11. Willing and able to abstain from alcohol 48 hours prior to all study procedures at study visits 1 and 2. Group C 1. No clinical evidence or history of Parkinson disease 2. Male or female matched to a participant in Group A and/or Group B for gender, race, age (+/- 5 years) and BMI (+/- 3.5), with a minimum weight of 50 kg at screening). 3. Able to speak, read, and understand study procedures in Dutch sufficiently to allow completion of all study assessments. 4. Must understand and provide written informed consent prior to the initiation of any protocol-specific procedures. 5. Willing and able to maintain stable doses and regimens for all medications, herbal treatments, dietary supplements and caffeine intake from the screening visit through the last study visit. 6. Willing and able to abstain from alcohol 48 hours prior to all study procedures at study visits 1 and 2.
Exclusion criteria
Exclusion criteria: 8. Exclusion Criteria 1. Self-reported substance or alcohol dependence (excluding caffeine), and/or participated in a substance or alcohol rehabilitation program to treat substance or alcohol dependence within the past 6 months 2. History or presence of clinically significant or unstable abnormality as assessed by physical examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in the opinion of the investigator would jeopardize the safety of the participant or the validity of the study results 3. Positive urine drug screen, except for medical marijuana which is permitted 4. Positive breath alcohol test. Participants with a positive result may be rescheduled at the investigator’s discretion 5. Group A and B: Parkinson disease associated mutations in the GBA gene, as determined by genetic testing or documented before screening. 6. Group C only: first order relative with Parkinson disease 7. Females who have a positive serum or urine pregnancy test 8. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening 9. Hemoglobin level <7.0 mmol/L (males) or <6.0 mmol/L (females) 10. Donation or loss of more than 500 mL whole blood within 30 days preceding entry into the treatment period 11. Difficulty with venous access or unsuitable or unwilling to undergo catheter insertion 12. 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 lumbar puncture 13. Significant coagulation abnormality (e.g. hemophilia, platelet count <100,000/microliter or clinically significant elevation in PT or PTT at screening), or has a medical condition requiring treatment with an anticoagulant (e.g. warfarin) or with two or more antiplatelet agents 14. Treatment with an investigational drug within 5 times the elimination half-life or within 30 days (whichever is longer) prior to Visit 1, or is currently enrolled in any research judged not to be scientifically or medically compatible with this study 15. Hospitalization during the 6 weeks prior to Visit 1 16. An employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, child or sibling, whether biological or legally adopted 17. Anyone who, in the opinion of the investigator or designee, is not considered to be suitable and is unlikely to comply with the study protocol for any reason 18. Current smoker or tobacco use within 6 months 19. Groups B and C only: presence of Type 2 diabetes based on medical history or screening laboratories, unless matched to a patient from Group A with Type 2 diabetes 20. Group B only: presence of a deep brain stimulator, unless matched to a patient from Group A with a deep brain stimulator
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| - LRRK2 phosphorylation (pS935, total LRRK2 and pS935/Total LRRK2 ratio) in PBMCs, Whole blood, Neutrophils, Urine exosomes, CSF exosomes. - Rab GTPase phosphorylation in PBMCs, whole blood, Neutrophils, Urine exosomes, CSF exosomes, lipidomic, metabolomic and/or proteomic analysis of CSF Urine and/or Plasma. - CSF lysosomal enzyme activity, Cathepsin D, Glucocerebrosidase. - CSF alpha-synuclein, Total, pS129 and/or Oligomeric alpha-synuclein. - CSF and plasma cytokines (65-cytokine panel) - Cellular analyses of fibroblast cultures, e.g. lysosome imaging, immunohistochemistry for lysosome markers (LAMP1, LAMP2, etc), lysotracker, LRRI€pS93S and pRabl0 immunoassays, LC/MS analysis, protein turnover analysis, and Lysosome enzyme activity assays. - Potential other parameters related to LRRK2 that become available | — |
Contacts
Public ContactJules Heuberger
Centre for Human Drug Research
Outcome results
None listed