Dopaminergic drugs were established as an effective treatment for Parkinson disease (PD) in the 1960s, and are still the mainstay of therapy for this condition
Experiments that heralded the modern era of neural grafting for PD began in the 1970s in Sweden
Despite limited preclinical data, adrenal medullary transplantation was adopted by many groups during the 1980s, with largely disappointing results
Human fetal ventral mesencephalic (fVM) allografts have been shown to survive and function for over 20 years in some patients
The protocol for neural transplantation in patients with PD remains to be optimized
Human fVM grafts are currently being revisited, and stem cell-based dopamine replacement therapies are close to clinical trials
Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route. We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.
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The authors' own work is supported by grants from Neurostemcellrepair (grant no. 602278) and the Swedish Research Council (grants K2012-99X-22324-01-5 and K2014-61X-20391-08-4) and TRANSEURO, and by the National institute for Health Research (NIHR)-funded Biomedical Research Centre in Cambridge, UK. M.P. is funded from the European Research Council ERC Grant Agreement no. 309712. We would also like to thank Hakan Widner, Olle Lindvall and Anders Björklund for their advice and input, especially relating to information on the patients grafted in Lund.
The authors declare no competing financial interests.
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Barker, R., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease—past insights and future potential. Nat Rev Neurol 11, 492–503 (2015). https://doi.org/10.1038/nrneurol.2015.123
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