CT1-DAP001 iPS Cell-derived Dopaminergic Progenitors for Parkinson's Disease (NCT06482268)

Overview

The CT1-DAP001 trial is a pioneering Phase 1/2 clinical study evaluating the safety and efficacy of human induced pluripotent stem cell (iPSC)-derived dopaminergic progenitor cells for the treatment of Parkinson's disease. Sponsored by the University of California, San Diego, this trial represents a significant collaboration between academic research and industry partners including Sumitomo Pharma America, Kyoto University, and the CiRA Foundation["@NCT06482268"].

Overview

The CT1-DAP001 trial is a pioneering Phase 1/2 clinical study evaluating the safety and efficacy of human induced pluripotent stem cell (iPSC)-derived dopaminergic progenitor cells for the treatment of Parkinson's disease. Sponsored by the University of California, San Diego, this trial represents a significant collaboration between academic research and industry partners including Sumitomo Pharma America, Kyoto University, and the CiRA Foundation["@NCT06482268"].

This investigator-initiated clinical trial aims to evaluate whether transplantation of CT1-DAP001 cells into the corpus striatum can safely restore dopaminergic function and improve motor symptoms in Parkinson's disease patients. The iPSC approach offers advantages over earlier cell therapy methods, including the potential for unlimited cell supply, standardized manufacturing, and controlled differentiation into dopaminergic progenitors["@Takahashi2007"].

Background and Rationale

Parkinson's Disease and the Need for Cell Therapy

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting approximately 10 million people worldwide. The disease is characterized by[@Kalia2015]:

• Motor Symptoms: Resting tremor, bradykinesia, rigidity, and postural instability
• Non-Motor Symptoms: Sleep disorders, depression, constipation, hyposmia, and cognitive impairment
• Neuropathology: Progressive loss of dopaminergic neurons in the substantia nigra pars compacta and presence of Lewy bodies (alpha-synuclein inclusions)

The iPSC Approach

The CT1-DAP001 therapy uses human induced pluripotent stem cells as the starting material:

This approach differs from autologous iPSC therapies (like iNSC-DAP) in that it uses allogeneic cells from master cell banks, enabling standardized manufacturing and off-the-shelf availability.

Historical Context

Cell therapy for Parkinson's disease has evolved significantly:

• 1980s-90s: Fetal ventral mesencephalic tissue transplants showed promise but faced ethical challenges
• 2000s: Embryonic stem cell-derived dopamine neurons entered clinical development
• 2010s: iPSC approaches emerged as a more accessible cell source
• 2020s: Multiple groups advancing iPSC-derived cell therapies toward clinical trials

Trial Details

| Property | Value |
|----------|-------|
| Phase | Phase 1/2 |
| Status | Recruiting |
| NCT Number | NCT06482268 |
| Acronym | CT1-DAP001 |
| Sponsor | University of California, San Diego |
| Collaborators | Sumitomo Pharma America, Kyoto University, Sumitomo Pharma Co., Ltd., CiRA Foundation |
| Principal Investigator | Joseph Ciacci, MD |
| Enrollment | 7 patients (estimated) |
| Start Date | June 2024 |
| Primary Completion | February 2025 (estimated) |
| Study Completion | May 2028 (estimated) |
| Duration | 24 months follow-up |
| Location | UC San Diego, La Jolla, CA |
| Study Design | Single-center, open-label, uncontrolled |

Mechanism of Action

Cell Replacement Strategy

CT1-DAP001 implements a cell replacement approach:

Differentiation Protocol

The CT1-DAP001 cells undergo sophisticated differentiation:

• Pluripotent Stem Cell Starting Material: Human iPSCs
• Directed Differentiation: Growth factors and small molecules guide cells toward dopaminergic lineage
• Midbrain Specification: Protocols emulate development of substantia nigra pars compacta neurons
• Purification: Progenitors enriched for expression of markers including LMX1A, FOXA2, and tyrosine hydroxylase (TH)
• Quality Control: Each lot undergoes extensive testing for identity, potency, and safety

Expected Mechanism

Following implantation, the progenitor cells are expected to:

• Mature: Differentiate into fully functional dopaminergic neurons
• Extend Axons: Project processes to appropriate target regions
• Establish Synapses: Form functional synapses with host neurons
• Produce Dopamine: Synthesize and release dopamine in response to physiological signals
• Integrate: Become part of the nigrostriatal circuit

Surgical Delivery

The cells are delivered using stereotactic surgery:

Inclusion Criteria

Patients must meet all of the following criteria:

• Diagnosis of Parkinson's disease per MDS Clinical Diagnostic Criteria (2015)
• Age 40-75 years at time of informed consent
• Disease duration of at least 5 years
• Inadequate response to current drug treatments
• Both ON and OFF medication states (demonstrated by MDS-UPDRS Part III and symptom diary)
• Hoehn and Yahr Stage 2 or higher at OFF time, Stage 3 or lower at ON time
• Levodopa response of 30% or more
• No debilitating dyskinesia (MDS-UPDRS Part 4, Item 4.1/4.2 < 3)
• Adequate organ function:
• Neutrophil count ≥ 2,000/μL
• Platelet count ≥ 50,000/μL
• AST/ALT ≤ 3.0 × upper limit of normal
• Total bilirubin ≤ 1.5 × upper limit of normal
• eGFR ≥ 60 mL/min/1.73 m²
• Willing to comply with protocol-required assessments
• Able to provide informed consent

Exclusion Criteria

Patients are excluded if they have:

