Advertisement

Cell Replacement Strategies for Parkinson’s Disease

  • Diptaman Chatterjee
  • Dustin R. Wakeman
  • Jeffrey H. KordowerEmail author
Chapter
Part of the Molecular and Translational Medicine book series (MOLEMED)

Abstract

Since the 1970s, studies have evaluated the efficacy of cell transplantation therapy in neurological disorders, particularly in Parkinson’s disease. Parkinson’s is a progressive neurodegenerative disorder predominantly affecting midbrain, dopaminergic neurons along the nigrostriatal pathway. Abrogation of dopamine supply induces motor dysfunction and may play a role in other areas such as cognition and behavioral dysfunction. Current targeted treatments are effective in remediating motor symptoms, but elicit involuntary dyskinesia and off-target effects in the long term, warranting efforts toward the development of regionally specific therapies such as dopamine cell replacement. Thus far, provision of dopamine transmitting cells from fetal grafts has proven effective in animal models, suggested to be effective in open-label clinical trials, but has faltered in double-blind clinical assessments. Fetal grafts that survive greater than 10 years can be filled with Lewy bodies suggestive of a prion-like transmission from the host to the graft. Additionally, some patients develop novel graft-induced dyskinesias. Recent enhancements in stem cell technology have reinvigorated efforts toward cell replacement therapy using both embryonic stem cells and induced pluripotent stem cells. In the past 10 years, rapid advances in dopaminergic stem cell differentiation protocols, characterizations of nigrostriatal graft microenvironments, and effective transplantation in animal models have reinvigorated hope for potential clinical efficacy. However, cell replacement strategies will necessitate widespread, robust standardization of protocols and rigorously controlled clinical trials with careful subject selection before they are designated suitable for clinical use in Parkinson’s patients.

Keywords

Parkinson’s disease Induced pluripotent stem cell Neural stem cells Neural grafting Cell transplantation Cell-based therapies Clinical trial Fetal tissue Dopamine 

