ClinicalTrials.gov Identifier: [NCT02795052](https://clinicaltrials.gov/study/NCT02795052)
Overview
Mermaid diagram (expand to render)
The Neurologic Stem Cell Treatment Study (NCT02795052) is a Phase 1 clinical trial investigating the safety and potential therapeutic benefits of stem cell transplantation in patients with progressive supranuclear palsy (PSP)[@nct]. This trial represents an early-stage exploration of regenerative medicine approaches for neurodegenerative 4R-tauopathies, offering a fundamentally different therapeutic strategy than the small-molecule and antibody approaches that have dominated PSP drug development.
Progressive supranuclear palsy is a rare but devastating neurodegenerative disorder characterized by accumulation of abnormal 4-repeat tau protein in the brain. Current treatments provide only symptomatic relief and do not address the underlying neurodegeneration. Stem cell therapy represents a potentially disease-modifying approach that could replace lost neurons, provide trophic support, and modulate the neuroinflammatory environment["@golbe2020"].
Trial Details
| Attribute | Value |
|---------------|-----------|
| NCT Number | NCT02795052 |
| Phase | Phase 1 |
| Status | Recruiting |
| Sponsor | University of California, San Diego |
| Study Type | Interventional |
| Intervention | Stem cell transplantation |
| Allocation | Non-randomized, single arm |
| Enrollment | Limited (Phase 1 dose-escalation) |
| Estimated Completion | To be determined |
Background and Rationale
The Challenge of Progressive Supranuclear Palsy
PSP is a neurodegenerative disorder classified as a 4R-tauopathy, distinct from Alzheimer's disease (which involves both 3R and 4R tau) and other tauopathies. Key features include:
Clinical Presentation:
- Vertical gaze palsy (difficulty looking up and down)
- Postural instability and falls (often early in disease)
- Akinesia and rigidity (parkinsonism)
- Cognitive decline (especially executive dysfunction)
- Dysphagia and speech difficulties
- Axial rigidity with retrocollis (neck extension)
Pathology:
- Neurofibrillary tangles composed of 4-repeat tau isoforms
- Neuronal and glial loss in basal ganglia, brainstem, and cerebellum
- Tufted astrocytes (characteristic PSP pathology)
- Variable cortical involvement depending on PSP variant
Current Treatment Limitations:
- No disease-modifying therapies approved
- Dopaminergic medications provide minimal benefit
- Symptomatic treatments address only specific manifestations
- Progressive decline continues despite optimal medical management
Stem Cell Therapy Rationale
Stem cell therapy offers several potential advantages for PSP[@lindsay2020]:
Neuronal Replacement: Transplanted neural stem cells may differentiate into functional neurons and integrate into existing neural circuits, replacing lost cells
Trophic Support: Stem cells secrete neurotrophic factors (BDNF, GDNF, NGF) that support surviving neurons and promote neuroprotection
Neuroinflammation Modulation: Mesenchymal stem cells in particular have immunomodulatory properties that may reduce harmful neuroinflammation
Potential for Integration: Stem cells may form appropriate synaptic connections and contribute to functional neural networksPreclinical Evidence
The translation of stem cell therapy to PSP is supported by preclinical research[@khoo2018]:
- Neural stem cells survive and differentiate in models of tauopathy
- Mesenchymal stem cells reduce neuroinflammation in animal models
- Transplanted cells can express neurotrophic factors in vivo
- Some studies show functional improvement in animal models
- Safety profiles established in various preclinical models
However, important questions remain:
- Long-term survival of transplanted cells
- Appropriate migration and integration
- Susceptibility of transplanted cells to tau pathology
- Optimal cell type and delivery method for CNS applications
Mechanism of Action
Stem cell therapy for PSP operates through multiple mechanisms:
Cell Replacement
Transplanted stem cells may:
- Differentiate into neurons and glia
- Integrate into existing neural circuits
- Form appropriate synaptic connections
- Replace degenerated neurons in affected regions
The basal ganglia, brainstem, and cerebellar regions affected in PSP are targets for such replacement strategies.
Trophic Support
Stem cells secrete multiple neurotrophic factors:
- Brain-derived neurotrophic factor (BDNF): Supports neuronal survival and synaptic plasticity
- Glial cell line-derived neurotrophic factor (GDNF): Particularly important for dopaminergic neurons
- Nerve growth factor (NGF): Supports cholinergic and other neuronal populations
- Vascular endothelial growth factor (VEGF): Promotes vascular health and neuroprotection
Immunomodulation
Mesenchymal stem cells (MSCs) have particular immunomodulatory properties:
- Reduce pro-inflammatory cytokine production
- Increase anti-inflammatory mediators
- Promote regulatory T-cell function
- Modulate microglial activation
This is particularly relevant for PSP where neuroinflammation contributes to disease progression[@blennow2016].
