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Fetal Transplantation for the Treatment of Neurodegenerative Diseases

Current Status and Future Potential

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Summary

Patients with neurodegenerative diseases currently have few treatment options. However, neurotransplantation represents one potential treatment avenue. Animal studies using lesion-induced models of neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease and Alzheimer’s disease have shown that transplantation of appropriate fetal tissue can improve motor and cognitive deficits. Clinical trials of transplantation for Parkinson’s disease and, recently, Huntington’s disease have demonstrated limited success in controlling symptoms, with some patients exhibiting greater improvement than others.

Among the many factors that may influence the clinical success of transplantation, graft volume has recently been shown to correlate with motor improvement. Additional factors such as the age of the transplanted tissue or the disease stage of the host must also be investigated.

Other potential means of improving the symptoms of neurodegenerative diseases include gene transfer or administration of neurotrophic factors, either through direct infusion or by transplantation of biological sources. Currently, however, these treatment strategies are still under development and have not been assessed clinically. Continued refinement of the technique of neurotransplantation, possibly in combination with these alternative approaches, promises steady improvement in the treatment options for patients with neurodegenerative disease.

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References

  1. Lindvall O, Bjorklund A. Transplantation strategies in the treatment of Parkinson’s disease: experimental basis and clinical trials. Acta Neurol Scand Suppl 1989; 126: 197–210

    Article  PubMed  CAS  Google Scholar 

  2. Sinden JD, Patel SN, Hodges H. Neural transplantation: problems and prospects for therapeutic application. Curr Opin Neurol Neurosurg 1992 Dec; 5(6): 902–8

    PubMed  CAS  Google Scholar 

  3. Borlongan CV, Cahill DW, Freeman TB, et al. Recent advances in neural transplantation: relevance to neurodegenerative disorders. J Fla Med Assoc 1994; 81(10): 689–94

    PubMed  CAS  Google Scholar 

  4. Dunnett SB, Bjorklund A. Functional neural transplantation. New York: Raven Press, 1994

    Google Scholar 

  5. Eadie MJ. The neuropathology of Parkinson’s disease. Aust NZ J Med 1971 May; 1Suppl. 1: 7–13

    Article  Google Scholar 

  6. Steg G. Pathological aspects of Parkinson’s syndrome. Acta Neurol Scand Suppl 1972; 51: 139–50

    PubMed  CAS  Google Scholar 

  7. Brundin P, Strecker RE, Clarke DJ, et al. Can human fetal dopamine neuron grafts provide a therapy for Parkinson’s disease? Prog Brain Res 1988; 78: 441–8

    Article  PubMed  CAS  Google Scholar 

  8. Bruyn GW. Huntington’s chorea: historical, clinical and laboratory synopsis. In: Vinken PJ, Bruyn EW, editors. Handbook of clinical neurology. Vol. 6. Diseases of the basal ganglia. Amsterdam: North-Holland Publishing Co., 1968: 298–378

    Google Scholar 

  9. Vonsattel JP, Myers RH, Stevens TJ, et al. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 1985; 44(6): 559–77

    Article  PubMed  CAS  Google Scholar 

  10. Hoffer B, Olson L. Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques. J Neural Transm Suppl 1997; 49: 1–10

    PubMed  CAS  Google Scholar 

  11. Rosenfeld JV. Current issues in neural transplantation. Ann Acad Med Singapore 1993; 22(3): 464–9

    PubMed  CAS  Google Scholar 

  12. Boulton AA, Baker GB, Butterworth RF, editors. Animal models of neurological disease. Totowa(NJ): Humana Press, 1992

    Google Scholar 

  13. Schwarting RK, Huston JP. The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 1996; 50(2-3): 275–331

    Article  PubMed  CAS  Google Scholar 

  14. Sanberg PR, Koutouzis TK, Freeman TB, et al. Behavioral effects of fetal neural transplants: relevance to Huntington’s disease. Brain Res Bull 1993; 32(5): 493–6

