Phase 1/2a Clinical Trial of PR001 (LY3884961) in Patients With Parkinson's Disease With at Least One GBA1 Mutation (PROPEL)

Inclusion Criteria:

• Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lbs) and a body mass index (BMI) of 18 to 34 kg/m2.

• Diagnosis of Parkinson's Disease (PD) per UK Parkinson's Disease Society Brain BankClinical Diagnostic Criteria.

• Hoehn and Yahr Stage III-IV (as determined in Practically Defined OFF state).

• Stable use of background medications at least 8 weeks prior to investigationalproduct (IP) administration, including but not limited to those used for treatmentof PD. Gaucher Disease-PD patients receiving GD treatments should be on a stableregimen of their ERT or substrate replacement therapy (SRT) medication for at least 3 months prior to screening.

• At least 1 pathogenic GBA1 mutation confirmed by the central laboratory

• Negative screening test for Mycobacterium tuberculosis (MTB), documented negativeMTB test within 1 year prior to Screening, or clearance by an infectious diseasespecialist.

• Patient and/or patient's legally authorized representative (LAR) has the ability tounderstand the purpose and risks of the study and provide written informed consentand authorization to use protected health information in accordance with nationaland local privacy regulations.

• Patient has a reliable study partner/informant (e.g., family member, friend) willingand able to participate in the study as a source of information on the patient'shealth status and cognitive and functional abilities (including providing input intothe rating scales). The study partner should have regular contact with the patient (in person or via phone/video communication). The study partner must sign a separatepartner informed consent form (ICF) indicating that she/he understands the studyrequirements and is willing to participate and attend study visits requiring studypartner input.

• Women of nonchildbearing potential must be either surgically sterile orpostmenopausal. Men and women of childbearing potential must use a highly effectivemethod of contraception consistently and correctly for the duration of the studyincluding the long-term follow-up. Individuals in an exclusively same sexrelationship (as their preferred and usual lifestyle) are not required to usecontraception.

• Men must agree to abstain from sperm donation for the duration of the study,including long-term follow-up.

• Women must agree to abstain from egg donation for the duration of the study,including long-term follow-up.

• Women of childbearing potential cannot be pregnant or lactating/breastfeeding andmust have a negative result for serum pregnancy test at Screening.

• Patient is generally ambulatory, not dependent on walker or wheelchair

• Patient is living in the community (i.e., not in nursing home); some levels ofassisted living may be permitted at the discretion of the Investigator.

• Pneumococcal and shingles vaccines are required within 10 years of Screening (allowed to be performed during Screening but must be given at least 4 weeks priorto start of the immunosuppressant treatment).

• Patient is up to date with age and gender-appropriate cancer screening as per localstandard of care based on Principal Investigator's (PI) judgment.

Exclusion Criteria:

• Diagnosis of a significant CNS disease other than Parkinson's Disease (PD) that maybe a cause for the patient's PD symptoms or may confound study objectives.

• MoCA (Montreal Cognitive Assessment) score of <14

• Spinal, cervical, or brain MRI/magnetic resonance angiography (MRA) indicatingclinically significant abnormality, including evidence of prior hemorrhage, infarct >1 cm3 or >3 lacunar infarcts, or a structural abnormality deemed a contraindicationto intracisternal injection.

• Hypersensitivity or contraindications to corticosteroid and/or, sirolimus use (including but not limited to osteoporosis with vertebral fractures within 1 yearprior to Screening, uncontrolled hypertension, poorly controlled diabetes,uncontrolled hyperlipidemia or hypercholesterolemia as per Investigator assessment.

