Advertisement

Exploitation of Genetically Modified Neural Stem Cells for Neurological Disease

  • Allen L. Ho
  • Sassan Keshavarzi
  • Michael L. Levy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 671)

Abstract

The successful treatment and potential treatment of the central nervous system (CNS) pathology remains the most challenging frontier in medical science. The clinical modalities presently available are mostly of limited efficacy and with the aging population, neurodegerative diseases and CNS neoplasms are increasingly prevalent.

Neural stem cells (NSCs) have provided optimism for the horizon of therapeutic progress in treating neurological diseases. These mutipotent (able to differentiate into neurons, astrocytes and oligodendrocytes) cells can be obtained directly from the CNS or derived from of embryonic stem cells (ESCs). NSCs can be genetically manipulated in vitro to express desired transgenes for improved expandability, as well as for delivery of toxic payloads. NSCs also demonstrate the ability to engraft within the CNS, migrate to CNS pathology and in certain scenarios to reconstitute the injured or diseased nervous system.

Keywords

Spinal Cord Injury Amyotrophic Lateral Sclerosis Neural Stem Cell Middle Cerebral Artery Occlusion Neural Progenitor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Snyder E, Deitcher D, Walsh C et al. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 1992; 68(1):33–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Renfranz P, Cunningham M, McKay R. Region-specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell 1991; 66(4):713–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Flax J, Aurora S, Yang C et al. Engraftable human neural stem cells respond to developmental cues, replace neurons and express foreign genes. Nat Biotechnol 1998; 16(11):1033–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Rubio F, Bueno C, Villa A et al. Genetically perpetuated human neural stem cells engraft and differentiate into the adult mammalian brain. Mol Cell Neurosci 2000; 16(1):1–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Martinez-Serrano A, Rubio F, Navarro B et al. Human neural stem and progenitor cells: in vitro and in vivo properties and potential for gene therapy and cell replacement in the CNS. Curr Gene Ther 2001; 1(3):279–99.CrossRefPubMedGoogle Scholar
  6. 6.
    Ourednik V, Ourednik J, Flax J et al. Segregation of human neural stem cells in the developing primate forebrain. Science 2001; 293(5536):1820–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Aboody K, Brown A, Rainov N et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 2000; 97(23):12846–51.CrossRefPubMedGoogle Scholar
  8. 8.
    Fallon J, Reid S, Kinyamu R et al. In vivo induction of massive proliferation, directed migration and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci USA 2000; 97(26):14686–91.CrossRefPubMedGoogle Scholar
  9. 9.
    Park K, Teng Y, Snyder E. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol 2002; 20(11):1111–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Imitola J, Raddassi K, Park K et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci USA 2004; 101(52):18117–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Glass R, Synowitz M, Kronenberg G et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 2005; 25(10):2637–46.CrossRefPubMedGoogle Scholar
  12. 12.
    Ehtesham M, Kabos P, Kabosova A et al. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 2002; 62(20):5657–63.PubMedGoogle Scholar
  13. 13.
    Ziu M, Schmidt N, Cargioli T et al. Glioma-produced extracellular matrix influences brain tumor tropism of human neural stem cells. J Neurooncol 2006; 79(2):125–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Yip S, Aboody K, Burns M et al. Neural stem cell biology may be well suited for improving brain tumor therapies. Cancer J 2003; 9(3):189–204.CrossRefPubMedGoogle Scholar
  15. 15.
    Lundberg C, Horellou P, Mallet J et al. Generation of DOPA-producing astrocytes by retroviral transduction of the human tyrosine hydroxylase gene: in vitro characterization and in vivo effects in the rat Parkinson model. Exp Neurol 1996; 139(1):39–53.CrossRefPubMedGoogle Scholar
  16. 16.
    Anton R, Kordower J, Maidment N et al. Neural-targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol 1994; 127(2):207–18.CrossRefPubMedGoogle Scholar
  17. 17.
    Ryu M, Lee M, Ahn Y et al. Brain transplantation of neural stem cells cotransduced with tyrosine hydroxylase and GTP cyclohydrolase 1 in Parkinsonian rats. Cell Transplant 2005; 14(4):193–202.CrossRefPubMedGoogle Scholar
  18. 18.
    Akerud P, Canals J, Snyder E et al. 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(20):8108–18.PubMedGoogle Scholar
  19. 19.
    Akerud P, Holm P, Castelo-Branco G et al. Persephin-overexpressing neural stem cells regulate the function of nigral dopaminergic neurons and prevent their degeneration in a model of Parkinson’s disease. Mol Cell Neurosci 2002; 21(2):205–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Kim J, Auerbach J, Rodríguez-Gómez J et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 2002; 418(6893):50–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Martínez-Serrano A, Björklund A. Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J Neurosci 1996; 16(15):4604–16.PubMedGoogle Scholar
  22. 22.
    McBride J, Behrstock S, Chen E et al. Human neural stem cell transplants improve motor function in a rat model of Huntington’s disease. J Comp Neurol 2004; 475(2):211–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee S, Park J, Lee K et al. Noninvasive method of immortalized neural stem-like cell transplantation in an experimental model of Huntington’s disease. J Neurosci Methods 2006; 152(1–2):250–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Azzouz M, Ralph G, Storkebaum E et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004; 429(69):413–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Kaspar B, Lladó J, Sherkat N et al. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 2003; 301(5634):839–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Tuszynski M, Thal L, Pay M et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005; 11(5):551–5.CrossRefGoogle Scholar