• Abnormal brain MRI suggestive of pathology other than Parkinson's disease
• Atypical parkinsonism (Parkinsonism-Plus, secondary parkinsonism, hereditary parkinsonism)
• Clinical indication of abnormal immune function
• Major neurocognitive disorder or dementia
• Bleeding tendency or abnormal coagulation (platelets <50,000/μL or PT/PTT >1.5× normal)
• Active infection: Hepatitis B, C, HIV, HTLV-1, syphilis
• Hypersensitivity to tacrolimus, levodopa, carbidopa, MRI contrast, or their components
• Contraindications to general anesthesia
• Serious comorbidities:
• Malignant neoplasm
• Epilepsy
• Uncontrolled psychiatric disease (anxiety, depression, bipolar, schizophrenia)
• Poorly controlled diabetes (HbA1c >9.0% or fasting glucose ≥200 mg/dL)
• Cerebrovascular disorder, heart disease, chronic respiratory disease
• Inadequately controlled hypertension
• History of: malignancy <5 years, epilepsy, cerebral hemorrhage, stroke, psychiatric disease, congenital long QT syndrome
• Prior pallidotomy, thalamotomy, or deep brain stimulation
• Previous iPSC-derived dopaminergic progenitor transplantation
• Pregnancy or lactation

Outcome Measures

Primary Outcomes

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| Graft Expansion | Assessed by presence or absence of graft expansion (>3 cm³) in the brain | 24 months |
| Safety | Incidence and severity of treatment emergent adverse events | 24 months |

Secondary Outcomes

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| Quality of Life | Dyskinesia score changes from Baseline | 24 months |
| MRI Assessment | FDOPA PET imaging of tissue expansion at each timepoint | Baseline, day before/after transplant, 4 weeks, 12 weeks, 6 months, 12 months, 18 months, 24 months |
| Motor Function | MDS-UPDRS Part III total score at OFF time | 24 months |
| Motor Function | MDS-UPDRS Part III total score at ON time | 24 months |
| Daily ON/OFF Duration | Average daily ON duration (with/without dyskinesia) and OFF duration | 24 months |
| Medication | L-dopa equivalent dose changes | 4 weeks, 12 weeks, 6 months, 12 months, 18 months, 24 months |

Efficacy Definitions

• Excellent Response: Decrease of ≥5 in MDS-UPDRS Part III at OFF time
• Good Response: Decrease of 0-4 in MDS-UPDRS Part III at OFF time

Regulatory and Ethical Considerations

Oversight

• FDA Regulated: Yes (IND drug)
• Data Monitoring Committee: Yes
• Ethics: Approved by UC San Diego Institutional Review Board

Collaboration Partners

The trial represents a significant international collaboration:

• UC San Diego: Clinical trial site, principal investigator
• Sumitomo Pharma America: Manufacturing and regulatory support
• Kyoto University: Cell technology and differentiation protocols
• CiRA Foundation: iPSC cell bank and quality control

Comparison with Other PD Cell Therapy Trials

This trial differs from other ongoing iPSC/dopaminergic progenitor trials:

| Trial | Sponsor | Cell Type | Approach |
|-------|----------|-----------|----------|
| CT1-DAP001 (this trial) | UCSD | Allogeneic iPSC-derived DAP | Master cell bank |
| iNSC-DAP (NCT05901818) | Xuanwu Hospital | Autologous iNSC-derived DAP | Patient-derived |
| RNDP-001 (NCT07106021) | Kenai Therapeutics | Allogeneic ESC/iPSC-derived DAP | Master cell bank |
| CiRA Trial | Kyoto University | Allogeneic iPSC-derived DA neurons | Autologous (matched) |

Advantages of CT1-DAP001

• Off-the-shelf availability from master cell banks
• Standardized manufacturing through Sumitomo Pharma
• Proven differentiation protocols from Kyoto University/CiRA
• Single-center design allows careful monitoring

Risks and Safety Considerations

Surgical Risks

• Intracranial hemorrhage
• Infection
• Cerebrospinal fluid leak
• Headache

Cell Therapy Risks (Theoretical)

• Immune rejection (allogeneic cells)
• Tumor formation (undifferentiated cells)
• Dyskinesias (as seen in historical fetal transplant trials)
• Graft failure or insufficient engraftment
• Inflammation or immune response

Monitoring Protocol

• MRI at multiple timepoints (day before, immediately after, day after, 4 weeks, 12 weeks, 6 months, 12 months, 18 months, 24 months)
• Regular neurological examinations
• Comprehensive safety laboratory testing
• FDOPA PET imaging for graft survival and function

Future Directions

If Successful

This trial could establish:

• iPSC-derived dopaminergic progenitors as a viable Parkinson's disease therapy
• Safety profile for allogeneic iPSC cell therapy
• Foundation for broader clinical application
• Pathway for combination with other regenerative approaches

Scalability

Successful trials would require:

• Expansion of manufacturing capacity
• Development of additional master cell banks
• Optimization of delivery protocols
• Establishment of global distribution network

Contact Information

• Principal Investigator: Joseph Ciacci, MD
• Study Coordinator: Christian Fulinara — chfulinara@health.ucsd.edu — (858) 249-4020
• Study Coordinator: Donna Brusch — dbrusch@health.ucsd.edu — (760) 505-6649
• Location: UC San Diego Health, La Jolla, CA 92037

Related NeuroWiki Pages

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
• [Cell Therapy for Parkinson's](/therapeutics/cell-therapy-parkinsons)
• [iPSC-derived Dopaminergic Neurons](/therapeutics/ipsc-dopaminergic-therapy)
• [LRRK2 Pathogenesis](/mechanisms/lrrk2-pathogenesis)
• [Alpha-Synuclein](/proteins/alpha-synuclein-protein)
• [Substantia Nigra](/brain-regions/substantia-nigra)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving CT1-DAP001 iPS Cell-derived Dopaminergic Progenitors for Parkinson's Disease (NCT06482268) discovered through SciDEX knowledge graph analysis: