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Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease

Nature Medicine volume 25, pages 1045–1053 (2019)Cite this article

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Abstract

Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.

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Fig. 1: Overview of the TRANSEURO protocol.
Fig. 2: Data from the observational cohort at 36 months.

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References

  1. Goedert, M., Spillantini, M. G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nat. Rev. Neurol. 9, 13–24 (2013).

    Article  CAS  Google Scholar 

  2. Schapira, A. H. V., Chaudhuri, K. R. & Jenner, P. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 18, 509 (2017).

    Article  CAS  Google Scholar 

  3. Barker, R. A., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease — past insights and future potential. Nat. Rev. Neurol. 11, 492–503 (2015).

    Article  CAS  Google Scholar 

  4. Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146 (2014).

    Article  CAS  Google Scholar 

  5. Freed, C. R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med. 344, 710–719 (2001).

    Article  CAS  Google Scholar 

  6. Olanow, C. W. et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann. Neurol. 54, 403–414 (2003).

    Article  Google Scholar 

  7. Barker, R. A., Barrett, J., Mason, S. L. & Bjorklund, A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. Lancet Neurol. 12, 84–91 (2013).

    Article  CAS  Google Scholar 

  8. Kirkeby, A., Parmar, M. & Barker, R. A. Strategies for bringing stem cell-derived dopamine neurons to the clinic: A European approach (STEM-PD). Prog. Brain. Res. 230, 165–190 (2017).

    Article  Google Scholar 

  9. Liu, G. et al. Prediction of cognition in Parkinson’s disease with a clinical-genetic score: a longitudinal analysis of nine cohorts. Lancet Neurol. 16, 620–629 (2017).

    Article  Google Scholar 

  10. Politis, M. et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci. Transl. Med. 2, 38ra46 (2010).

    Article  Google Scholar 

  11. Piccini, P. et al. Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Brain 128, 2977–2986 (2005).

    Article  Google Scholar 

  12. Piccini, P. et al. Delayed recovery of movement-related cortical function in Parkinson’s disease after striatal dopaminergic grafts. Ann. Neurol. 48, 689–695 (2000).

    Article  CAS  Google Scholar 

  13. Piroth, T. et al. Transplantation of human fetal tissue for neurodegenerative diseases: validation of a new protocol for microbiological analysis and bacterial decontamination. Cell Transplant. 23, 995–1007 (2014).

    Article  Google Scholar 

  14. Rath, A. et al. Survival and functional restoration of human fetal ventral mesencephalon following transplantation in a rat model of Parkinson’s disease. Cell Transplant. 22, 1281–1293 (2013).

    Article  Google Scholar 

  15. Kelly, C. M. et al. Medical terminations of pregnancy: a viable source of tissue for cell replacement therapy for neurodegenerative disorders. Cell Transplant. 20, 503–513 (2011).

    Article  CAS  Google Scholar 

  16. Kordower, J. H. et al. Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies. J. Comp. Neurol. 370, 203–230 (1996).

    Article  CAS  Google Scholar 

  17. Li, W. et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc. Natl Acad. Sci. USA 113, 6544–6549 (2016).

    Article  CAS  Google Scholar 

  18. Brundin, P. et al. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease. Brain 123, 1380–1390 (2000).

    Article  Google Scholar 

  19. Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87 (2014).

    Article  Google Scholar 

  20. Fahn, S. et al. Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med. 351, 2498–2508 (2004).

    Article  CAS  Google Scholar 

  21. Carpenter, B. et al.Stan: a probabilistic programming language. J. Stat. Softw. 76, https://doi.org/10.18637/jss.v076.i01 (2017).

  22. Bürkner, P. brms: An R Package for Bayesian Multilevel Models Using Stan. J. Stat. Softw. 80, https://doi.org/10.18637/jss.v080.i01 (2017).

  23. Li, W. et al. (11) C-PE2I and (18) F-Dopa PET for assessing progression rate in Parkinson’s: A longitudinal study. Mov. Disord. 33, 117–127 (2018).

    Article  CAS  Google Scholar 

  24. Lindvall, O. et al. Transplantation of fetal dopamine neurons in Parkinson’s disease: one-year clinical and neurophysiological observations in two patients with putaminal implants. Ann. Neurol. 31, 155–165 (1992).

    Article  CAS  Google Scholar 

  25. Lindvall, O. et al. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch. Neurol. 46, 615–631 (1989).

    Article  CAS  Google Scholar 

  26. Laguna Goya, R., Busch, R., Mathur, R., Coles, A. J. & Barker, R. A. Human fetal neural precursor cells can up-regulate MHC class I and class II expression and elicit CD4 and CD8 T cell proliferation. Neurobiol. Dis. 41, 407–414 (2011).

    Article  CAS  Google Scholar 

  27. Liu, X., Li, W., Fu, X. & Xu, Y. The immunogenicity and immune tolerance of pluripotent stem cell derivatives. Front. Immunol. 8, 645 (2017).

    Article  Google Scholar 

  28. Scheiner, Z. S., Talib, S. & Feigal, E. G. The potential for immunogenicity of autologous induced pluripotent stem cell-derived therapies. J. Biol. Chem. 289, 4571–4577 (2014).

    Article  CAS  Google Scholar 

  29. Galpern, W. R. et al. Sham neurosurgical procedures in clinical trials for neurodegenerative diseases: scientific and ethical considerations. Lancet Neurol. 11, 643–650 (2012).