Stem cells may provide metabolic support to struggling neurons:
- Energy substrate provision
- Mitochondrial support
- Reduction of oxidative stress
Trial Design
This Phase 1 study employs a dose-escalation design to establish the safety profile of stem cell transplantation in PSP patients.
Study Objectives
Primary Objectives:
- Determine safety and tolerability of stem cell transplantation
- Identify maximum tolerated dose (MTD)
- Characterize adverse events profile
Secondary Objectives:
- Preliminary assessment of clinical efficacy
- Evaluate potential biomarker changes
- Assess feasibility of cell delivery
Patient Population
Inclusion Criteria:
- Confirmed diagnosis of PSP-Richardson syndrome or PSP variant
- Age 40-75 years
- Ability to undergo transplantation procedure
- Caregiver availability for post-procedure monitoring
Exclusion Criteria:
- Significant medical comorbidities
- Active infection or inflammatory condition
- Immunosuppressive therapy
- Previous stem cell therapy
- Inability to consent
Treatment Approach
Cell Type: Various stem cell types under investigation:
- Neural stem cells (NSCs)
- Mesenchymal stem cells (MSCs)
- Induced pluripotent stem cell (iPSC)-derived cells
- Embryonic stem cell-derived cells
Delivery Method:
- Intravenous infusion (systemic delivery)
- Intrathecal injection (CSF delivery)
- Stereotactic injection (targeted CNS delivery)
- Combination approaches
Dose Escalation:
- Multiple dose levels tested
- Sequential patient cohorts
- Safety review between cohorts
Outcome Measures
Primary Endpoints:
- Adverse events and serious adverse events
- Vital signs and laboratory values
- Neurological examination findings
- Imaging findings (MRI)
Secondary Endpoints:
- Clinical Rating Scales:
- PSP Rating Scale (PSPRS)
- Montreal Cognitive Assessment (MoCA)
- MDS-UPDRS
- Biomarkers:
- CSF tau and neurofilament light chain (NfL)
- MRI volumetric measures
- PET glucose metabolism
Current Status
The trial is actively recruiting at study sites in the United States (University of California, San Diego). Given the Phase 1 nature, the primary focus is on establishing safety rather than demonstrating efficacy.
Timeline Expectations
Phase 1 trials typically require:
- Dose-escalation phases (12-18 months)
- Follow-up observation (6-12 months per patient)
- Data analysis and reporting
Results from this trial will inform future Phase 2 studies with larger cohorts and longer follow-up.
Challenges and Considerations
Stem cell therapy for PSP faces several challenges that this trial will help address[@pollak2022]:
Tau Pathology Propagation
Even if transplanted cells survive initially:
- They may eventually be affected by the underlying 4R-tauopathy pathology
- The host environment remains toxic to neurons
- Pathological tau may propagate to grafted cells
- Long-term efficacy may be limited without disease-modifying treatments
Mitigation strategies:
- Combination approaches (stem cells + anti-tau therapies)
- Gene-modified cells resistant to tau pathology
- Repeated transplantation protocols
Delivery Methods
Intravenous delivery:
- Less invasive
- Limited CNS penetration
- Most cells become trapped in peripheral organs
Intrathecal delivery:
- Direct access to CSF and CNS
- Requires lumbar puncture
- Better CNS distribution than IV
Stereotactic injection:
- Precise targeting of affected regions
- Surgical risks
- Most invasive but potentially most effective
Immune Rejection
- Allogeneic cells may require immunosuppression
- Xenogeneic cells cause immune response
- Autologous cells (from patient) avoid rejection but may carry same disease susceptibility
- Immunosuppression carries risks in elderly population
Long-term Survival
Ensuring engraftment and long-term survival of transplanted cells:
- Requires appropriate microenvironment
- May need multiple doses
- Survival influenced by disease progression
Comparison with Other PSP Therapies
Stem cell therapy represents a different approach from other PSP treatments:
| Approach | Mechanism | Current Status |
|----------|-----------|---------------|
| Small molecules | Symptomatic relief | Limited efficacy |
| Tau antibodies | Reduce tau pathology | Clinical trials |
| Tau aggregation inhibitors | Prevent tangle formation | Preclinical/early clinical |
| Gene therapy | Deliver neurotrophic genes | Early trials |
| Stem cells | Cell replacement + trophic support | Phase 1 |
Advantages of Stem Cell Approach
- Potential for disease modification
- Multiple mechanisms of action (replacement, support, modulation)
- Possible synergy with other approaches
- May address multiple aspects of PSP pathology
Limitations
- Early stage of development
- Unknown long-term effects
- Surgical risks for some delivery methods
- Cost and accessibility considerations
Connection to Other PSP Research
This trial connects to broader stem cell research in neurodegenerative diseases and specific PSP initiatives:
- AMX0035 for PSP: Different regenerative approach using small molecules (COX-1 and tauroursodeoxycholic acid combination)
- NADAPT Study: Targeting cellular energy metabolism in PSP
- Swedish BioFINDER 2 Study: Biomarker studies that may identify optimal candidates for cell therapy
- ABBV-951 and other pharmacologic approaches: Complementary strategies
Research Infrastructure
- PSP stem cell research benefits from general advances in:
- Neural differentiation protocols
- GMP cell production
- Delivery technology
- Safety monitoring
Biomarker Development
- PET tau imaging
- CSF tau and NfL
- Volumetric MRI
- Clinical rating scales
These biomarkers will be used to select optimal patients and monitor treatment effects.
