Gene therapy approaches for Neuroprotection and axonal regeneration after spinal cord and spinal root injury

Current Gene Therapy

Volumn 11, Issue 2, 2011, Pages 101-115

  Bo, Xuenong ^a   Wu, Dongsheng ^a   Yeh, John ^a   Zhang, Yi ^a  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

Axonal regeneration; Cell therapy; Gene therapy; Neurotrophic factor; Spinal cord injury; Viral vector

Indexed keywords

ARTEMIN; BETA GALACTOSIDASE; BRAIN DERIVED NEUROTROPHIC FACTOR; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; FIBROBLAST GROWTH FACTOR 2; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; GROWTH FACTOR; INTEGRIN; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MYELIN ASSOCIATED GLYCOPROTEIN; MYELIN PROTEIN; NERVE CELL ADHESION MOLECULE; NERVE GROWTH FACTOR; NEURONAL CALCIUM SENSOR; NEUROTROPHIN; NEUROTROPHIN 3; NOGO RECEPTOR; OLIGODENDROCYTE MYELIN GLYCOPROTEIN; POLYSIALIC ACID; POLYSIALYLTRANSFERASE; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN VP16; RETINOIC ACID RECEPTOR BETA; RETINOIC ACID RECEPTOR BETA2; RHO KINASE; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; SIALYLTRANSFERASE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN;

ATROPHY; BONE MARROW TRANSPLANTATION; CELL DEATH; CELL TRANSPLANTATION; CENTRAL NERVOUS SYSTEM; EX VIVO STUDY; FIBROBLAST; IN VIVO STUDY; MOLECULE; NERVE FIBER GROWTH; NERVE FIBER REGENERATION; NERVE INJURY; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; NEURAL STEM CELL TRANSPLANTATION; NEUROPROTECTION; NONHUMAN; OPTIC NERVE INJURY; REVIEW; RNA INTERFERENCE; SCHWANN CELL; SPINAL CORD INJURY; SPINAL ROOT INJURY; STEM CELL; STROMA CELL; VIRAL GENE DELIVERY SYSTEM; ANIMAL; CONVALESCENCE; GENE THERAPY; GENE TRANSFER; GENE VECTOR; GENETICS; HUMAN; METABOLISM; NERVE CELL; NERVE FIBER; NERVE REGENERATION; PROCEDURES; SPINAL CORD INJURIES; SPINAL ROOT;

ANIMALS; AXONS; GENE THERAPY; GENE TRANSFER TECHNIQUES; GENETIC VECTORS; HUMANS; NERVE GROWTH FACTORS; NERVE REGENERATION; NEURONS; RECOVERY OF FUNCTION; SPINAL CORD INJURIES; SPINAL NERVE ROOTS; GENETIC THERAPY;

ANIMALIA;

EID: 79953008858     PISSN: 15665232     EISSN: None     Source Type: Journal    
DOI: 10.2174/156652311794940773     Document Type: Review

References (149)

1. Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR. Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J 2004; 4: 451-464.
2. Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 2008; 25: E2.
3. Abe N, Cavalli V. Nerve injury signaling. Curr Opin Neurobiol 2008; 18: 276-283.
4. Richardson PM, Miao T, Wu D, Zhang Y, Yeh J, Bo X. Responses of the nerve cell body to axotomy. Neurosurgery 2009; 65: A74-9.
5. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006; 7: 617-627.
6. Sun F, He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr Opin Neurobiol 2010; 20: 510-518.
7. Schnell L, Schneider R, Kolbeck R, Barde YA, Schwab ME. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 1994; 367: 170-173.
8. Liebscher T, Schnell L, Schnell D, et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann Neurol 2005; 58: 706-719.
9. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 2002; 417: 547-551.
10. Li S, Liu BP, Budel S, et al. Blockade of Nogo-66, myelinassociated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J Neurosci 2004; 24: 10511-10520.
11. Bradbury EJ, Moon LD, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002; 416: 636-640.
12. Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev 2009; 109: 259-302.
13. Bergen JM, Park IK, Horner PJ, Pun SH. Nonviral approaches for neuronal delivery of nucleic acids. Pharm Res 2008; 25: 983-998.
14. Wells DJ. Electroporation and ultrasound enhanced non-viral gene delivery in vitro and in vivo. Cell Biol Toxicol 2010; 26: 21-28.
15. Lim ST, Airavaara M, Harvey BK. Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol Res 2010; 61: 14-26.
16. Bouard D, Alazard-Dany D, Cosset FL. Viral vectors: from virology to transgene expression. Br J Pharmacol 2009; 157: 153-165.
17. Papale A, Cerovic M, Brambilla R. Viral vector approaches to modify gene expression in the brain. J Neurosci Methods 2009; 185: 1-14.
18. Mandel RJ, Manfredsson FP, Foust KD, et al. Recombinant adenoassociated viral vectors as therapeutic agents to treat neurological disorders. Mol Ther 2006; 13: 463-483.
19. Wong LF, Goodhead L, Prat C, Mitrophanous KA, Kingsman SM, Mazarakis ND. Lentivirus-mediated gene transfer to the central nervous system: therapeutic and research applications. Hum Gene Ther 2006; 17: 1-9.
20. Lu P, Tuszynski MH. Growth factors and combinatorial therapies for CNS regeneration. Exp Neurol 2008; 209: 313-320.
21. Logan A, Ahmed Z, Baird A, Gonzalez AM, Berry M. Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain 2006; 129: 490-502.
22. Eftekharpour E, Karimi-Abdolrezaee S, Fehlings MG. Current status of experimental cell replacement approaches to spinal cord injury. Neurosurg Focus 2008; 24: E19.
23. Blits B, Bunge MB. Direct gene therapy for repair of the spinal cord. J Neurotrauma 2006; 23: 508-520.
24. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677-736.
25. Zhang Y, Dijkhuizen PA, Anderson PN, Lieberman AR, Verhaagen J. NT-3 delivered by an adenoviral vector induces injured dorsal root axons to regenerate into the spinal cord of adult rats. J Neurosci Res 1998; 54: 554-562.
26. Fortun J, Puzis R, Pearse DD, Gage FH, Bunge MB. Muscle injection of AAV-NT3 promotes anatomical reorganization of CST axons and improves behavioral outcome following SCI. J Neurotrauma 2009; 26: 941-53.
27. Raineteau O, Schwab ME. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci 2001; 2: 263-273.
28. Zhou L, Baumgartner BJ, Hill-Felberg SJ, McGowen LR, Shine HD. Neurotrophin-3 expressed in situ induces axonal plasticity in the adult injured spinal cord. J Neurosci 2003; 23: 1424-1431.
29. Chen Q, Zhou L, Shine HD. Expression of neurotrophin-3 promotes axonal plasticity in the acute but not chronic injured spinal cord. J Neurotrauma 2006; 23: 1254-1260.
30. Zhou L, Shine HD. Neurotrophic factors expressed in both cortex and spinal cord induce axonal plasticity after spinal cord injury. J Neurosci Res 2003; 74: 221-6.
31. Ruitenberg MJ, Blits B, Dijkhuizen PA, et al. Adeno-associated viral vector-mediated gene transfer of brain-derived neurotrophic factor reverses atrophy of rubrospinal neurons following both acute and chronic spinal cord injury. Neurobiol Dis 2004; 15: 394-406.
32. Kwon BK, Liu J, Lam C, et al. Brain-derived neurotrophic factor gene transfer with adeno-associated viral and lentiviral vectors prevents rubrospinal neuronal atrophy and stimulates regenerationassociated gene expression after acute cervical spinal cord injury. Spine (Phila Pa 1976) 2007; 32: 1164-1173.