    Article  PubMed  CAS  Google Scholar 

  15. Emerich EF, Ragozzino MR, Lehman MN, et al. Behavioral effects of neural transplantation. Cell Transplant 1992; 1(6): 401–27

    PubMed  CAS  Google Scholar 

  16. Annett LE, Martol FL, Rogers DC, et al. Behavioral assessment of the effects of embryonic nigral grafts in marmosets with unilateral 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 1994; 125(2): 228–46

    Article  PubMed  CAS  Google Scholar 

  17. Anett LE. Functional studies of neural grafts in parkinsonian primates. In: Dunnett SB, Bjorklund A, editors. Functional neural transplantation. New York: Raven Press, 1994:71–102

    Google Scholar 

  18. Dunnett S. Cholinergic grafts, memory and aging. Trends Neurosci 1991; 14: 371–6

    Article  PubMed  CAS  Google Scholar 

  19. Zhou FC, Buchwald N. Connectivities of the striatal grafts in adult rat brain: a rich afference and scant striatonigral efference. Brain Res 1989; 505(1): 15–30

    Article  Google Scholar 

  20. Wictorin K, Simerly RB, Isacson O, et al. Connectivity of striatal grafts implanted into the ibotenic acid-lesioned striatum. III. Efferent projecting graft neurons and their relation to host afferents within the grafts. Neuroscience 1989; 29(3): 313–30

    Article  Google Scholar 

  21. Xu ZC, Wilson CJ, Emson PC. Restoration of the corticostriatal projection in rat neostriatal grafts: electron microscopic analysis. Neuroscience 1989; 29(3): 539–50

    Article  PubMed  CAS  Google Scholar 

  22. Xu ZC, Wilson CJ, Emson PC. Restoration of thalamostriatal projections in rat neostriatal grafts: an electron microscopic analysis. J Comp Neurol 1991; 303(1): 22–34

    Article  PubMed  CAS  Google Scholar 

  23. Xu ZC, Wilson CJ, Emson PC. Synaptic potentials evoked in spiny neurons in rat neostriatal grafts by cortical and thalamic stimulation. J Neurophysiol 1991; 65(3): 477–93

    PubMed  CAS  Google Scholar 

  24. Walsh JP, Zhou FC, Hull CD, et al. Physiological and morphological characterization of striatal neurons transplanted into the striatum of adult rats. Synapse 1988; 2(1): 37–44

    Article  PubMed  CAS  Google Scholar 

  25. van Horne C, Mahalik T, Hoffer B, et al. Behavioral and electrophysiological correlates of human mesencephalic dopaminergic xenograft function in the rat striatum. Brain Res Bull 1990; 25: 325–34

    Article  PubMed  Google Scholar 

  26. Rioux L, Gaudin DP, Bui LK, et al. Correlation of functional recovery after a 6-hydroxydopamine lesion with survival of grafted fetal neurons and release of dopamine in the striatum of the rat. Neuroscience 1991; 40: 123–31

    Article  PubMed  CAS  Google Scholar 

  27. Earl CD, Reum T, Xie JX, et al. Foetal nigral cell suspension grafts influence dopamine release in the non-grafted side in the 6-hydroxydopamine rat model of Parkinson’s disease: in. vivo voltammetric data. Exp Brain Res 1996 Apr; 109(1): 179–84

    Article  PubMed  CAS  Google Scholar 

  28. Lindvall O, Rehncrona S, Brundin P, 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

    Article  PubMed  CAS  Google Scholar 

  29. Spencer DD, Robbins RJ, Naftolin F, et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease. N Engl J Med 1992; 327(22): 1541–8

    Article  PubMed  CAS  Google Scholar 

  30. Freed CR, Breeze RE, Rosenberg NL, et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson’s disease. N Engl J Med 1992; 327(22): 1549–55

