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Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.

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References

  1. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F . GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993; 260: 1130–1132.

    CAS  Article  Google Scholar 

  2. 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: 252–255.

    CAS  Article  Google Scholar 

  3. Bjorklund A, Rosenblad C, Winkler C, Kirik D . Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease. Neurobiol Dis 1997; 4: 186–200.

    CAS  Article  Google Scholar 

  4. Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws Jr ER et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003; 60: 69–73.

    CAS  Article  Google Scholar 

  5. Kordower JH, Palfi S, Chen EY, Ma SY, Sendera T, Cochran EJ et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. Ann Neurol 1999; 46: 419–424.

    CAS  Article  Google Scholar 

  6. Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003; 9: 589–595.

    CAS  Article  Google Scholar 

  7. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS . Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005; 57: 298–302.

    CAS  Article  Google Scholar 

  8. Love S, Plaha P, Patel NK, Hotton GR, Brooks DJ, Gill SS . Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Nat Med 2005; 11: 703–704.

    CAS  Article  Google Scholar 

  9. Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B . Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg 2005; 102: 216–222.

    CAS  Article  Google Scholar 

  10. Choi-Lundberg DL, Lin Q, Chang YN, Chiang YL, Hay CM, Mohajeri H et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 1997; 275: 838–841.

    CAS  Article  Google Scholar 

  11. Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000; 290: 767–773.

    CAS  Article  Google Scholar 

  12. Bjorklund A, Kirik D, Rosenblad C, Georgievska B, Lundberg C, Mandel RJ . Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res 2000; 886: 82–98.

    CAS  Article  Google Scholar 

  13. Hsich G, Sena-Esteves M, Breakefield XO . Critical issues in gene therapy for neurologic disease. Hum Gene Ther 2002; 13: 579–604.

    CAS  Article  Google Scholar 

  14. Gage FH . Cell Therapy. Nature 1998; 392 (Suppl): 18–24.

    CAS  Google Scholar 

  15. Blesch A, Tuszynski MH . Gene therapy and cell transplantation for Alzheimer's disease and spinal cord injury. Yonsei Med J 2004; 45 (Suppl): 28–31.

    Article  Google Scholar 

  16. Tuszynski MH, Thal L, Pay M, Salmon DP, HS U, Bakay R et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005; 11: 551–555.

    CAS  Article  Google Scholar 

  17. Lindvall O . Neural transplants in Parkinson's disease. Dunnett SB, Björklund A (eds). Functional Neural Transplantation. Raven Press: New York, 1994, pp 103–137.

    Google Scholar 

  18. Svendsen CN, ter Borg MG, Armstrong RJ, Rosser AE, Chandran S, Ostenfeld T et al. A new method for the rapid and long term growth of human neural precursor cells. J Neurosci Methods 1998; 85: 141–152.

    CAS  Article  Google Scholar 

  19. Wright LS, Li J, Caldwell MA, Wallace K, Johnson JA, Svendsen CN . Gene expression in human neural stem cells: effects of leukemia inhibitory factor. J Neurochem 2003; 86: 179–195.

    CAS  Article  Google Scholar 

  20. Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P et al. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol 1997; 148: 135–146.

    CAS  Article  Google Scholar 

  21. McBride JL, Behrstock SP, Chen EY, Jakel RJ, Siegel I, Svendsen CN et al. Human neural stem cell transplants improve motor function in a rat model of Huntington's disease. J Comp Neurol 2004; 475: 211–219.

    Article  Google Scholar 

  22. Vescovi AL, Parati EA, Gritti A, Poulin P, Ferrario M, Wanke E et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp Neurol 1999; 156: 71–83.

    CAS  Article  Google Scholar 

  23. Fricker RA, Carpenter MK, Winkler C, Greco C, Gates MA, Bjorklund A . Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain. J Neurosci 1999; 19: 5990–6005.

    CAS  Article  Google Scholar 

  24. Flax JD, Aurora S, Yang C, Simonin C, Wills AM, Billinghurst LL et al. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol 1998; 16: 1033–1039.

    CAS  Article  Google Scholar 

  25. Englund U, Fricker-Gates RA, Lundberg C, Bjorklund A, Wictorin K . Transplantation of human neural progenitor cells into the neonatal rat brain: extensive migration and differentiation with long-distance axonal projections. Exp Neurol 2002; 173: 1–21.

    CAS  Article  Google Scholar 

  26. Burnstein RM, Foltynie T, He X, Menon DK, Svendsen CN, Caldwell MA . Differentiation and migration of long term expanded human neural progenitors in a partial lesion model of Parkinson's disease. Int J Biochem Cell Biol 2004; 36: 702–713.

    CAS  Article  Google Scholar 

  27. Ostenfeld T, Tai YT, Martin P, Deglon N, Aebischer P, Svendsen CN . Neurospheres modified to produce glial cell line-derived neurotrophic factor increase the survival of transplanted dopamine neurons. J Neurosci Res 2002; 69: 955–965.

