Neurologic Stem Cell Treatment Study for Progressive Supranuclear Palsy (NCT02795052)

ClinicalTrials.gov Identifier: [NCT02795052](https://clinicaltrials.gov/study/NCT02795052)

Overview

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.

ClinicalTrials.gov Identifier: [NCT02795052](https://clinicaltrials.gov/study/NCT02795052)

Overview

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)

• 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

• 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]:

Preclinical 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

• 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

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

Metabolic Support

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

• 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

• 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

• Intravenous infusion (systemic delivery)
• Intrathecal injection (CSF delivery)
• Stereotactic injection (targeted CNS delivery)
• Combination approaches

• 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)

• 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

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

• 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

• Direct access to CSF and CNS
• Requires lumbar puncture
• Better CNS distribution than IV

• 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:

Related Clinical Trials

• 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

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

• 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)

• 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

• 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

• 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

• Minimal risk
• No surgery required
• Can be repeated easily
• Outpatient procedure

• 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

• Direct access to CNS
• Better distribution than IV
• Cells can circulate in CSF
• Targets spinal cord and brain surfaces

• 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

• Precise delivery to target region
• Highest CNS delivery efficiency
• Can target specific nuclei affected in PSP
• Bypasses blood-brain barrier

• 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

• 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

• Chronic graft-versus-host disease
• Immune rejection
• Sensitization to future therapies

• 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

• 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

• Conditional and time-limited approval pathway
• Regenerative medicine law

• 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