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BioDrugs

, Volume 32, Issue 4, pp 357–366 | Cite as

Regenerative Therapies for Parkinson’s Disease: An Update

  • Thomas B. Stoker
  • Roger A. Barker
Review Article

Abstract

Parkinson’s disease is the second most common neurodegenerative disorder. It is characterised by a typical movement disorder that occurs in part because of the selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. Current treatment for the motor disorder of Parkinson’s disease consists of dopaminergic medications, but these come with significant adverse effects, themselves an important part of the clinical course of Parkinson’s disease, particularly in advanced stages. Therefore, treatment is needed that can restore dopaminergic tone in the striatum in a physiological and targeted manner to avert these side effects. A number of potential regenerative treatments have been developed with a view to achieving this. Following decades of optimisation and development of stem-cell-based treatments and viral gene delivery, clinical trials are on the horizon. For these treatments to be widely useful, they must be clinically effective, cost efficient and safe, and a number of practical aspects regarding storage and delivery of treatment must be optimised. Many barriers have been overcome, and the field of regenerative medicine for Parkinson’s disease is now increasingly focussed on how these treatments will be delivered, demonstrating the significant progress that has been made and the optimism surrounding these approaches.

Notes

Acknowledgements

The authors acknowledge financial support from the following organisations: Medical Research Council, Wellcome Trust Stem Cell Institute (Cambridge), National Institute for Health Research Biomedical Research Centre and the Cure Parkinson’s Trust.

Compliance with Ethical Standards

Funding

No funding was received for the preparation of this review.

Conflict of interest

TB Stoker and RA Barker have no conflicts of interest.

References

  1. 1.
    Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912.CrossRefPubMedGoogle Scholar
  2. 2.
    Khoo TK, Yarnall AJ, Duncan GW, Coleman S, O’Brien JT, Brooks DJ, et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology. 2013;80(3):276–81.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, et al. The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry. 2013;84(11):1258–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Dickson DW. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med. 2012;2(8):a009258.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A clinico-pathological study of subtypes in Parkinson’s disease. Brain. 2009;132(Pt 11):2947–57.CrossRefPubMedGoogle Scholar
  7. 7.
    Jenner P. Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr Opin Neurol. 2003;16(Suppl 1):S3–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM. The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev. 2013;65(1):171–222.CrossRefPubMedGoogle Scholar
  9. 9.
    Nutt JG. On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol. 1987;22(4):535–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol. 2012;72(6):893–901.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord. 2012;27(5):617–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013;136(Pt 8):2419–31.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Madrazo I, Drucker-Colín R, Díaz V, Martínez-Mata J, Torres C, Becerril JJ. Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N Engl J Med. 1987;316(14):831–4.CrossRefPubMedGoogle Scholar
  14. 14.
    Backlund EO, Granberg PO, Hamberger B, Knutsson E, Mårtensson A, Sedvall G, et al. Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J Neurosurg. 1985;62(2):169–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Allen GS, Burns RS, Tulipan NB, Parker RA. Adrenal medullary transplantation to the caudate nucleus in Parkinson’s disease. Initial clinical results in 18 patients. Arch Neurol. 1989;46(5):487–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Drucker-Colín R, Madrazo I, Ostrosky-Solís F, Shkurovich M, Franco R, Torres C. Adrenal medullary tissue transplants in the caudate nucleus of Parkinson’s patients. Prog Brain Res. 1988;78:567–74.CrossRefPubMedGoogle Scholar
  17. 17.
    Goetz CG, Tanner CM, Penn RD, Stebbins GT, Gilley DW, Shannon KM, et al. Adrenal medullary transplant to the striatum of patients with advanced Parkinson’s disease: 1-year motor and psychomotor data. Neurology. 1990;40(2):273–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Jankovic J, Grossman R, Goodman C, Pirozzolo F, Schneider L, Zhu Z, et al. Clinical, biochemical, and neuropathologic findings following transplantation of adrenal medulla to the caudate nucleus for treatment of Parkinson’s disease. Neurology. 1989;39(9):1227–34.CrossRefPubMedGoogle Scholar
  19. 19.
    Kelly PJ, Ahlskog JE, van Heerden JA, Carmichael SW, Stoddard SL, Bell GN. Adrenal medullary autograft transplantation into the striatum of patients with Parkinson’s disease. Mayo Clin Proc. 1989;64(3):282–90.CrossRefPubMedGoogle Scholar
  20. 20.
    Jiao SS, Zhang WC, Cao JK, Zhang ZM, Wang H, Ding MC, et al. Study of adrenal medullary tissue transplantation to striatum in parkinsonism. Prog Brain Res. 1988;78:575–80.CrossRefPubMedGoogle Scholar
  21. 21.
    Goetz CG, Stebbins GT, Klawans HL, Koller WC, Grossman RG, Bakay RA, et al. United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up. Neurology. 1991;41(11):1719–22.CrossRefPubMedGoogle Scholar
  22. 22.
    Waters C, Itabashi HH, Apuzzo ML, Weiner LP. Adrenal to caudate transplantation–postmortem study. Mov Disord. 1990;5(3):248–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Lindvall O, Rehncrona S, Brundin P, Gustavii B, Astedt B, Widner H, 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. 1989;46(6):615–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science. 1990;247(4942):574–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Wenning GK, Odin P, Morrish P, Rehncrona S, Widner H, Brundin P, et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann Neurol. 1997;42(1):95–107.CrossRefPubMedGoogle Scholar
  26. 26.
    Brundin P, Pogarell O, Hagell P, Piccini P, Widner H, Schrag A, et al. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease. Brain. 2000;123(Pt 7):1380–90.CrossRefPubMedGoogle Scholar
  27. 27.
    Lindvall O, Sawle G, Widner H, Rothwell JC, Björklund A, Brooks D, et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol. 1994;35(2):172–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Li W, Englund E, Widner H, Mattsson B, van Westen D, Lätt J, et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci USA. 2016;113(23):6544–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344(10):710–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003;54(3):403–14.CrossRefPubMedGoogle Scholar
  31. 31.
    Gross RE, Watts RL, Hauser RA, Bakay RA, Reichmann H, von Kummer R, et al. Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2011;10(6):509–19.CrossRefPubMedGoogle Scholar
  32. 32.
    Arjona V, Mínguez-Castellanos A, Montoro RJ, Ortega A, Escamilla F, Toledo-Aral JJ, et al. Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease. Neurosurgery. 2003;53(2):321–8 (discussion 8-30).CrossRefPubMedGoogle Scholar
  33. 33.
    Mínguez-Castellanos A, Escamilla-Sevilla F, Hotton GR, Toledo-Aral JJ, Ortega-Moreno A, Méndez-Ferrer S, et al. Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. J Neurol Neurosurg Psychiatry. 2007;78(8):825–31.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Schumacher JM, Ellias SA, Palmer EP, Kott HS, Dinsmore J, Dempsey PK, et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology. 2000;54(5):1042–50.CrossRefPubMedGoogle Scholar
  35. 35.
    Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature. 1996;380(6571):252–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Stoker TB, Blair NF, Barker RA. Neural grafting for Parkinson’s disease: challenges and prospects. Neural Regen Res. 2017;12(3):389–92.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480(7378):547–51.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L, et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells. 2006;24(6):1433–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, et al. In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem. 2005;92(5):1265–76.CrossRefPubMedGoogle Scholar
  41. 41.
    Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 2006;12(11):1259–68.CrossRefPubMedGoogle Scholar
  42. 42.
    Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A, Bramoulle Y, et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson’s disease. Cell Stem Cell. 2014;15(5):653–65.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kirkeby A, Nolbrant S, Tiklova K, Heuer A, Kee N, Cardoso T, et al. Predictive markers guide differentiation to improve graft outcome in clinical translation of hESC-based therapy for Parkinson’s Disease. Cell Stem Cell. 2017;20(1):135–48.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMedGoogle Scholar
  45. 45.
    Takahashi K, Okita K, Nakagawa M, Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc. 2007;2(12):3081–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009;136(5):964–77.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature. 2017;548(7669):592–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Barker RA, de Beaufort I. Scientific and ethical issues related to stem cell research and interventions in neurodegenerative disorders of the brain. Prog Neurobiol. 2013;110:63–73.CrossRefPubMedGoogle Scholar
  49. 49.
    Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell. 2012;11(2):147–52.CrossRefPubMedGoogle Scholar
  50. 50.
    Sonntag KC, Pruszak J, Yoshizaki T, van Arensbergen J, Sanchez-Pernaute R, Isacson O. Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin. Stem Cells. 2007;25(2):411–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Offen D, Barhum Y, Levy YS, Burshtein A, Panet H, Cherlow T, Melamed E. Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson’s disease. J Neural Transm Suppl. 2007;72:133–43.CrossRefGoogle Scholar
  52. 52.
    Barker RA, Drouin-Ouellet J, Parmar M. Cell-based therapies for Parkinson disease—past insights and future potential. Nat Rev Neurol. 2015;11(9):492–503.CrossRefPubMedGoogle Scholar
  53. 53.
    Delcroix GJ, Garbayo E, Sindji L, Thomas O, Vanpouille-Box C, Schiller PC, et al. The therapeutic potential of human multipotent mesenchymal stromal cells combined with pharmacologically active microcarriers transplanted in hemi-parkinsonian rats. Biomaterials. 2011;32(6):1560–73.CrossRefPubMedGoogle Scholar
  54. 54.
    Kim YJ, Park HJ, Lee G, Bang OY, Ahn YH, Joe E, Kim HO, Lee PH. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia. 2009;57(1):13–23.CrossRefPubMedGoogle Scholar
  55. 55.
    Venkataramana NK, Kumar SK, Balaraju S, Radhakrishnan RC, Bansal A, Dixit A, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res. 2010;155(2):62–70.CrossRefPubMedGoogle Scholar
  56. 56.
    Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009;73(20):1662–9.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther. 2010;18(9):1731–5.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Palfi S, Gurruchaga JM, Ralph GS, Lepetit H, Lavisse S, Buttery PC, 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. 2014;383(9923):1138–46.CrossRefPubMedGoogle Scholar
  59. 59.
    Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet. 2007;369(9579):2097–105.CrossRefPubMedGoogle Scholar
  60. 60.
    Marks WJ, Ostrem JL, Verhagen L, Starr PA, Larson PS, Bakay RA, et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol. 2008;7(5):400–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Marks WJ, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9(12):1164–72.CrossRefPubMedGoogle Scholar
  62. 62.
    LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011;10(4):309–19.CrossRefPubMedGoogle Scholar
  63. 63.
    Niethammer M, Tang CC, LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, et al. Long-term follow-up of a randomized AAV2-. JCI Insight. 2017;2(7):e90133.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med. 2010;2(38):38ra46.CrossRefPubMedGoogle Scholar
  65. 65.
    Politis M, Oertel WH, Wu K, Quinn NP, Pogarell O, Brooks DJ, et al. Graft-induced dyskinesias in Parkinson’s disease: High striatal serotonin/dopamine transporter ratio. Mov Disord. 2011;26(11):1997–2003.CrossRefPubMedGoogle Scholar
  66. 66.
    Merkle FT, Ghosh S, Kamitaki N, Mitchell J, Avior Y, Mello C, et al. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature. 2017;545(7653):229–33.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Garber K. RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat Biotechnol. 2015;33(9):890–1.CrossRefPubMedGoogle Scholar
  68. 68.
    Blair NF, Barker RA. Making it personal: the prospects for autologous pluripotent stem cell-derived therapies. Regen Med. 2016;11(5):423–5.CrossRefPubMedGoogle Scholar
  69. 69.
    Barker RA, Parmar M, Studer L, Takahashi J. Human Trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell. 2017;21(5):569–73.CrossRefPubMedGoogle Scholar
  70. 70.
    Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013;525(2):174–81.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Kalia SK, Sankar T, Lozano AM. Deep brain stimulation for Parkinson’s disease and other movement disorders. Curr Opin Neurol. 2013;26(4):374–80.CrossRefPubMedGoogle Scholar
  73. 73.
    Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, et al. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord. 2014;29(2):229–37.CrossRefPubMedGoogle Scholar
  74. 74.
    Evans JR, Mason SL, Williams-Gray CH, Foltynie T, Brayne C, Robbins TW, et al. The natural history of treated Parkinson’s disease in an incident, community based cohort. J Neurol Neurosurg Psychiatry. 2011;82(10):1112–8.CrossRefPubMedGoogle Scholar
  75. 75.
    Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463(7284):1035–41.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    di Val Rivetti, Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, et al. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model. Nat Biotechnol. 2017;35(5):444–52.CrossRefGoogle Scholar
  77. 77.
    Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol. 2017;298(Pt B):225–35.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.John van Geest Centre for Brain Repair, Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
  2. 2.Wellcome Trust - Medical Research Council Stem Cell InstituteUniversity of CambridgeCambridgeUK

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