    Article  PubMed  CAS  Google Scholar 

  31. Lindvall O, Sawle G, Widner H, et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol 1994; 35(2): 172–80

    Article  PubMed  CAS  Google Scholar 

  32. Wenning GK, Odin P, Morrish BM, et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann Neurol 1997; 42: 95–107

    Article  PubMed  CAS  Google Scholar 

  33. Freeman TB, Olanow CW, Hauser RA, et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson’s disease. Ann Neurol 1995; 38(3): 379–88

    Article  PubMed  CAS  Google Scholar 

  34. Kopyov OV, Jacques D, Lieberman A, et al. Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson’s disease. Cell Transplant 1996; 5(2): 327–37

    Article  PubMed  CAS  Google Scholar 

  35. Olanow CW, Kordower JH, Freeman TB. Fetal nigral transplantation as a therapy for Parkinson’s disease. Trends Neurosci 1996; 19: 102–9

    Article  PubMed  CAS  Google Scholar 

  36. Langston JW, Widner H, Goetz CG, et al. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992; 7(1): 2–13

    Article  PubMed  CAS  Google Scholar 

  37. Peschanski M, Cesaro P, Hantraye P. Rationale for intrastriatal grafting of striatal neuroblasts in patients with Huntington’s disease. Neuroscience 1995; 68(2): 273–85

    Article  PubMed  CAS  Google Scholar 

  38. Shannon KM, Kordower JH. Neural transplantation for Huntington’s disease: experimental rationale and recommendations for clinical trials. Cell Transplant 1996; 5(2): 339–52

    Article  PubMed  CAS  Google Scholar 

  39. Kopyov OV, Jacques DS, Lieberman A, et al. Safety of intrastriatal neurotransplantation for Huntington’s disease patients. Exp Neurol. In press

  40. Philpott LM, Kopyov OV, Lec AJ, et al. Neuropsychological functioning following fetal striatal transplantation in Huntington’s chorea: three case presentations. Cell Transplant 1997; 6(3): 203–12

    Article  PubMed  CAS  Google Scholar 

  41. Quinn N, Brown R. Craufurd D, et al. Core Assessment Program for Intracerebral Transplantation in Huntington’s Disease (CAPIT-HD). Mov Disord 1996; 11(2): 143–50

    Article  PubMed  CAS  Google Scholar 

  42. Kopyov OV, Jacques DS, Lieberman A, et al. Outcome following intrastriatal fetal mesencephalic grafts for Parkinson’s patients is directly related to the volume of grafted tissue. Exp Neurol 1997; 146(2): 536–45

    Article  PubMed  CAS  Google Scholar 

  43. Nikkhah G, Odin P, Smits A, et al. Platelet-derived growth factor promotes survival of rat and human mesencephalic dopaminergic neurons in culture. Exp Brain Res 1993; 92(3): 516–23

    Article  PubMed  CAS  Google Scholar 

  44. Nikkhah G, Bentlage C, Cunningham MG, et al. Intranigral fetal dopamine grafts induce behavioral compensation in the rat Parkinson model. J Neurosci 1994; 14(6): 3449–61

    PubMed  CAS  Google Scholar 

  45. Heim RC, Willingham G, Freed WJ. A comparison of solid intraventricular and dissociated intraparenchymal fetal substantia nigra grafts in a rat model of Parkinson’s disease: impaired graft survival is associated with high baseline rotational behavior. Exp Neurol 1993; 122(1): 5–15

    Article  PubMed  CAS  Google Scholar 

  46. Hefti F. Pharmacology of neurotrophic factors. Annu Rev Pharmacol Toxicol 1997; 37: 239–67

    Article  PubMed  CAS  Google Scholar 

  47. Bartus RT, Dean RL, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217(4558): 408–14

    Article  PubMed  CAS  Google Scholar 

  48. Knusel B, Gao H. Neurotrophins and Alzheimer’s disease: beyond the cholinergic neurons. Life Sci 1996; 58(22): 2019–27

