¶ Section 217: Advanced Cell Therapy and Regenerative Medicine in CBS/PSP
Advanced cell therapy and regenerative medicine represent the most forward-looking therapeutic strategies for corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). These approaches move beyond neuroprotection to attempt actual restoration of lost neuronal function and circuit connectivity.
This section provides comprehensive coverage of:
- Cell replacement therapies: iPSC-derived, ESC-derived, and neural stem cells
- MSC-based approaches: Immunomodulation and trophic support
- Exosome/EV therapy: Cell-free regenerative medicine
- Mitochondrial transplantation: Restoring cellular energy
- Gene therapy: GDNF, CDNF, and related neurotrophic approaches
- Clinical trial landscape: Current status and future opportunities
iPSC technology offers unique advantages for 4R-tauopathies:
- Patient-specific modeling: Disease-specific mechanisms can be studied in patient-derived neurons
- Autologous potential: Patient-derived cells may reduce immune rejection
- Genetic correction: CRISPR can correct pathogenic variants before transplantation (e.g., MAPT, GBA
- 4R-tau modeling: Patient iPSCs can be differentiated into neurons expressing 4R-tau isoforms specific to PSP/CBS
Foundational trials in Parkinson's disease establish the template for CBS/PSP applications:
| Trial |
Cell Type |
Phase |
Key Findings |
| Kyoto University (Japan) |
iPSC-derived DA progenitors |
I/II (2025) |
44.7% increase in putaminal dopamine, motor improvement |
| Bemdaneprocel (BlueRock) |
hESC-derived DA progenitors |
III |
Enrollment ongoing, FDA Fast Track |
| STEM-PD (Lund/Cambridge) |
hESC-derived DA neurons |
I/II |
Active, first patient transplanted |
While Parkinson's disease trials focus on dopaminergic neurons, CBS/PSP require additional considerations:
Target Cell Types:
- Dopaminergic neurons for parkinsonian features
- Cholinergic neurons for cognitive/basal forebrain involvement
- GABAergic neurons for cortical inhibition
- Mixed neuronal populations for broader circuit restoration
Delivery Targets:
Current Status for CBS/PSP:
No iPSC trials specifically in CBS/PSP as of early 2026. The Parkinson's disease foundation will likely enable atypical parkinsonism applications by 2027-2028.
For patients with resources to pursue personalized approaches:
- Cell source: Skin fibroblasts or peripheral blood mononuclear cells
- Reprogramming: Send to specialized facility (e.g., WiCell, Kyoto University)
- Differentiation: 6-12 months to dopaminergic progenitors
- Quality control: Genomic stability, teratoma risk, dopaminergic specification
- Transplantation: Autologous or HLA-matched allogeneic
Cost estimate: $150,000-300,000 for full autologous program
ESC-derived dopaminergic neurons represent the most advanced cell therapy platform:
Bemdaneprocel (BRT-LEW):
- Source: Clinically compliant hESC line
- Product: DA progenitors (post-mitotic)
- Delivery: Stereotactic injection to putamen
- Status: Phase III registrational trial for PD
- Manufacturer: BlueRock Therapeutics (Bayer/BMS)
STEM-PD:
- Source: Clinically validated hESC line
- Product: Mature dopaminergic neurons
- Delivery: Putaminal transplantation
- Status: Phase I/II in Europe
- Consortium: Lund University, Cambridge University
- Standardized manufacturing: Single-cell line → consistent product
- Scalability: Easier large-scale production
- Regulatory pathway: Established cell line with known characteristics
- Cost: Lower per-dose cost than autologous iPSC
ESC programs may expand to atypical parkinsonism after PD registration:
Expected timeline:
- 2026-2027: PD Phase III completion
- 2027-2028: FDA/EMA review and potential approval
- 2028+: Expansion to PSP/CBS trials
Eligibility factors:
- Age <70 (younger patients more likely to benefit)
- Relatively preserved baseline function
- Absence of significant medical comorbidities