References

  1. 1.
    Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson’s disease. Parkinsonism Relat Disord. 2010;16:79–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Rinne UK. Dopamine agonists as primary treatment in Parkinson’s disease. Adv Neurol. 1987;45:519–23.PubMedGoogle Scholar
  3. 3.
    Lindvall O. Clinical translation of stem cell transplantation in Parkinson’s disease. J Intern Med. 2016;279:30–40.CrossRefPubMedGoogle Scholar
  4. 4.
    Bjorklund A, Stenevi U, Svendgaard N. Growth of transplanted monoaminergic neurones into the adult hippocampus along the perforant path. Nature. 1976;262:787–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Hoffer B, Olson L, Seiger A, Bloom F. Formation of a functional adrenergic input to intraocular cerebellar grafts: ingrowth of inhibitory sympathetic fibers. J Neurobiol. 1975;6:565–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Hoffer BJ, Seiger A, Taylor D, Olson L, Freedman R. Seizures and related epileptiform activity in hippocampus transplanted to the anterior chamber of the eye I. Characterization of seizures, interictal spikes, and synchronous activity. Exp Neurol. 1977;54:233–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Olson L, Seiger A. Locus coeruleus: fibre growth regulation in oculo. Med Biol. 1976;54:142–5.PubMedGoogle Scholar
  8. 8.
    Perlow MJ, Freed WJ, Hoffer BJ, Seiger A, Olson L, Wyatt RJ. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science. 1979;204:643–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Seiger A, Olson L, Farnebo LO. Brain tissue transplanted to the anterior chamber of the eye. 4. Drug-modulated transmitter release in central monoamine nerve terminals lacking normal postsynaptic receptors. Cell Tissue Res. 1976;165:157–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Stenevi U, Bjorklund A. Transplantation techniques for the study of regeneration in the central nervous system. Prog Brain Res. 1978;48:101–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Stenevi U, Bjorklund A, Svendgaard NA. Transplantation of central and peripheral monoamine neurons to the adult rat brain: techniques and conditions for survival. Brain Res. 1976;114:1–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Bjorklund A, Dunnett SB, Stenevi U, Lewis ME, Iversen SD. Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 1980a;199:307–33.CrossRefPubMedGoogle Scholar
  13. 13.
    Bjorklund A, Schmidt RH, Stenevi U. Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substantia nigra. Cell Tissue Res. 1980b;212:39–45.CrossRefPubMedGoogle Scholar
  14. 14.
    Brundin P, Bjorklund A. Survival, growth and function of dopaminergic neurons grafted to the brain. Prog Brain Res. 1987;71:293–308.CrossRefPubMedGoogle Scholar
  15. 15.
    Brundin P, Isacson O, Gage FH, Bjorklund A. Intrastriatal grafting of dopamine-containing neuronal cell suspensions: effects of mixing with target or non-target cells. Brain Res. 1986a;389:77–84.CrossRefPubMedGoogle Scholar
  16. 16.
    Brundin P, Nilsson OG, Strecker RE, Lindvall O, Astedt B, Bjorklund A. Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson’s disease. Exp Brain Res. 1986b;65:235–40.CrossRefPubMedGoogle Scholar
  17. 17.
    Dunnett SB, Bjorklund A, Stenevi U, Iversen SD. Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. I. Unilateral lesions. Brain Res. 1981;215:147–61.CrossRefPubMedGoogle Scholar
  18. 18.
    Bakay RA, Fiandaca MS, Barrow DL, Schiff A, Collins DC. Preliminary report on the use of fetal tissue transplantation to correct MPTP-induced Parkinson-like syndrome in primates. Appl Neurophysiol. 1985;48:358–61.PubMedGoogle Scholar
  19. 19.
    Redmond DE Jr, Sladek JR Jr, Roth RH, Collier TJ, Elsworth JD, Deutch AY, Haber S. Transplants of primate neurons. Lancet. 1986a;2:1046.CrossRefPubMedGoogle Scholar
  20. 20.
    Redmond DE, Sladek JR Jr, Roth RH, Collier TJ, Elsworth JD, Deutch AY, Haber S. Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine. Lancet. 1986b;1:1125–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Sladek JR Jr, Collier TJ, Haber SN, Deutch AY, Elsworth JD, Roth RH, Redmond DE Jr. Reversal of parkinsonism by fetal nerve cell transplants in primate brain. Ann N Y Acad Sci. 1987;495:641–57.CrossRefPubMedGoogle Scholar
  22. 22.
    Sladek JR Jr, Collier TJ, Haber SN, Roth RH, Redmond DE Jr. Survival and growth of fetal catecholamine neurons transplanted into primate brain. Brain Res Bull. 1986;17:809–18.CrossRefPubMedGoogle Scholar
  23. 23.