  27. 27.
    Martínez-Serrano A, Björklund A. Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle-aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging. Proc Natl Acad Sci USA 1998; 95(4):1858–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Yamasaki T, Blurton-Jones M, Morrissette D et al. Neural stem cells improve memory in an inducible mouse model of neuronal loss. J Neurosci 2007; 27(44):11925–33.CrossRefGoogle Scholar
  29. 29.
    Benedetti S, Pirola B, Pollo B et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000; 6(4):447–50.CrossRefPubMedGoogle Scholar
  30. 30.
    Li S, Tokuyama T, Yamamoto J et al. Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther 2005; 12(7):600–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim S, Cargioli T, Machluf M et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin Cancer Res 2005; 11(16):5965–70.CrossRefGoogle Scholar
  32. 32.
    Schwab M. Repairing the injured spinal cord. Science 2002; 295(5557):1029–31.CrossRefPubMedGoogle Scholar
  33. 33.
    Ogawa Y, Sawamoto K, Miyata T et al. Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 2002; 69(6):925–33.CrossRefPubMedGoogle Scholar
  34. 34.
    Teng Y, Lavik E, Qu X et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci USA 2002; 99(5):3024–9.CrossRefGoogle Scholar
  35. 35.
    Lu P, Jones L, Snyder E et al. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 2003; 181(2):115–29.CrossRefPubMedGoogle Scholar
  36. 36.
    Hofstetter C, Holmström N, Lilja J et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 2005; 8(3):346–53.CrossRefPubMedGoogle Scholar
  37. 37.
    Blesch A, Lu P, Tuszynski M. Neurotrophic factors, gene therapy and neural stem cells for spinal cord repair. Brain Res Bull 2002; 57(6):833–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Cummings B, Uchida N, Tamaki S et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci USA 2005; 102(39):14069–74.CrossRefPubMedGoogle Scholar
  39. 39.
    Iwanami A, Kaneko S, Nakamura M et al. Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res 2005; 80(2):182–90.CrossRefPubMedGoogle Scholar
  40. 40.
    Andsberg G, Kokaia Z, Björklund A et al. Amelioration of ischaemia-induced neuronal death in the rat striatum by NGF-secreting neural stem cells. Eur J Neurosci 1998; 10(6):2026–36.CrossRefGoogle Scholar
  41. 41.
    Arvidsson A, Collin T, Kirik D et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002; 8(9):963–70.CrossRefPubMedGoogle Scholar
  42. 42.
    Nakatomi H, Kuriu T, Okabe S et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002; 110(4):429–41.CrossRefPubMedGoogle Scholar
  43. 43.
    Zhang Z, Jiang Q, Zhang R et al. Magnetic resonance imaging and neurosphere therapy of stroke in rat. Ann Neurol 2003; 53(2):259–63.CrossRefPubMedGoogle Scholar
  44. 44.
    Kelly S, Bliss T, Shah A et al. Transplanted human fetal neural stem cells survive, migrate and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci USA 2004; 101(32):11839–44.CrossRefPubMedGoogle Scholar
  45. 45.
    Snyder E, Taylor R, Wolfe J. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995; 374(6520):367–70.CrossRefPubMedGoogle Scholar
  46. 46.
    Lacorazza H, Flax J, Snyder E et al. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med 1996; 2(4):424–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Shihabuddin L, Numan S, Huff M et al. Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to a marked decrease in lysosomal storage pathology. J Neurosci 2004; 24(47):10642–51.CrossRefPubMedGoogle Scholar
  48. 48.
    Lee J, Jeyakumar M, Gonzalez R et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med 2007; 13(4):439–47.CrossRefPubMedGoogle Scholar
  49. 49.
    Cameron H, McKay R. Restoring production of hippocampal neurons in old age. Nat Neurosci 1999; 2(10):894–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Kempermann G, Gast D, Gage F. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 2002; 52(2):135–43.CrossRefPubMedGoogle Scholar
  51. 51.
    Hallbergson A, Gnatenco C, Peterson D. Neurogenesis and brain injury: managing a renewable resource for repair. J Clin Invest 2003; 112(8):1128–33.PubMedGoogle Scholar
  52. 52.
    Tang Y, Shah K, Messerli S et al. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum Gene Ther 2003; 14(13):1247–54.CrossRefPubMedGoogle Scholar
  53. 53.
    Shah K, Bureau E, Kim D et al. Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression. Ann Neurol 2005; 57(1):34–41.CrossRefPubMedGoogle Scholar
  54. 54.
    Kim D, Schellingerhout D, Ishii K et al. Imaging of stem cell recruitment to ischemic infarcts in a murine model. Stroke 2004; 35(4):952–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Magnitsky S, Watson D, Walton R et al. In vivo and ex vivo MRI detection of localized and disseminated neural stem cell grafts in the mouse brain. Neuroimage 2005; 26(3):744–54.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang Z, Jiang Q, Jiang F et al. In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage 2004; 23(1):281–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Arbab A, Bashaw L, Miller B et al. Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 2003; 229(3):838–46.CrossRefPubMedGoogle Scholar
  58. 58.
    Kostura L, Kraitchman D, Mackay A et al. Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed 2004; 17(7):513–7.CrossRefPubMedGoogle Scholar
  59. 59.
    de Vries I, Lesterhuis W, Barentsz J et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 2005; 23(11):1407–13.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Allen L. Ho
    • 1
  • Sassan Keshavarzi
    • 2
  • Michael L. Levy
    • 3
  1. 1.Harvard Medical SchoolBostonUSA
  2. 2.Division of NeurosurgeryUCSD Medical CenterSan DiegoUSA
  3. 3.Pediatric NeurosurgeryRady Children’s HospitalSan DiegoUSA

Personalised recommendations