- Willingness to undergo immunosuppression
MSCs exert therapeutic effects primarily through paracrine mechanisms rather than cell replacement:
| Mechanism |
Effect |
| Trophic factor secretion |
BDNF, GDNF, NGF, VEGF support neuron survival |
| Immunomodulation |
Suppress pro-inflammatory microglia, reduce IL-1β, TNF-α |
| Anti-apoptotic |
Secretion of survival factors protecting neurons |
| Endogenous repair |
Stimulate native neural stem cell proliferation |
| Mitochondrial transfer |
Direct mitochondrial donation to damaged neurons |
Multiple trials establish safety and preliminary efficacy:
Parkinson's Disease:
- IV MSC: Generally safe, some motor improvement signals
- Intrathecal MSC: Shows promise for neuroinflammation modulation
Amyotrophic Lateral Sclerosis:
- Multiple Phase I/II trials establish safety
- Variable efficacy signals depending on delivery route
Multiple System Atrophy:
- Small trials suggest safety
- Autonomic function improvement in some patients
For CBS/PSP patients considering MSC therapy:
Delivery routes:
| Route |
Advantages |
Considerations |
| Intravenous |
Minimally invasive, repeatable |
Limited CNS penetration |
| Intrathecal |
Direct CSF exposure |
Requires lumbar puncture |
| Intra-arterial |
Targeted brain delivery |
Higher procedural risk |
| Intracerebral |
Direct parenchymal delivery |
Most invasive |
Dosing considerations:
- 1-2 × 10⁶ cells/kg typical dose
- 2-3 infusions spaced 1-2 months apart
- Monitoring: MRI, immunological markers, clinical assessment
Clinical trial opportunities:
- Active trials in PD and ALS establish safety
- Specific CBS/PSP trials expected to emerge 2026-2027
| Factor |
MSC Therapy |
Neuronal Cell Therapy |
| Mechanism |
Trophic support, immunomodulation |
Cell replacement |
| Onset |
Weeks to months |
Months to years |
| Durability |
May require repeat dosing |
Potentially permanent |
| Invasive |
Variable |
Stereotactic neurosurgery |
| Evidence base |
More established |
Emerging (PD) |
| CBS/PSP suitability |
Promising (neuroinflammation) |
Requires PD foundation |
Exosomes (30-150 nm) represent a cell-free approach to regenerative medicine:
- Natural delivery vehicles: Carry parent-cell-derived proteins, RNAs
- BBB penetration: Can cross blood-brain barrier via receptor-mediated transcytosis
- Cargo flexibility: Can be loaded with therapeutic siRNA, ASOs, small molecules
- Safety profile: Lack nuclear DNA, lower oncogenic risk than cells
- Off-the-shelf potential: Scalable manufacturing from cell lines
| Cargo |
Mechanism |
Status |
| siRNA/ASO |
Gene silencing (e.g., MAPT) |
Preclinical |
| Small molecules |
Neuroprotection, anti-inflammatory |
Preclinical |
| Proteins |
Trophic factors (GDNF, BDNF) |
Preclinical |
| miRNA |
Epigenetic modulation |
Preclinical |
| mRNA |
Protein replacement |
Early development |
MSCs and neural stem cells secrete therapeutically active exosomes:
MSC-derived EVs:
- Carry immunomodulatory cargo
- Reduce microglial activation in preclinical models
- Safety established in wound healing trials (NCT02565264)
Neuronal EV cargo:
- Disease-specific therapeutic targets
- Patient-derived iPSC neurons for personalized EV production
Completed trials:
- Stem cell-derived EVs for wound healing (NCT02565264)
- Cancer immunotherapy (NCT03436356)
Neurology trials:
- No completed trials in neurodegeneration yet
- Multiple programs in preclinical development
Timeline for CBS/PSP:
- 2026-2027: First-in-human trials likely in PD
- 2028+: Expansion to tauopathies
Mitochondrial dysfunction is central to CBS/PSP pathology:
- Complex I deficiency: Early finding in substantia nigra
- mtDNA mutations: Accumulate with age, accelerate neurodegeneration
- Mitophagy impairment: Damaged mitochondria accumulate
- Energy crisis: Reduced ATP compromises neuronal function
Mitochondrial transplantation delivers healthy mitochondria directly to affected neurons.
