Transplantation of Human iPS Cell-derived Dopaminergic Progenitors (CT1-DAP001) for Parkinson's Disease (Phase I/II)

Open to people ages 40-75

1. The subject has a diagnosis of PD (clinically established or clinically probable) following the MDS Clinical Diagnostic Criteria for Parkinson's Disease (2015)
2. The subject has an inadequate response to drug treatments.

3. The subject is ≥ 40 years and < 75 years of age at the time of informed consent.

   Note: upper age limit to be revisited in future protocol amendment.

4. The subject has had PD for at least 5 years.
5. The subject has both ON and OFF (as demonstrated by the MDS-UPDRS Part III and a symptom diary).
6. The subject is in stage 2.5 or higher on the Hoehn and Yahr scale at OFF time. Our rationale for enrolling patients at stage 2.5 or higher on the Hoehn and Yahr scale at OFF time is as follows: i) it is well established that the PD patients with higher Hoehn and Yahr scale at OFF time have more extensive neurodegenerative changes affecting multiple brain regions including multiple cortical regions. ii) we believe that the treatment of patients at earlier stages of disease increases the likelihood of clinically relevant treatment effect, as it is site- targeted treatment aimed at the restoration of local DOPA-ergic tone. We would like to note that the injection of the cell doses we propose to use as well asrequired immunosuppression were well tolerated in patients in the ongoing Phase 1/2 trial in Kyoto, Japan.
7. The subject is in stage 3 or lower on the Hoehn and Yahrscale at ON time.
8. The subject has an L-dopa response of 30% or more without the influence of antiparkinsonian drugs.
9. The subject has the following organ functions as determined by laboratory tests at the Screening visit:
   1. Neutrophil count ≥ 2,000/μL
   2. Platelet count ≥ 5.0 × 104/μL
   3. AST,ALT ≤ 3.0 × upper limit of normal
   4. Total bilirubin ≤ 1.5 × upper limit of normal
   5. eGFR ≥ 60 mL/min/1.73 m2 As part of Creatinine testing, an estimated glomerular filtration rate (mL/min/1.73 m2) will be calculated based on the CKD-EPI 2021 equation
10. The subject provides written informed consent to participate in the study. If the subject cannot sign due to physical constraints, verbal consent may be provided with signature of a Legally Authorized Representative.
11. The subject is willing to avoid pregnancy using abstinence, highly effective means of birth control, surgical sterility, or menopause.
12. The subject does not have a debilitating dyskinesia score greater than or equal to 3 on the UPDRS.
13. The subject is willing to comply with the protocol-required assessments.

1. The subject has an abnormal brain MRI suggestive of brain pathology other than Parkinson's disease.
2. The subject has a clinical indication or diagnosis of abnormal immune function.
3. The subject has been diagnosed with a major neurocognitive disorder such as dementia, or is high risk for this.
4. The subject has bleeding tendency or abnormal coagulation function as evidenced by platelets <50 or PT/PTT > 1.5x normal.
5. The subject is HBs antigen-positive, or HBs antibody- or HBc antibody-positive with evidence of HBV-DNA.
6. The subject is anti-HIV antibody positive.
7. The subject is anti-HTLV-1 antibody-positive.
8. The subject has an active infection such as hepatitis C or syphilis (STS/TPHA).
9. Tacrolimus, concomitant drugs(e.g., levodopa, carbidopa, MRI contrast) are contraindicated in the subject.
10. The performance of or use of gadolinium-based contrast agents in patients with acute kidney injury or patients who develop severe chronic kidney disease during unless the contrast images are necessary for clinical management.
11. The subject has hypersensitivity to Tacrolimus, concomitant drugs(e.g., levodopa, carbidopa, MRI contrast), and/or their components.
12. The subject has a serious allergy to a component (e.g., gentamicin, component of bovine origin, or component of porcine origin) used in the preparation of the study product.
13. The subject has undergone transplantation of human iPSC-derived dopaminergic progenitors.
14. The subject has any of the following diseases concurrently:
    1. Malignant neoplasm
    2. Epilepsy
    3. Psychiatric disease (e.g., depression, bipolar disorder, schizophrenia)
    4. Other serious concurrent diseases (e.g., cerebrovascular disorder, heart disease, chronic respiratory disease, inadequately controlled hypertension, diabetes mellitus) as determined by the investigator.
15. The subject has a history of any of the following:
    1. Malignant neoplasm
    2. Epilepsy
    3. Cerebral hemorrhage
    4. Psychiatric disease (e.g., depression, bipolar disorder, schizophrenia)
    5. Pallidotomy, thalamotomy, or deep brain stimulation
16. The subject has a history of congenital long QT syndrome
17. The subject is pregnant or lactating or does not agree to avoid pregnancy throughout the study.
18. The subject in the opinion of the investigator or sub-investigator, is not appropriate to conduct the study safely.
19. Neutrophil count < 2,000/μL
20. Platelet count < 5.0 × 104/μL
21. AST, ALT > 3.0 × upper limit of normal
22. Total bilirubin > 1.5 × upper limit of normal
23. eGFR <60mL/min/1.73m2
24. Diabetes with poorly controlled blood glucose (glycosylated hemoglobin > 9.0%, or fasting plasma glucose (FPG) ≥ 200 mg/dL (11.1 mmol/L).
25. Atypical parkinsonism (Parkinsonism-Plus syndrome, secondary parkinsonism, hereditary parkinsonism).
26. Contraindications to general anesthesia as evaluated by subject matter experts.