    Article  PubMed  CAS  Google Scholar 

  49. Koliatsos VE. Biological therapies for Alzheimer’s disease: focus on trophic factors. Crit Rev Neurobiol 1996; 10(2): 205–38

    Article  PubMed  CAS  Google Scholar 

  50. Weinstock M. The pharmacotherapy of Alzheimer’s disease based on the cholinergic hypothesis: an update. Neurodegeneration 1995; 4(4): 349–56

    Article  PubMed  CAS  Google Scholar 

  51. Lapchak PA, Gash DM, Jiao S, et al. Glial cell line-derived neurotrophic factor: a novel therapeutic approach to treat motor dysfunction in Parkinson’s disease. Exp Neurol 1997; 144(1): 29–34

    Article  PubMed  CAS  Google Scholar 

  52. Clarkson ED, Zawada WM, Freed CR. GDNF improves survival and reduces apoptosis in human embryonic dopaminergic neurons in vitro. Cell Tissue Res 1997; 289(2): 207–10

    Article  PubMed  CAS  Google Scholar 

  53. 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(4): 979–85

    Article  PubMed  CAS  Google Scholar 

  54. Granholm AC, Mott JL, Bowenkamp K, et al. Glial cell line-derived neurotrophic factor improves survival of ventral mesencephalic grafts to the 6-hydroxydopamine lesioned striatum. Exp Brain Res 1997; 116(1): 29–38

    Article  PubMed  CAS  Google Scholar 

  55. Lapchak PA, Gash DM, Collins F, et al. Pharmacological activities of glial cell line-derived neurotrophic factor (GDNF): preclinical development and application to the treatment of Parkinson’s disease. Exp Neurol 1997; 145 (2 Pt 1): 309–21

    Article  PubMed  CAS  Google Scholar 

  56. Zurn AD, Baetge EE, Hammang JP, et al. Glial cell line-derived neurotrophic factor (GDNF), a new neurotrophic factor for motorneurones. Neuroreport 1994 Dec; 6(1): 113–8

    Article  PubMed  CAS  Google Scholar 

  57. Wang Y, Tien LT, Lapchak PA, et al. GDNF triggers fiber out-growth of fetal ventral mesencephalic grafts from nigra to striatum in 6-OHDA-lesioned rats. Cell Tissue Res 1996; 286(2): 225–33

    Article  PubMed  CAS  Google Scholar 

  58. Lapchak PA, Miller PJ, Collins F, et al. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intra-ventricular and intranigral delivery. Neuroscience 1997; 78(1): 61–72

    Article  PubMed  CAS  Google Scholar 

  59. Anderson KD, Panayotatos N, Corcoran TL, et al. Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington’s disease. Proc Natl Acad Sci USA 1996; 93(14): 7346–51

    Article  PubMed  CAS  Google Scholar 

  60. Emerich DF, Cain CK, Greco C, et al. Cellular delivery of human CNTF prevents motor and cognitive dysfunction in a rodent model of Huntington’s disease. Cell Transplant 1997; 6(3): 249–66

    Article  PubMed  CAS  Google Scholar 

  61. Seiger A, Nordberg A, von Holst H, et al. Intracranial infusion of purified nerve growth factor to an Alzheimer patient: the first attempt of a possible future treatment strategy. Behav Brain Res 1993 Nov; 57(2): 255–61

    Article  PubMed  CAS  Google Scholar 

  62. Van Home C, Stromberg I, Young D, et al. Functional enhancement of intrastriatal dopamine-containing grafts by the co-transplantation of sciatic nerve tissue in 6-hydroxydopamine-lesioned rats. Exp Neurol 1991; 113(2): 143–54

    Article  Google Scholar 

  63. Collier TJ, Elsworth JD, Taylor JR, et al. Peripheral nervedopamine neuron co-grafts in MPTP-treated monkeys: augmentation of tyrosine hydroxylase-positive fiber staining and dopamine content in host systems. Neuroscience 1994; 61(4): 875–89