Animal models:
- Mitochondrial transfer improves motor function in PD models
- Astrocyte-to-neuron mitochondrial transfer documented
- Intracerebral delivery shows neuronal uptake
Mechanisms:
- Direct mitochondrial incorporation
- Tunneling nanotube transfer
- Extracellular vesicle-mediated delivery
NCT04998357 (University of Washington):
- First human brain mitochondrial transplantation
- Phase I, safety focus
- Safe in initial cohort
Delivery approaches:
| Method |
Target |
Status |
| Intracerebral |
Putamen/substantia nigra |
Phase I |
| Intra-arterial |
Cerebral circulation |
Preclinical |
| IV |
Systemic, limited CNS |
Preclinical |
Suitability factors:
- Strong mitochondrial pathology in PSP
- Target: substantia nigra, basal ganglia
- May combine with other cell therapies
Current status: No specific CBS/PSP trials. Monitor PD program expansion.
GDNF (Glial Cell Line-Derived Neurotrophic Factor) is the most extensively studied neurotrophic factor for parkinsonism.
Mechanism:
- Potent dopaminergic neuron survival factor
- Supports axonal sprouting
- Protects substantia nigra neurons
AAV-GDNF Approaches:
| Program |
Vector |
Delivery |
Status |
| Voyager Therapeutics |
AAV2-GDNF |
Intraparenchymal |
Phase I/II |
| Roche/ch2 |
AAV2-GDNF |
Intracerebral |
Preclinical |
| NBI-578 |
AAV-GDNF |
Targeted |
Preclinical |
Challenges:
- AAV2 limited to neurons expressing appropriate receptors
- Distribution across putamen requires multiple injection tracks
- GDNF not secreted efficiently from transduced cells
- Clinical trials in PD showed mixed results
Next-generation approaches:
- AAV5 or AAV9 for broader transduction
- AAV-GDNF with optimized secretion
- Combinations with cell therapy
CDNF (Cerebral Dopamine Neurotrophic Factor) offers advantages over GDNF:
Mechanism:
- ER stress reduction
- Unfolded protein response modulation
- Anti-apoptotic effects
- Both dopaminergic and non-dopaminergic protection
AAV-CDNF Clinical Program:
- Phase I/II trial (NCT04174190): First-in-human AAV-CDNF
- Delivery: Intracerebral to putamen
- Sponsor: Herantis Pharma
- Status: Ongoing, safety established
Advantages over GDNF:
- Secreted protein (better diffusion)
- ER stress protection relevant to tauopathies
- May benefit non-dopaminergic circuits
TrkB (NTRK2) activation supports multiple neuronal populations:
- BDNF signaling: Synaptic plasticity, cognitive function
- GABAergic neurons: Cortical inhibition
- Cholinergic neurons: Basal forebrain function
Approach: AAV-TrkB to nucleus basalis for cognitive function in CBS
| Factor |
Consideration |
| Target selection |
GDNF/CDNF for motor, TrkB for cognitive |
| Delivery |
Stereotactic intracerebral injection |
| Immunosuppression |
Not typically required for AAV |
| Duration |
Potential multi-year effect from single dose |
| Combination |
May combine with cell therapy |
Combining neuronal cell replacement with anti-inflammatory approaches:
Rationale:
- Transplanted cells face hostile neuroinflammatory environment
- Reducing microglia activation improves graft survival
- TREM2 modulators may enhance phagocytosis of pathological tau
Approaches:
- MSC co-transplantation: MSC + neuronal progenitors
- CSF1R inhibitor preconditioning
- Anti-inflammatory cytokine delivery
Enhancing graft survival and integration:
GDNF-secreting cells:
- Engineered cells co-expressing GDNF
- Sustained neurotrophic support at transplant site
Combination with small molecules:
- Exercise + cell therapy: synergistic BDNF elevation
- CoQ10 + cell therapy: enhanced mitochondrial function
Multi-phase treatment strategies:
Phase 1: Immunomodulation
- MSC or anti-inflammatory treatment
