A Randomized, Placebo-Controlled, Double-Blind, Parallel Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Oral Doses of LTI-291 in Patients with Parkinson*s Disease and a GBA1 Mutation

1. Signed informed consent prior to any study-mandated procedure.
2. Minimum age of 18 years.
3. Clinical diagnosis of Parkinson*s Disease at least 6 months prior to screening, confirmed by a neurologist.
4. A score of 1-4 on Hoehn & Yahr Scale.
5. Mutation(s) in glucocerebrosidase GBA1 gene.
6. 6. Mini Mental State Exam score >/<= 18 and assessed by the investigator or qualified designee as able to provide informed consent.
7. Body mass index (BMI) between 18 and 35 kg/m2, inclusive, and with a minimum weight of 45 kg at screening.
8. All females must be at least 2 years post-menopausal or surgically sterile or practice higly effective contraception until at least 90 days after their last dose of study treatment.
9. All males must practice effective contraception and abstain from sperm donation during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment.
10. Has the ability to communicate well with the investigator in the Dutch language and willing to comply with the study restrictions.

1. Any active or chronic disease or condition other than PD that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following medical history review, physical examination, vital signs (supine systolic and diastolic blood pressure, pulse rate, body temperature), 12-lead electrocardiogram (ECG), and clinical laboratory parameters (hematology, blood chemistry, and urinalysis)). Minor deviations of laboratory values from the normal range may be accepted, if judged by the investigator to have no clinical relevance.
2. History of recent major surgery (within 60 days of screening) that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator.
3. Atypical or secondary parkinsonism by medical history or in the opinion of the investigator. Atypical parkinsonism includes, but not limited to a diagnoses of progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy. Secondary parkinsonism includes drug-induced, post-infectious, post-traumatic and vascular parkinsonisms.
4. Patients that experience Freezing Of Gait (FOG) in the on-state of L-dopa treatment (paradoxical response), which might interfere with the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator.
5. Current (within last 30 days prior to start of clinical phase) use of a strong CYP3A4 modulator. Reference Appendix B for a list of prohibited CYP3A4 modulators.
6. Current use of any drug known to significantly inhibit blood coagulation in the opinion of the investigator.
7. Vaccination within 7 days prior to start of dosing.
8. Any contra-indication for undergoing a lumbar puncture procedure (e.g. anatomical variations or local skin infection).
9. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
10. Participation in an investigational drug or therapeutic device study within 3 months prior to first dosing, or within 6 months for a biologic investigational product.
11. Recent history (last 6 months) of abuse of addictive substances (alcohol, illegal substances) or current use of more than 21 units of alcohol per week, drug abuse, or regular recreational user of sedatives, hypnotics, tranquillizers, or any other addictive agent.
12. Positive test for drugs of abuse at screening or pre-dose.
13. Women currently pregnant or breastfeeding.
14. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening or intention to donate blood or blood products during the study.
15. Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.