33. Nakajima H, Uchida K, Kobayashi S, et al. Rescue of rat anterior horn neurons after spinal cord injury by retrograde transfection of adenovirus vector carrying brain-derived neurotrophic factor gene. J Neurotrauma 2007; 24: 703-712.
34. Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24:1 217-81.
35. Grothe C, Wewetzer K. Fibroblast growth factor and its implications for developing and regenerating neurons. Int J Dev Biol 1996; 40: 403-410.
36. Reuss B, von Bohlen and Halbach O. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 2003; 313: 139-157.
37. Romero MI, Rangappa N, Garry MG, Smith GM. Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. J Neurosci 2001; 21: 8408-8416.
38. Tang XQ, Cai J, Nelson KD, Peng XJ, Smith GM. Functional repair after dorsal root rhizotomy using nerve conduits and neurotrophic molecules. Eur J Neurosci 2004; 20: 1211-1218.
39. Baumgartner BJ, Shine HD. Neuroprotection of spinal motoneurons following targeted transduction with an adenoviral vector carrying the gene for glial cell line-derived neurotrophic factor. Exp Neurol 1998; 153: 102-12.
40. Watabe K, Ohashi T, Sakamoto T, et al. Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotrophic factor. J Neurosci Res 2000; 60: 511-519.
41. Natsume A, Mata M, Wolfe D, et al. Bcl-2 and GDNF delivered by HSV-mediated gene transfer after spinal root avulsion provide a synergistic effect. J Neurotrauma 2002; 19: 61-68.
42. Natsume A, Wolfe D, Hu J, et al. Enhanced functional recovery after proximal nerve root injury by vector-mediated gene transfer. Exp Neurol 2003; 184: 878-86.
43. Blits B, Carlstedt TP, Ruitenberg MJ, et al. Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brainderived neurotrophic factor. Exp Neurol 2004; 189: 303-316.
44. Eggers R, Hendriks WT, Tannemaat MR, et al. Neuroregenerative effects of lentiviral vector-mediated GDNF expression in reimplanted ventral roots. Mol Cell Neurosci 2008; 39: 105-117.
45. Koelsch A, Feng Y, Fink DJ, Mata M. Transgene-mediated GDNF expression enhances synaptic connectivity and GABA transmission to improve functional outcome after spinal cord contusion. J Neurochem 2010; 113: 143-152.
46. Airaksinen MS, Holm L, Hatinen T. Evolution of the GDNF family ligands and receptors. Brain Behav Evol 2006; 68: 181-190.
47. Zhou Z, Peng X, Fink DJ, Mata M. HSV-mediated transfer of artemin overcomes myelin inhibition to improve outcome after spinal cord injury. Mol Ther 2009; 17: 1173-1179.
48. Facchiano F, Fernandez E, Mancarella S, et al. Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor. J Neurosurg 2002; 97: 161-168.
49. Gonzenbach RR, Schwab ME. Disinhibition of neurite growth to repair the injured adult CNS: focusing on Nogo. Cell Mol Life Sci 2008; 65: 161-176.
50. Fournier AE, Gould GC, Liu BP, Strittmatter SM. Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin. J Neurosci 2002; 22: 8876-8883.
51. Fischer D, He Z, Benowitz LI. Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J Neurosci 2004; 24: 1646-1651.
52. Peng X, Zhou Z, Hu J, Fink DJ, Mata M. Soluble Nogo receptor down-regulates expression of neuronal Nogo-A to enhance axonal regeneration. J Biol Chem 2010; 285: 2783-2795.
53. Xie F, Zheng B. White matter inhibitors in CNS axon regeneration failure. Exp Neurol 2008; 209: 302-312.
54. McKerracher L, Higuchi H. Targeting Rho to stimulate repair after spinal cord injury. J Neurotrauma 2006; 23: 309-317.
55. Kubo T, Hata K, Yamaguchi A, Yamashita T. Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration. Curr Pharm Des 2007; 13: 2493-2499.
56. Fournier AE, Takizawa BT, Strittmatter SM. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci 2003; 23: 1416-1423.
57. Wu D, Yang P, Zhang X, et al. Targeting a dominant negative rho kinase to neurons promotes axonal outgrowth and partial functional recovery after rat rubrospinal tract lesion. Mol Ther 2009; 17: 2020-2030.
58. Zhang Y, Yeh J, Richardson PM, Bo X. Cell adhesion molecules of the immunoglobulin superfamily in axonal regeneration and neural repair. Restor Neurol Neurosci 2008; 26: 81-96.
59. Chen J, Wu J, Apostolova I, et al. Adeno-associated virus-mediated L1 expression promotes functional recovery after spinal cord injury. Brain 2007; 130: 954-969.
60. Zhang Y, Bo X, Schoepfer R, et al. Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo. Proc Natl Acad Sci USA 2005; 102: 14883-14888.
