Adaeze Ekwe, MSc, PhD
Junior Associate Editor, ISCT Telegraft
Queensland University of Technology (QUT)
Australia
 
Joaquim Vives, PhD
Contributing Editor, ISCT Telegraft
Banc de Sang i Teixits (BST)
Spain

Topic Overview

Cell-based regenerative therapies are entering a transformative phase in human medicine. Among the most transformative frontiers in regenerative medicine are pluripotent stem cell (PSC)-derived therapies, designed to restore or replace specific cell types in disorders with well-defined cellular targets. Early-phase clinical trials are evaluating retinal pigment epithelium (RPE) cells or photoreceptors derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) for macular degeneration (e.g., NCT01344993) and Stargardt disease (NCT01345006, NCT01625559), with encouraging signs of safety and structural integration. Similar approaches are being explored in spinal cord injuries (NCT02302157) and type 1 diabetes (NCT04786262) where PSC-derived progenitors aim to reconstitute lost neuronal or β-cell function¹. Providing a pivotal breakthrough for the field, recent data from a first-in-human trial demonstrated that CRISPR-Cas12b-edited “hypoimmune” islet cells can survive and maintain glucose-responsive insulin secretion for 12 weeks without any systemic immunosuppression, offering a potential blueprint for overcoming allogeneic rejection in other tissues². Yet perhaps the most compelling demonstration of clinical maturity is emerging in Parkinson’s disease (PD), where the selective loss of nigrostriatal dopaminergic neurons provides a uniquely defined substrate for cell replacement. Recent first-in-human studies of hESC- and iPSC-derived dopaminergic progenitors have delivered the first tangible evidence of long-term graft survival and dopaminergic activity on PET imaging up to 24 months post-transplant, marking a decisive step from conceptual promise to clinical reality in PSC-based neuroregeneration^3,4.

In this Scientific Spotlight, we examine key insights from these trials on PD, pose critical questions for next-stage development, and reflect on how this case illustrates broader opportunities and challenges in cell-based therapy.

Expert Perspectives

• Prof. Dr. Angel Raya, ICREA/IDIBELL (Spain): “These first-in-human trials are a historic milestone, demonstrating that stem-cell derived neurons can survive long-term in the human brain. This shifts the paradigm from symptomatic care to potential restoration. However, the critical next hurdle is moving beyond graft survival to functional maturity and integration. The disconnect between positive PET signals and modest clinical improvements suggests the transplanted cells may not be forming the sophisticated synaptic connections needed to fully reconstitute neural circuitry. Ensuring iPSC-derived progenitors mature into fully functional, network-integrated neurons is now the central challenge for transforming this promising proof-of-concept into a truly disease-modifying therapy.”
• Prof. Tilo Kunath, Centre for Regenerative Medicine, The University of Edinburgh (UK): “What we are witnessing is the shift from ‘is it possible?’ to ‘how do we implement it in real clinical settings?’ Dopaminergic cell replacement therapy has now demonstrated survival, dopamine release, and acceptable safety in humans. The next challenge is showing that it can meaningfully alter the trajectory of disease in patients. Achieving that will require standardized products, reproducible surgical delivery, and carefully designed randomized trials with endpoints that matter to patients. And beyond the biology, real clinical adoption will depend on manufacturing capacity, cost, and regulatory alignment. If those pieces come together, dopaminergic cell therapy could reshape how we treat Parkinson’s.” 
• Dr. John De Vos, IRMB, University of Montpellier, INSERM, CHU Montpellier, Saint-Eloi Hospital, Montpellier (France): “Only a limited number of PSC-based therapies have progressed to phase III clinical trials, and Parkinson’s disease represents one of the leading examples, with encouraging clinical improvement in early-phase studies. A key unresolved issue, however, concerns the long-term survival of the allogeneic grafts used in these trials, as immunosuppression is discontinued one year after implantation. Autologous strategies may ultimately provide greater durability, albeit at substantially higher manufacturing costs. In this context, several early-phase trials are now evaluating autologous hiPSC-derived therapies for Parkinson’s disease, reflecting continued efforts to define the most sustainable clinical approach.”
  
  

Insights Across the Ecosystem

For Patients

• Impact: Cell-based dopaminergic replacement could shift PD treatment from symptomatic control to disease-modifying (or restorative) intervention, alleviating motor fluctuations, reducing dependency on dopaminergic medications and improving quality of life.
  
• Safety and Access: The early data suggest acceptable safety over two years (no tumorigenesis, no graft overgrowth) in small cohorts³. However, broader safety in more diverse populations remains untested. Access may be limited initially by cost, manufacturing bottlenecks, and geographic disparity in centers capable of stereotactic grafting. 

For Clinicians and Researchers

• Applicability: These therapies will likely find their initial niche in patients with moderate disease (not too advanced but needing more than symptomatic therapy). The inclusion/exclusion criteria in the current trials (e.g. avoiding severe cognitive impairment or severe dyskinesia) reflect anticipated challenges in patient selection³.
• Evidence Needs: Clinicians will demand randomized, sham-surgery control, blinded trials demonstrating not only motor score improvements but effects on medication burden, imaging correlates, long-term durability (>5 years), and safety (e.g. graft-induced dyskinesia).
  
• Practice-Changing Implications: If effective, grafting of stem-cell derived dopamine progenitors could become a third pillar of PD therapy, complementing pharmacology and neurosurgery (e.g. deep brain stimulation). Neurorehabilitation integration and post-graft management protocols (immunosuppression, imaging surveillance) will need to be standardized.