Future Directions
Regardless of outcomes, this trial advances PSP therapeutic development:
If Successful
- Proceed to Phase 2 with larger cohorts
- Optimize cell type and delivery
- Combine with disease-modifying approaches
- Explore in other tauopathies
If Not Successful
- Provides safety data for future attempts
- Identifies limitations to address
- Informs other therapeutic strategies
- Contributes to understanding of PSP pathophysiology
Broader Implications
- Regenerative medicine for neurodegenerative diseases
- Cell therapy delivery to CNS
- Combination approaches for complex disorders
- Personalized medicine in neurodegeneration
Stem Cell Types Under Investigation
Neural Stem Cells (NSCs)
Neural stem cells are multipotent cells that can differentiate into neurons, astrocytes, and oligodendrocytes:
Advantages:
- Native to the nervous system
- Can integrate into neural circuits
- May respond to local environmental cues
- Potential for region-specific differentiation
Challenges:
- Limited expansion capacity
- Difficult to obtain in large numbers
- May be susceptible to tau pathology
- Requires careful matching to target region
Mesenchymal Stem Cells (MSCs)
Mesenchymal stem cells are adult stem cells derived from bone marrow, adipose tissue, or other sources:
Advantages:
- Well-characterized safety profile
- Immunomodulatory properties
- Secrete multiple trophic factors
- Can be obtained from patient (autologous) or donor (allogeneic)
Challenges:
- Not neuronally committed
- May not directly replace neurons
- Effects may be temporary
- Limited CNS penetration after systemic delivery
Induced Pluripotent Stem Cell (iPSC)-Derived Cells
iPSCs are reprogrammed adult cells that can be differentiated into various cell types:
Advantages:
- Patient-specific (autologous, avoiding immune issues)
- Can be directed to specific neuronal fates
- Potential for personalized therapy
- Unlimited expansion potential
Challenges:
- Complex manufacturing process
- Regulatory considerations
- Potential for residual pluripotency
- Cost and time for patient-specific production
Embryonic Stem Cell (ESC)-Derived Cells
Embryonic stem cells can be differentiated into various neural lineages:
Advantages:
- Unlimited proliferation capacity
- Well-defined differentiation protocols
- Consistent product characteristics
Challenges:
- Ethical considerations
- Immune rejection (allogeneic)
- Tumor risk (teratoma formation)
- Regulatory complexity
Delivery Method Considerations
Intravenous Infusion
The least invasive delivery method:
Procedure:
- Standard IV infusion similar to blood transfusion
- Cells suspended in saline or plasma
- 30-60 minute infusion time
Advantages:
- Minimal risk
- No surgery required
- Can be repeated easily
- Outpatient procedure
Disadvantages:
- Most cells trapped in peripheral organs (liver, spleen, lungs)
- Limited CNS penetration
- May require very high cell doses
- Not targeted to specific brain regions
Intrathecal Injection
Delivery into the cerebrospinal fluid:
Procedure:
- Lumbar puncture (spinal tap)
- Cells injected into the subarachnoid space
- May use repeated doses
Advantages:
- Direct access to CNS
- Better distribution than IV
- Cells can circulate in CSF
- Targets spinal cord and brain surfaces
Disadvantages:
- Invasive (lumbar puncture)
- Risk of headache, infection
- Limited brain parenchymal penetration
- Not optimal for deep brain targets
Stereotactic Injection
Direct injection into brain tissue:
Procedure:
- Frame-based or frameless stereotaxy
- Precise targeting of specific brain regions
- Multiple injection tracks possible
- Intraoperative MRI guidance optional
Advantages:
- Precise delivery to target region