    Grow DA, McCarrey JR, Navara CS. Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson’s disease. Stem Cell Res. 2016;17:352–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Sladek JR Jr, Collier TJ, Elsworth JD, Roth RH, Taylor JR, Redmond DE Jr. Intrastriatal grafts from multiple donors do not result in a proportional increase in survival of dopamine neurons in nonhuman primates. Cell Transplant. 1998;7:87–96.CrossRefPubMedGoogle Scholar
  25. 25.
    Jankovic J, Grossman R, Goodman C, Pirozzolo F, Schneider L, Zhu Z, Scardino P, Garber AJ, Jhingran SG, Martin S. Clinical, biochemical, and neuropathologic findings following transplantation of adrenal medulla to the caudate nucleus for treatment of Parkinson’s disease. Neurology. 1989;39:1227–34.CrossRefPubMedGoogle Scholar
  26. 26.
    Schumacher JM, Ellias SA, Palmer EP, Kott HS, Dinsmore J, Dempsey PK, Fischman AJ, Thomas C, Feldman RG, Kassissieh S, Raineri R, Manhart C, Penney D, Fink JS, Isacson O. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology. 2000;54:1042–50.CrossRefPubMedGoogle Scholar
  27. 27.
    Lindvall O, Rehncrona S, Gustavii B, Brundin P, Astedt B, Widner H, Lindholm T, Bjorklund A, Leenders KL, Rothwell JC, Frackowiak R, Marsden CD, Johnels B, Steg G, Freedman R, Hoffer BJ, Seiger L, Stromberg I, Bygdeman M, Olson L. Fetal dopamine-rich mesencephalic grafts in Parkinson’s disease. Lancet. 1988;2:1483–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Bjorklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci. 2007;30:194–202.CrossRefPubMedGoogle Scholar
  29. 29.
    Lindvall O. Cerebral implantation in movement disorders: state of the art. Mov Disord. 1999a;14:201–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Lindvall O. Engineering neurons for Parkinson’s disease. Nat Biotechnol. 1999b;17:635–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Olanow CW, Freeman TB, Kordower JH. Neural transplantation as a therapy for Parkinson’s disease. Adv Neurol. 1997;74:249–69.PubMedGoogle Scholar
  32. 32.
    Redmond DE Jr. Cellular replacement therapy for Parkinson’s disease—where we are today? Neuroscientist. 2002;8:457–88.CrossRefPubMedGoogle Scholar
  33. 33.
    Rehncrona S. A critical review of the current status and possible developments in brain transplantation. Adv Tech Stand Neurosurg. 1997;23:3–46.CrossRefPubMedGoogle Scholar
  34. 34.
    Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord. 1999;14:572–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, Watts R. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord. 1992;7:2–13.CrossRefPubMedGoogle Scholar
  36. 36.
    Barker RA, Barrett J, Mason SL, Bjorklund A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. Lancet Neurol. 2013;12:84–91.CrossRefPubMedGoogle Scholar
  37. 37.
    Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344:710–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003;54:403–14.CrossRefPubMedGoogle Scholar
  39. 39.
    Carlsson T, Carta M, Munoz A, Mattsson B, Winkler C, Kirik D, Bjorklund A. Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration. Brain. 2009;132:319–35.CrossRefPubMedGoogle Scholar
  40. 40.
    Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain. 2007;130:1819–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Carta M, Carlsson T, Munoz A, Kirik D, Bjorklund A. Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias. Prog Brain Res. 2008;172:465–78.CrossRefPubMedGoogle Scholar
  42. 42.
    Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, Bjorklund A, Lindvall O, Piccini P. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med. 2010;2:38ra46.CrossRefPubMedGoogle Scholar
  43. 43.
    Kuan WL, Lin R, Tyers P, Barker RA. The importance of A9 dopaminergic neurons in mediating the functional benefits of fetal ventral mesencephalon transplants and levodopa-induced dyskinesias. Neurobiol Dis. 2007;25:594–608.CrossRefPubMedGoogle Scholar
  44. 44.
    Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain. 2005;128:1498–510.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Barker RA, Dunnett SB, Faissner A, Fawcett JW. The time course of loss of dopaminergic neurons and the gliotic reaction surrounding grafts of embryonic mesencephalon to the striatum. Exp Neurol. 1996;141:79–93.CrossRefPubMedGoogle Scholar
  46. 46.
    Hebb AO, Hebb K, Ramachandran AC, Mendez I. Glial cell line-derived neurotrophic factor-supplemented hibernation of fetal ventral mesencephalic neurons for transplantation in Parkinson disease: long-term storage. Neurosurg Focus. 2002;13:e4.CrossRefPubMedGoogle Scholar
  47. 47.
    Mehta V, Hong M, Spears J, Mendez I. Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor. J Neurosurg. 1998;88:1088–95.CrossRefPubMedGoogle Scholar
  48. 48.
    Rosenblad C, Martinez-Serrano A, Bjorklund A. Glial cell line-derived neurotrophic factor increases survival, growth and function of intrastriatal fetal nigral dopaminergic grafts. Neuroscience. 1996;75:979–85.CrossRefPubMedGoogle Scholar