- Reduce hostile microenvironment
Phase 2: Cell replacement
- iPSC or ESC-derived neurons
- Establish new circuits
Phase 3: Circuit strengthening
- Exercise, BDNF elevation
- Neurotrophic factor support
Phase 4: Maintenance
- Repeat MSC treatments
- Monitor and support long-term function
| Trial |
Therapy |
Disorder |
Phase |
Expected |
| BlueRock Bemdaneprocel |
ESC-DA |
PD |
III |
2026-2027 |
| STEM-PD |
ESC-DA |
PD |
I/II |
2027 |
| Kyoto iPSC |
iPSC-DA |
PD |
I/II |
Ongoing |
| Herantis CDNF |
AAV-CDNF |
PD |
I/II |
2026 |
| NCT04998357 |
Mitochondria |
PD/Brain |
I |
Ongoing |
For patients with resources:
- Travel to trial sites: PD trials accepting international patients
- Compassionate use: Some programs offer expanded access
- Private cell banking: Store cells for future therapies
- Specialized centers: Movement disorder centers with cell therapy programs
Key institutions:
- Kyoto University (Japan): iPSC program
- McGill University: NTRK2 trials
- Lund University: STEM-PD
- University of Washington: Mitochondrial transplantation
Expected based on PD timeline:
2027-2028:
- First ESC or iPSC trials in PSP likely
- CDNF expansion to PSP
- MSC trials in CBS/PSP
2028-2030:
- Registrational trials if early signals positive
- Combination therapy approaches
- Personalized iPSC programs
Factors predicting better outcomes:
| Factor |
Impact |
| Age <65 |
Better graft integration |
| Disease duration <5 years |
Less neurodegeneration |
| Preserved cognition |
Better functional recovery |
| Limited comorbidity |
Able to tolerate procedure |
| Strong social support |
Adherence to follow-up |
Potential benefits:
- Motor function improvement
- Disease modification (if cell therapy effective)
- Reduced medication needs
- Improved quality of life
Risks:
- Surgical complications (hemorrhage, infection)
- Immunosuppression-related complications
- Graft failure or rejection
- Tumor formation (theoretical, very low with current protocols)
- Dyskinesias (particularly with cell therapy)
| Approach |
Estimated Cost |
| MSC therapy (clinical trial) |
Typically free |
| iPSC autologous |
$150,000-300,000 |
| Private cell banking |
$2,000-5,000 |
| Gene therapy (compassionate) |
$500,000-1,500,000 |
| International trial participation |
Variable |
Cell and regenerative therapies should be positioned within the broader treatment framework:
Immediate term (now):
- Exercise, existing medications, clinical trial participation
- Standard disease management
Near term (1-2 years):
- Monitor PD cell therapy trials
- Consider MSC therapy if available
- Prepare for eventual CBS/PSP trials
Medium term (2-5 years):
- Access to first-generation cell therapies
- Potential combination approaches
- Personalized iPSC options for those with resources
Advanced cell therapy and regenerative medicine represent the frontier of CBS/PSP treatment. While Parkinson's disease establishes the clinical foundation, translation to 4R-tauopathies will follow. Key considerations:
Near-term opportunities:
- MSC therapy for immunomodulation
- Monitor AAV-CDNF expansion
- Mitochondrial transplantation trials
Medium-term prospects:
- ESC/iPSC trials likely in PSP by 2027-2028
- Personalized iPSC for select patients
- Combination approaches emerging
Patient preparation:
- Monitor trial databases (ClinicalTrials.gov)
- Establish care at academic centers
- Consider cell banking for future use
- Maintain overall health to remain trial-eligible
The field is evolving rapidly. Patients and clinicians should stay informed of developments while building the foundation of standard care that optimizes readiness for advanced therapies when they become available.