    CAS  Article  Google Scholar 

  28. Akerud P, Canals JM, Snyder EY, Arenas E . Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J Neurosci 2001; 21: 8108–8118.

    CAS  Article  Google Scholar 

  29. Ourednik J, Ourednik V, Lynch WP, Schachner M, Snyder EY . Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol 2002; 20: 1103–1110.

    CAS  Article  Google Scholar 

  30. Mohajeri MH, Figlewicz DA, Bohn MC . Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis. Hum Gene Ther 1999; 10: 1853–1866.

    CAS  Article  Google Scholar 

  31. Keller-Peck CR, Feng G, Sanes JR, Yan Q, Lichtman JW, Snider WD . Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction. J Neurosci 2001; 21: 6136–6146.

    CAS  Article  Google Scholar 

  32. Behrstock S, Svendsen CN . Combining growth factors, stem cells, and gene therapy for the aging brain. Ann NY Acad Sci 2004; 1019: 5–14.

    CAS  Article  Google Scholar 

  33. Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 2005; 16: 509–521.

    CAS  Article  Google Scholar 

  34. Deglon N, Tseng JL, Bensadoun JC, Zurn AD, Arsenijevic Y, Pereira dA et al. Self-inactivating lentiviral vectors with enhanced transgene expression as potential gene transfer system in Parkinson's disease. Hum Gene Ther 2000; 11: 179–190.

    CAS  Article  Google Scholar 

  35. Ostenfeld T, Horn P, Aardal C, Orpen I, Caldwell MA, Svendsen CN . Mouse epidermal growth factor-responsive neural precursor cells increase the survival and functional capacity of embryonic rat dopamine neurons in vitro. NeuroReport 1999; 10: 1985–1992.

    CAS  Article  Google Scholar 

  36. Kirik D, Rosenblad C, Bjorklund A . Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 1998; 152: 259–277.

    CAS  Article  Google Scholar 

  37. Ai Y, Markesbery W, Zhang Z, Grondin R, Elseberry D, Gerhardt GA et al. Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects. J Comp Neurol 2003; 461: 250–261.

    CAS  Article  Google Scholar 

  38. Matsuura K, Makino H, Ogawa N . Cyclosporin a attenuates the decrease in tyrosine hydroxylase immunoreactivity in nigrostriatal dopaminergic neurons and in striatal dopamine content in rats with intrastriatal injection of 6-hydroxydopamine. Exp Neurol 1997; 146: 526–535.

    CAS  Article  Google Scholar 

  39. Georgievska B, Kirik D, Bjorklund A . Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer. Exp Neurol 2002; 177: 461–474.

    CAS  Article  Google Scholar 

  40. Levi-Montalcini R, Angeletti PU . Essentiality of nerve growth factor in the survival and maintenance of dissociated sensory and sympathetic embryonic nerve cells in vitro. Dev Biol 1963; 7: 653–659.

    Article  Google Scholar 

  41. Airaksinen MS, Saarma M . The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002; 3: 383–394.

    CAS  Article  Google Scholar 

  42. Corti O, Sabate O, Horellou P, Colin P, Dumas S, Buchet D et al. A single adenovirus vector mediates doxycycline-controlled expression of tyrosine hydroxylase in brain grafts of human neural progenitors. Nat Biotechnol 1999; 17: 349–354.

    CAS  Article  Google Scholar 

  43. Georgievska B, Jakobsson J, Persson E, Ericson C, Kirik D, Lundberg C . Regulated delivery of glial cell line-derived neurotrophic factor into rat striatum, using a tetracycline-dependent lentiviral vector. Hum Gene Ther 2004; 15: 934–944.

    CAS  Article  Google Scholar 

  44. Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 2002; 99: 2344–2349.

    CAS  Article  Google Scholar 

  45. Mitalipova MM, Rao RR, Hoyer DM, Johnson JA, Meisner LF, Jones KL et al. Preserving the genetic integrity of human embryonic stem cells. Nat Biotechnol 2005; 23: 19–20.

    CAS  Article  Google Scholar 

  46. Ostenfeld T, Caldwell MA, Prowse KR, Linskens MH, Jauniaux E, Svendsen CN et al. Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Exp Neurol 2000; 164: 215–226.

    CAS  Article  Google Scholar 

  47. Martin MJ, Muotri A, Gage F, Varki A . Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nat Med 2005; 11: 228–232.

    CAS  Article  Google Scholar 

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Acknowledgements

We gratefully acknowledge Kristin Hoffman for technical assistance and Nicole Deglon for development of the lentiviral constructs. This work was supported by the Department of Defense (DAMD17-03-1-0122, CNS), The Michael J Fox Foundation (CNS) and the Kinetics Foundation (CNS).

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Correspondence to C N Svendsen.

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Behrstock, S., Ebert, A., McHugh, J. et al. Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates. Gene Ther 13, 379–388 (2006). https://doi.org/10.1038/sj.gt.3302679

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  • DOI: https://doi.org/10.1038/sj.gt.3302679

Keywords

  • GDNF
  • stem cell
  • cell therapy
  • neurodegeneration

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