  49. 49.
    Appel SH, Armon C. Stem cells in amyotrophic lateral sclerosis: ready for prime time? Neurology. 2016;87:348–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Kordower JH, Goetz CG, Chu Y, Halliday GM, Nicholson DA, Musial TF, Marmion DJ, Stoessl AJ, Sossi V, Freeman TB, Olanow CW. Robust graft survival and normalized dopaminergic innervation do not obligate recovery in a Parkinson disease patient. Ann Neurol. 2017;81:46–57.CrossRefPubMedGoogle Scholar
  51. 51.
    Piccini P, Pavese N, Hagell P, Reimer J, Bjorklund A, Oertel WH, Quinn NP, Brooks DJ, Lindvall O. Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Brain. 2005;128:2977–86.CrossRefPubMedGoogle Scholar
  52. 52.
    Petit GH, Olsson TT, Brundin P. The future of cell therapies and brain repair: Parkinson’s disease leads the way. Neuropathol Appl Neurobiol. 2014;40:60–70.CrossRefPubMedGoogle Scholar
  53. 53.
    Hess DC, Borlongan CV. Stem cells and neurological diseases. Cell Prolif. 2008;41(Suppl 1):94–114.PubMedGoogle Scholar
  54. 54.
    Laguna Goya R, Kuan WL, Barker RA. The future of cell therapies in the treatment of Parkinson’s disease. Expert Opin Biol Ther. 2007;7:1487–98.CrossRefPubMedGoogle Scholar
  55. 55.
    Morizane A, Li JY, Brundin P. From bench to bed: the potential of stem cells for the treatment of Parkinson’s disease. Cell Tissue Res. 2008;331:323–36.CrossRefPubMedGoogle Scholar
  56. 56.
    Isacson O, Deacon TW. Specific axon guidance factors persist in the adult brain as demonstrated by pig neuroblasts transplanted to the rat. Neuroscience. 1996;75:827–37.CrossRefPubMedGoogle Scholar
  57. 57.
    Wictorin K, Brundin P, Gustavii B, Lindvall O, Bjorklund A. Reformation of long axon pathways in adult rat central nervous system by human forebrain neuroblasts. Nature. 1990;347:556–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Wictorin K, Brundin P, Sauer H, Lindvall O, Bjorklund A. Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6-hydroxydopamine lesioned adult rats. J Comp Neurol. 1992;323:475–94.CrossRefPubMedGoogle Scholar
  59. 59.
    Thompson LH, Grealish S, Kirik D, Bjorklund A. Reconstruction of the nigrostriatal dopamine pathway in the adult mouse brain. Eur J Neurosci. 2009;30:625–38.CrossRefPubMedGoogle Scholar
  60. 60.
    Elsworth JD, Redmond DE Jr, Leranth C, Bjugstad KB, Sladek JR Jr, Collier TJ, Foti SB, Samulski RJ, Vives KP, Roth RH. AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons. Exp Neurol. 2008;211:252–8.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Rossler R, Boddeke E, Copray S. Differentiation of non-mesencephalic neural stem cells towards dopaminergic neurons. Neuroscience. 2010;170:417–28.CrossRefPubMedGoogle Scholar
  62. 62.
    Li JY, Christophersen NS, Hall V, Soulet D, Brundin P. Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci. 2008a;31:146–53.CrossRefPubMedGoogle Scholar
  63. 63.
    Ostenfeld T, Joly E, Tai YT, Peters A, Caldwell M, Jauniaux E, Svendsen CN. Regional specification of rodent and human neurospheres. Brain Res Dev Brain Res. 2002;134:43–55.CrossRefPubMedGoogle Scholar
  64. 64.
    Redmond DE Jr, Bjugstad KB, Teng YD, Ourednik V, Ourednik J, Wakeman DR, Parsons XH, Gonzalez R, Blanchard BC, Kim SU, Gu Z, Lipton SA, Markakis EA, Roth RH, Elsworth JD, Sladek JR Jr, Sidman RL, Snyder EY. Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A. 2007;104:12175–80.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB. Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol. 1996;137:376–88.CrossRefPubMedGoogle Scholar
  66. 66.
    Rhee YH, Kim TH, Jo AY, Chang MY, Park CH, Kim SM, Song JJ, SM O, Yi SH, Kim HH, You BH, Nam JW, Lee SH. LIN28A enhances the therapeutic potential of cultured neural stem cells in a Parkinson’s disease model. Brain. 2016;139:2722–39.CrossRefPubMedGoogle Scholar
  67. 67.
    Behrstock S, Svendsen CN. Combining growth factors, stem cells, and gene therapy for the aging brain. Ann N Y Acad Sci. 2004;1019:5–14.CrossRefPubMedGoogle Scholar
  68. 68.
    Bjugstad KB, Teng YD, Redmond DE Jr, Elsworth JD, Roth RH, Cornelius SK, Snyder EY, Sladek JR Jr. Human neural stem cells migrate along the nigrostriatal pathway in a primate model of Parkinson's disease. Exp Neurol. 2008;211:362–9.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Emborg ME, Ebert AD, Moirano J, Peng S, Suzuki M, Capowski E, Joers V, Roitberg BZ, Aebischer P, Svendsen CN. GDNF-secreting human neural progenitor cells increase tyrosine hydroxylase and VMAT2 expression in MPTP-treated cynomolgus monkeys. Cell Transplant. 2008;17:383–95.PubMedGoogle Scholar
  70. 70.