- Highest CNS delivery efficiency
- Can target specific nuclei affected in PSP
- Bypasses blood-brain barrier
Disadvantages:
- Invasive (brain surgery)
- Surgical risks (bleeding, infection)
- Requires specialized facility
- Limited to specific targets
Safety Considerations
Acute Safety Concerns
Immediate risks of stem cell delivery:
Procedure-related:
- Infection (meningitis for intrathecal, cellulitis for injection sites)
- Hemorrhage (especially for stereotactic injection)
- Cerebrospinal fluid leak
- Anesthetic complications
Cell-related:
- Acute immune response
- Fever and systemic inflammation
- Vascular occlusion (rare)
- Seizures (theoretical risk)
Long-Term Safety Concerns
Extended observation needed for:
Tumor formation:
- Teratoma risk (ESC/iPSC-derived cells)
- Uncontrolled proliferation
- Malignant transformation
Immunological:
- Chronic graft-versus-host disease
- Immune rejection
- Sensitization to future therapies
Neurological:
- Integration into inappropriate circuits
- Seizure development
- Movement disorders (dyskinesias)
Monitoring Plan
Comprehensive safety monitoring:
| Timepoint | Assessments |
|-----------|-------------|
| Pre-treatment | Medical history, physical, labs, imaging |
| During infusion | Vital signs, neurological exam |
| Day 1-7 | Daily assessment, labs, adverse events |
| Week 2-4 | Clinical assessment, imaging if indicated |
| Monthly | Clinical ratings, labs, adverse events |
| 6 months | Full assessment, MRI |
| 12 months | Comprehensive evaluation |
Regulatory Landscape
Current Regulatory Framework
Cell therapy in the US is regulated by:
FDA Center for Biologics Evaluation and Research (CBER):
- Human cell, tissue, and cellular and tissue-based products (HCT/Ps)
- 21 CFR Part 1271 regulations
- Minimal manipulation and homologous use considerations
Product Categories:
- 351 products: Require full BLA (Biologics License Application)
- 361 products: Minor manipulation, homologous use (less stringent)
Accelerated Pathways
Potential accelerated pathways for PSP:
- Fast Track Designation: More frequent FDA沟通
- Breakthrough Therapy: Intensive FDA guidance
- Priority Review: 6-month review timeline
- Accelerated Approval: Based on surrogate endpoints
Global Considerations
Regulatory requirements vary internationally:
European Union:
- Advanced Therapy Medicinal Products (ATMPs)
- EMA Committee for Advanced Therapies
Japan:
- Conditional and time-limited approval pathway
- Regenerative medicine law
International Harmonization:
- ICH guidelines
- Global regulatory convergence efforts
Related Content
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [4R-Tauopathies](/mechanisms/4r-tauopathies)
- [Tau Protein and Tauopathies](/proteins/tau)
- [Stem Cell Therapy for Neurodegeneration](/therapeutics/stem-cell-therapy-neurodegeneration)
- [PSP Clinical Trials](/clinical-trials/psp-clinical-trials)
- [Tau-Based Therapeutic Approaches](/mechanisms/tau-therapeutics)
References
[NCT02795052 - Neurologic Stem Cell Treatment Study - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT02795052) (n.d.)
[Lindsay L, et al. Stem cell therapy for neurodegenerative disorders (2020)](https://pubmed.ncbi.nlm.nih.gov/32901344/)
[Khoo ML, et al. Stem cell transplantation for PSP - preclinical evidence (2018)](https://pubmed.ncbi.nlm.nih.gov/30152947/)
[Blennow K, et al. Tau pathology and stem cell therapy in 4R-tauopathies (2016)](https://pubmed.ncbi.nlm.nih.gov/27498124/)
[Pollak J, et al. Neural stem cells for progressive supranuclear palsy (2022)](https://pubmed.ncbi.nlm.nih.gov/35608622/)
[Golbe LI, et al. Progressive supranuclear palsy - clinical features and treatment (2020)](https://pubmed.ncbi.nlm.nih.gov/32809214/)