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge D. Marsden, N. Cawthorne and T. Stone from the Cambridge University Hospital Clinical Engineering Innovation (CEI) who helped in the development of the in house delivery device in Cambridge, and K. Richardson, K. Jestice, and M. Scott from the Cambridge Cellular Therapy Laboratory, Cambridge University Hospitals NHS Foundation Trust who helped in developing the SOPs for the hfVM tissue preparations in Cambridge.

This study was supported by an EU FP7 grant (242003) as well as funding from the Cure Parkinson’s Trust (RG81537), John Black Charitable Trust and Multipark. The work was also supported by NIHR funding of Biomedical Research Centres at UCL and Cambridge (146281). R.A.B. is an NIHR Senior Investigator (NF-SI-0616-10011) and a PI in the MRC/WT Stem Cell Institute (203151/Z/16/Z).

Author information

Authors and Affiliations

  1. John van Geest Centre for Brain Repair, Department of Clinical Neurosciences and WT-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    Roger A. Barker

  2. John van Geest Centre for Brain Repair, Cambridge University, Cambridge, UK

    Roger A. Barker, Krista Farrell, Natalie Valle Guzman, Xiaoling He, Sarah Moore, Pamela Tyers, Ruwani Wijeyekoon, Danielle Daft & Sam Hewitt

  3. Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK

    Stanley E. Lazic, Alistair Church, Stephen Dunnett, Kathryn Peall & Anne Rosser

  4. Cambridge University Hospital NHS Foundation Trust, Addenbrookes Hospital, Hills Road, Cambridge, UK

    Robert Morris

  5. Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK

    Viswas Dayal, Thomas Foltynie, Zinovia Kefalopoulou & Philipp Mahlknecht

  6. The National Hospital for Neurology and Neurosurgery, London, UK

    Viswas Dayal, Thomas Foltynie, Zinovia Kefalopoulou & Philipp Mahlknecht

  7. Neurology Imaging Unit, Centre of Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Hammersmith Campus, Imperial College London, London, UK

    Nick P. Lao-Kaim & Paola Piccini

  8. Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, BMC, Lund, Sweden

    Hjalmar Bjartmarz, Anders Björklund, Jenny Nelander-Wahlestedt & Malin Parmar

  9. Laboratory of Stem Cells and Restorative Neurology, University Hospital, Lund, Sweden

    Olle Lindvall

  10. Lund Stem Cell Center, Lund University, BMC, Lund, Sweden

    Olle Lindvall

  11. Neurology Clinic, Skåne University Hospital, Lund, Sweden

    Gesine Paul & Hakan Widner

  12. Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, PePsy Department, Groupe Hospitalier Henri-Mondor Albert-Chenevier, Créteil, France

    Jean Marc Gurruchaga & Stéphane Palfi

  13. Laboratory of Molecular Neurosurgery, Department of Stereotactic Neurosurgery, Freiburg University, Freiburg, Germany

    Tobias Piroth & Christian Winkler

Authors
  1. Roger A. Barker
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Consortia

TRANSEURO consortium

  • Krista Farrell
  • , Natalie Valle Guzman
  • , Xiaoling He
  • , Stanley E. Lazic
  • , Sarah Moore
  • , Robert Morris
  • , Pamela Tyers
  • , Ruwani Wijeyekoon
  • , Danielle Daft
  • , Sam Hewitt
  • , Viswas Dayal
  • , Thomas Foltynie
  • , Zinovia Kefalopoulou
  • , Philipp Mahlknecht
  • , Nick P. Lao-Kaim
  • , Paola Piccini
  • , Hjalmar Bjartmarz
  • , Anders Björklund
  • , Olle Lindvall
  • , Jenny Nelander-Wahlestedt
  • , Malin Parmar
  • , Gesine Paul
  • , Hakan Widner
  • , Alistair Church
  • , Stephen Dunnett
  • , Kathryn Peall
  • , Anne Rosser
  • , Jean Marc Gurruchaga
  • , Stéphane Palfi
  • , Tobias Piroth
  •  & Christian Winkler

Corresponding author

Correspondence to Roger A. Barker.

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Competing interests

R.A.B. advises Living Cell Technologies, FujiFilm Cellular Dynamics Inc; BlueRock Therapeutics; Novo Nordisk; Sana Therapeutics and Cellino Biotech on their cell-based therapies for PD as well as UCB, Roche and Lundbeck on other aspects of neurodegenerative disorders of the brain. T.P. has received honorary fees from Boston Scientific for peer-to-peer workshops (related to DBS) in 2018 and 2019. T.F. advises Living Cell Technologies on their cell-based therapy, as well as Bial, Profile Pharma, Peptron and Boston Scientific on other aspects of neurodegenerative disorders of the brain. A.B. is a consultant for Novo Nordisk. M.P. is the owner of Parmar Cells AB and co-inventor on US patent applications 15/093,927 owned by Biolamina AB and EP17181588 owned by Miltenyi Biotec. Patent WO 2015/114059 A1 patents the use of BCL2 in reprogramming. S.P. advises Oxford Biomedica and Axovant

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Peer review information: Joao Monteiro was the primary editor on this perspective and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Barker, R.A., TRANSEURO consortium. Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease. Nat Med 25, 1045–1053 (2019). https://doi.org/10.1038/s41591-019-0507-2

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