For Developers and Industry

• Technical Hurdles: i) Cell survival & integration: The observed modest effect sizes and disconnects between PET signal and clinical results suggest many transplanted cells may not survive, differentiate fully, or innervate the host striatum properly; ii) Delivery devices: There is no consensus "gold standard" for stereotactic cell delivery in the brain; shear stress, reflux, and cell loss during injection remain concerns; iii) Immune compatibility:  Even in the brain's relatively immunoprivileged environment, rejection or inflammatory damage remains a threat. Allogeneic cell products will demand immunomodulation strategies or HLA matching and hypoimmunogenic engineering (e.g. MHC editing or cloaking)⁵; and iv) Manufacturing scale & quality control: Generating GMP-grade, consistent, safe, cryopreservable batches and ensuring batch-to-batch reproducibility at scale is a formidable challenge. The recent clinical validation of “hypoimmune” islet cells demonstrates that MHC-editing and CD47-overexpression can successfully “cloak” allogeneic grafts from the host immune system, potentially eliminating the need for chronic immunosuppression in future PD transplant protocols².
• Regulatory Strategies: Developers must engage early with regulatory agencies to define acceptable endpoints (e.g. surrogate imaging biomarkers, composite clinical scores), safety monitoring plans (e.g. tumorigenicity), long-term follow-up commitments, and criteria for conditional approvals.
• Cost and reimbursement planning: The cost structure must be viable. Manufacturing, surgical delivery, immunosuppression, imaging follow-up and monitoring will all contribute. Early modeling of cost-effectiveness and payer engagement will be crucial.

For Regulators, Payers and Policy Makers

• Decision Frameworks: Regulatory bodies must balance the ethical urgency of unmet need in PD with the unknowns of long-term efficacy and safety. Adaptive or conditional approval pathways (with mandatory post-market follow-up) may be a sensible route.
• Assessment Tools: Payers will demand evidence of durable benefit, cost-offsets (reduced medication, fewer complications), and patient quality-of-life gains. Robust health economic modelling from early data will be essential.
  
• Reimbursement pathways: These advanced therapies may need bespoke reimbursement schemes (e.g. outcomes-based payments, annuity payments) given high upfront costs and uncertain long-term data. Planning for such schemes in parallel with trial development is prudent.
  
• Harmonization policies: Given the global nature of PD research, alignment across jurisdictions (e.g. common guidance on cell therapy endpoints, safety registries, standards) would reduce duplication and accelerate patient access.
  
  

Global Viewpoint

• Regional trends: Japan is well positioned to lead in earlier access: under its Pharmaceuticals and Medical Devices Act, the Kyoto iPSC trial team may apply for conditional approval sooner. North American and European regulators currently favor cautious, randomized controlled trials; proponents aim to move toward phase III or pivotal trials (e.g. BlueRock's exPDite-2 trial planned). Emerging markets (e.g. China, South Korea) are investing heavily in stem-cell infrastructure and may become important sites for multicenter trials, though regulatory harmonization and standards may vary.
• Harmonization efforts: International consortia and networks are exploring common standards in cell characterization, potency assays, safety registries and postmarket surveillance. Global trial access will be shaped by centers of neurosurgical expertise, regulatory alignment, and harmonized ethics frameworks.
  
  

What to Watch

• New guidance document for the development of pluripotent stem cell-based therapies by the International Society of Stem cell research (ISSCR).
• Initiation of phase III or pivotal trials, such as BlueRock's exPDite-2 (sham-controlled, randomized) for bemdaneprocel.
• Long-term follow-up data from current patients, especially regarding durability, graft overgrowth, and late adverse events.
• Innovative delivery device platforms (e.g. microcatheters, hydrogels, controlled-release scaffolds) to reduce cell loss during transplantation.
• Advances in immune evasion and hypoimmunogenic engineering (e.g. gene editing of HLA, immune cloaking, local immunomodulatory matrices).
• Development of robust potency assays or surrogate biomarkers (e.g. molecular imaging, functional connectivity, synaptic integration metrics).
• Public comment periods or draft guidance for advanced cell-based medicinal products.
• Workshops, symposia or sessions at major stem cell or neurology congresses focusing on pluripotent-derived transplant therapies (e.g. ISSCR, MDS, ISCT).
• Advocacy and patient engagement campaigns; inclusion of patient voice in trial design (e.g. endpoints meaningful to quality of life, risk tolerance).

References

1. Kirkeby, A., H. Main, and M. Carpenter, Pluripotent stem-cell-derived therapies in clinical trial: A 2025 update. Cell Stem Cell, 2025. 32(1): p. 10-37.
2. Carlsson, P.O., et al., Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression. N Engl J Med, 2025. 393(9): p. 887-894.
3. Sawamoto, N., et al., Phase I/II trial of iPS-cell-derived dopaminergic cells for Parkinson's disease. Nature, 2025. 641(8064): p. 971-977.
4. Tabar, V., et al., Phase I trial of hES cell-derived dopaminergic neurons for Parkinson's disease. Nature, 2025. 641(8064): p. 978-983.
5. Morizane, A., et al., Control of immune response in an iPSC-based allogeneic cell therapy clinical trial for Parkinson's disease. Cell Stem Cell, 2025. 32(9): p. 1346-1355 e3.