    Article  PubMed  CAS  Google Scholar 

  64. Schinstine M, Fiore DM, Winn SR, et al. Polymer-encapsulated Schwannoma cells expressing human nerve growth factor promote the survival of cholinergic neurons after a fimbria-fornix transection. Cell Transplant 1995 Jan–Feb; 4(1): 93–102

    Article  PubMed  CAS  Google Scholar 

  65. Date I, Miyoshi Y, Ono T, et al. Preliminary report of polymerencapsulated dopamine-secreting cell grafting into the brain. Cell Transplant 1996; 5(5 Suppl. 1): S17–9

    Article  PubMed  CAS  Google Scholar 

  66. Emerich DF, Winn SR, Hantraye PM, et al. Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 1997; 386(6623): 395–9

    Article  PubMed  CAS  Google Scholar 

  67. Raymon HK, Thode S, Gage FH. Application of ex vivo gene therapy in the treatment of Parkinson’s disease. Exp Neurol 1997; 144(1): 82–91

    Article  PubMed  CAS  Google Scholar 

  68. Blesch A, Tuszynski M. Ex vivo gene therapy for Alzheimer’s disease and spinal cord injury. Clin Neurosci 1995; 3(5): 268–74

    PubMed  Google Scholar 

  69. Yamada K, Nitta A, Hasegawa T, et al. Orally active NGF synthesis stimulators: potential therapeutic agents in Alzheimer’s disease. Behav Brain Res 1997; 83(1-2): 117–22

    Article  PubMed  CAS  Google Scholar 

  70. Albeck DS, Hoffer BJ, Quissell D, et al. A non-invasive transport system for GDNF across the blood-brain barrier. Neuroreport 1997; 8(9-10): 2293–8

    Article  PubMed  CAS  Google Scholar 

  71. Horellou P, Sabate O, Buc-Caron MH, et al. Adenovirus-mediated gene transfer to the central nervous system for Parkinson’s disease. Exp Neurol 1997; 144(1): 131–8

    Article  PubMed  CAS  Google Scholar 

  72. Freeman TB. From transplants to gene therapy for Parkinson’s disease. Exp Neurol 1997; 144(1): 47–50

    Article  PubMed  CAS  Google Scholar 

  73. Shvaloff A, Neuman E, Guez D. Lines of therapeutics research in Alzheimer’s disease. Psychopharmacol Bull 1996; 32(3): 343–52

    PubMed  CAS  Google Scholar 

  74. Sanders LM, Giudice L, Raffin TA. Ethics of fetal tissue transplantation. West J Med 1993; 159(3): 400–7

    PubMed  CAS  Google Scholar 

  75. Fine A. Human fetal tissue research: practice, prospects, and policy. Cell Transplant 1994; 3(2): 113–45

    PubMed  CAS  Google Scholar 

  76. MacDonald AS. Foetal neuroendocrine tissue transplantation for Parkinson’s disease: an institutional review board faces the ethical dilemma. Transplant Proc 1990; 22(3): 1030–2

    PubMed  CAS  Google Scholar 

  77. Boer GJ. Ethical guidelines for the use of human embryonic or fetal tissue for experimental and clinical neurotransplantation and research. Network of European CNS Transplantation and Restoration (NECTAR). J Neurol 1994; 242(1): 1–13

    Article  PubMed  CAS  Google Scholar 

  78. Kirschstein RL. Withdrawal of interim NIH guidelines for the support and conduct of therapeutic human fetal tissue transplantation research in light of superseding provisions of Public Law 103–43. Fed Regist 1993; 58(166): 45495–6

    Google Scholar 

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Kopyov, O.V., Jacques, S. & Eagle, K.S. Fetal Transplantation for the Treatment of Neurodegenerative Diseases. Mol Diag Ther 9, 77–83 (1998). https://doi.org/10.2165/00023210-199809020-00001

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