    Gonzalez R, Garitaonandia I, Crain A, Poustovoitov M, Abramihina T, Noskov A, Jiang C, Morey R, Laurent LC, Elsworth JD, Snyder EY, Redmond DE Jr, Semechkin R. Proof of concept studies exploring the safety and functional activity of human parthenogenetic-derived neural stem cells for the treatment of Parkinson’s disease. Cell Transplant. 2015;24:681–90.CrossRefPubMedGoogle Scholar
  71. 71.
    Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480:547–51.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Bjorklund LM, Isacson O. Regulation of dopamine cell type and transmitter function in fetal and stem cell transplantation for Parkinson's disease. Prog Brain Res. 2002;138:411–20.CrossRefPubMedGoogle Scholar
  73. 73.
    Kirkeby A, Nolbrant S, Tiklova K, Heuer A, Kee N, Cardoso T, Ottosson DR, Lelos MJ, Rifes P, Dunnett SB, Grealish S, Perlmann T, Parmar M. Predictive markers guide differentiation to improve graft outcome in clinical translation of hESC-based therapy for Parkinson’s disease. Cell Stem Cell. 2017;20:135–48.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L, Morizane A, Bergquist F, Riebe I, Nannmark U, Carta M, Hanse E, Takahashi J, Sasai Y, Funa K, Brundin P, Eriksson PS, Li JY. 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;24:1433–40.CrossRefPubMedGoogle Scholar
  75. 75.
    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;12:1259–68.CrossRefPubMedGoogle Scholar
  76. 76.
    Steinbeck JA, Choi SJ, Mrejeru A, Ganat Y, Deisseroth K, Sulzer D, Mosharov EV, Studer L. Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson’s disease model. Nat Biotechnol. 2015;33:204–9.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Lindvall O, Kokaia Z. Prospects of stem cell therapy for replacing dopamine neurons in Parkinson’s disease. Trends Pharmacol Sci. 2009;30:260–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Xiao B, Ng HH, Takahashi R, Tan EK. Induced pluripotent stem cells in Parkinson's disease: scientific and clinical challenges. J Neurol Neurosurg Psychiatry. 2016;87:697–702.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Vadori M, Denaro L, D'Avella D, Cozzi E. Indications and prospects of neural transplantation for chronic neurological diseases. Curr Opin Organ Transplant. 2016;21:490–6.CrossRefPubMedGoogle Scholar
  80. 80.
    Isacson O, Kordower JH. The neurobiological and clinical potential of neural cell transplantation: special issue based on the meeting of the American Society for Neural Transplantation, 1995. Cell Transplant. 1996;5:123–5.CrossRefGoogle Scholar
  81. 81.
    Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord. 2008;23:2303–6.CrossRefPubMedGoogle Scholar
  82. 82.
    Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJ, Mufson EJ, Sanberg PR, Hauser RA, Smith DA, Nauert GM, Perl DP, et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med. 1995;332:1118–24.CrossRefPubMedGoogle Scholar
  83. 83.
    Kordower JH, Rosenstein JM, Collier TJ, Burke MA, Chen EY, Li JM, Martel L, Levey AE, Mufson EJ, Freeman TB, Olanow CW. Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies. J Comp Neurol. 1996;370:203–30.CrossRefPubMedGoogle Scholar
  84. 84.
    Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008b;14:501–3.CrossRefPubMedGoogle Scholar
  85. 85.
    Li W, Englund E, Widner H, Mattsson B, van Westen D, Latt J, Rehncrona S, Brundin P, Bjorklund A, Lindvall O, Li JY. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A. 2016;113:6544–9.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Brundin P, Kordower JH. Neuropathology in transplants in Parkinson’s disease: implications for disease pathogenesis and the future of cell therapy. Prog Brain Res. 2012;200:221–41.CrossRefPubMedGoogle Scholar
  87. 87.
    Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O, Brundin P. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov Disord. 2010;25:1091–6.CrossRefPubMedGoogle Scholar
  88. 88.
    Shannon KM, Keshavarzian A, Mutlu E, Dodiya HB, Daian D, Jaglin JA, Kordower JH. Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord. 2012;27:709–15.CrossRefPubMedGoogle Scholar
  89. 89.
    Espay AJ, Brundin P, Lang AE. Precision medicine for disease modification in Parkinson disease. Nat Rev Neurol. 2017;13:119–26.Google Scholar
  90. 90.
    Barker RA, Parmar M, Kirkeby A, Bjorklund A, Thompson L, Brundin P. Are stem cell-based therapies for Parkinson’s disease ready for the clinic in 2016. Journal of Parkins Dis. 2016;6(1):57–63.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Diptaman Chatterjee
    • 1
  • Dustin R. Wakeman
    • 2
  • Jeffrey H. Kordower
    • 1
    Email author
  1. 1.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  2. 2.RxGen, Inc.SomervilleUSA

Personalised recommendations