• Concomitant disease or condition within 6 months of Screening that could interferewith, or treatment of which might interfere with, the conduct of the study or thatwould, in the opinion of the Investigator, pose an unacceptable safety risk to thepatient or interfere with the patient's ability to comply with study procedures;including, but not limited to the following:

1. Evidence of clinically significant liver pathology;

2. Unstable autoimmune disease; autoimmune disease requiring chronicimmunosuppression;

3. Poorly controlled/not adequately managed diabetes (Screening glycosylatedhemoglobin [HbA1C] ≥ 7%);

4. History of unstable angina, myocardial infarction, chronic heart failure (NewYork Heart Association Class III or IV), or clinically significant conductionabnormalities (e.g., unstable atrial fibrillation) within 1 year prior toScreening;

5. Clinically significant 12-lead electrocardiogram (ECG) abnormalities atScreening, as determined by the Investigator;

6. Uncontrolled hypertension;

7. History of cancer, including B-cell cancers, within 5 years of Screening withthe exception of fully excised non-melanoma skin cancers, non-metastaticprostate cancer, and full treated ductal carcinoma in situ, provided it hasbeen stable for at least 6 months;

8. History or current alcohol or drug abuse within 2 years of Screening;

9. Any current psychiatric diagnosis that may interfere with patient's ability toperform study procedures and all assessments;

10. At imminent risk of self-harm;

11. Any medical disorders that, in the opinion of the Investigator, could interferewith study-related procedures (including safe performance of lumbar puncture [LP] or intracisternal injection), such as prohibitive spinal diseases,bleeding diathesis, clinically significant coagulopathy,, thrombocytopenia, orincreased intracranial pressure;

12. Documented stroke or transient ischemic attack within 1 year prior toScreening;

13. History of seizure or unexplained blackouts within 10 years prior to Screening;

14. Currently active infection or a severe infection (e.g., pneumonia, septicemia,central nervous system infections [e.g. meningitis, encephalitis]) within 12weeks prior to Screening;

15. History of severe allergic or anaphylactic reactions. History ofhypersensitivity to any inactive ingredient of the IP or protocol-requiredimmunosuppressant medications.

16. Acute or chronic: hepatitis B (HBV); hepatitis C (HCV) infection must havecompleted curative antiviral treatment with HCV viral load below the limit ofquantification or be HCV RNA negative due to prior treatment or naturalresolution to be eligible for enrollment.

• Clinically significant abnormalities in laboratory test results at Screening.

• Participation within 3 months prior to Screening in another therapeuticinvestigational drug or device study with purported disease-modifying effects on PD,unless it can be documented that the patient received placebo.

• History of deep brain stimulator placement, focused ultrasound, or surgery for PD

• Any type of prior gene or cell therapy.

• Immunizations (live vaccines) in the 4 weeks prior to Screening. Note: Pneumococcaland shingles vaccine administrations are allowed during the Screening period (patients not previously vaccinated should receive pneumococcal and/or shinglesvaccine administration at least 4 weeks prior to initiation of Immunosuppressionregimen).

• Use of ambroxol within 8 weeks of dosing.

• Use of blood thinners in the 2 weeks prior to Screening lumbar puncture (LP) orintra-cisterna magna (ICM) procedure, or the anticipated need to initiate bloodthinners during the study. Antiplatelet therapies (e.g., prophylactic aspirin,clopidogrel) are acceptable if the patient is medically able to temporarily stop 48hours to 7 days (depending on the antiplatelet medication used) prior to and atleast 48 hours after intracisternal injection and lumbar puncture.

• Contraindications or intolerance to imaging methods (MRI, MRA, CT, DaT-SPECT)inducing claustrophobia and/or intolerance to contrast agents used for MRI, MRA orCT.

• Contraindications to general anesthesia or deep sedation.

• Positive urine test for drugs of abuse (including opiates, benzodiazepines,amphetamines, cocaine, barbiturates, and phencyclidine) without prescription, atScreening and Day -1. Note: Use of medical marijuana is permitted provided thepatient is on a stable regimen. It is also permitted if the patient resides in astate in which the recreational use of marijuana is legalized, so long as thepatient does not meet drug abuse criteria (as defined in the Diagnostic andStatistical Manual of Mental Disorders Fifth Edition).

• Patient is generally frail or has any medical condition, for which, in view of theInvestigator, participation in the study would not be in the best interest of thepatient or is likely to prohibit further participation during the study.

Other protocol-defined inclusion/exclusion criteria may apply.