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

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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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).

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