61. Pearse DD, Sanchez AR, Pereira FC, et al. Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery. Glia 2007; 55: 976-1000.
62. Andrews MR, Czvitkovich S, Dassie E, et al. Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. J Neurosci 2009; 29: 5546-5557.
63. Maness PF, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 2007; 10: 19-26.
64. Rutishauser U. Polysialic acid in the plasticity of the developing and adult vertebrate nervous system. Nat Rev Neurosci 2008; 9: 26-35.
65. Gascon E, Vutskits L, Kiss JZ. The role of PSA-NCAM in adult neurogenesis. Adv Exp Med Biol 2010; 663: 127-136.
66. Zhang Y, Ghadiri-Sani M, Zhang X, Richardson PM, Yeh J, Bo X. Induced expression of polysialic acid in the spinal cord promotes regeneration of sensory axons. Mol Cell Neurosci 2007; 35: 109-119.
67. Zhang Y, Zhang X, Wu D, et al. Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord. Mol Ther 2007; 15: 1796-1804.
68. Zhang Y, Zhang X, Yeh J, Richardson P, Bo X. Engineered expression of polysialic acid enhances Purkinje cell axonal regeneration in L1/GAP-43 double transgenic mice. Eur J Neurosci 2007; 25: 351-361.
69. El Maarouf A, Petridis AK, Rutishauser U. Use of polysialic acid in repair of the central nervous system. Proc Natl Acad Sci USA 2006; 103: 16989-16994.
70. Luo J, Bo X, Wu D, Yeh J, Richardson PM, Zhang Y. Promoting the survival, migration, and integration of transplanted Schwann cells by over-expressing polysialic acid. Glia 2011; 59: 424-434.
71. Zhou FQ, Snider WD. Intracellular control of developmental and regenerative axon growth. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1575-1592.
72. Miura T, Tanaka S, Seichi A, et al. Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1. Exp Neurol 2000; 166: 115-126.
73. Hannila SS, Filbin MT. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp Neurol 2008; 209: 321-332.
74. Qiu J, Cai D, Dai H, et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 2002; 34: 895-903.
75. Gao Y, Deng K, Hou J, et al. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 2004; 44: 609-621.
76. Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 2007; 8: 755-765.
77. Corcoran J, Shroot B, Pizzey J, Maden M. The role of retinoic acid receptors in neurite outgrowth from different populations of embryonic mouse dorsal root ganglia. J Cell Sci 2000; 113: 2567-25674.
78. Wong LF, Yip PK, Battaglia A, et al. Retinoic acid receptor beta2 promotes functional regeneration of sensory axons in the spinal cord. Nat Neurosci 2006; 9: 243-250.
79. Yip PK, Wong LF, Pattinson D, et al. Lentiviral vector expressing retinoic acid receptor beta2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord. Hum Mol Genet 2006; 15: 3107-3118.
80. Burgoyne RD. Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling. Nat Rev Neurosci 2007; 8: 182-193.
81. Yip PK, Wong LF, Sears TA, Yanez-Munoz RJ, McMahon SB. Cortical overexpression of neuronal calcium sensor-1 induces functional plasticity in spinal cord following unilateral pyramidal tract injury in rat. PLoS Biol 2010; 8: e1000399.
82. Lu J, Ashwell KW, Waite P. Advances in secondary spinal cord injury: role of apoptosis. Spine (Phila Pa 1976) 2000; 25: 1859-1866.
83. Springer JE. Apoptotic cell death following traumatic injury to the central nervous system. J Biochem Mol Biol 2002; 35: 94-105.
84. Shibata M, Murray M, Tessler A, Ljubetic C, Connors T, Saavedra RA. Single injections of a DNA plasmid that contains the human Bcl-2 gene prevent loss and atrophy of distinct neuronal populations after spinal cord injury in adult rats. Neurorehabil Neural Repair 2000; 14: 319-330.
85. Yukawa Y, Lou J, Fukui N, Lenke LG. Optimal treatment timing to attenuate neuronal apoptosis via Bcl-2 gene transfer in vitro and in vivo. J Neurotrauma 2002; 19: 1091-1103.
86. Natsume A, Mata M, Goss J, et al. Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration. Exp Neurol 2001; 169: 231-238.
87. Lee SI, Kim BG, Hwang DH, Kim HM, Kim SU. Overexpression of Bcl-XL in human neural stem cells promotes graft survival and functional recovery following transplantation in spinal cord injury. J Neurosci Res 2009; 87: 3186-3197.
88. Zhou Z, Peng X, Insolera R, Fink DJ, Mata M. IL-10 promotes neuronal survival following spinal cord injury. Exp Neurol 2009; 220: 183-190.
89. Willerth SM, Sakiyama-Elbert SE. Cell therapy for spinal cord regeneration. Adv Drug Deliv Rev 2008; 60: 263-276.
90. Liu Y, Murray M, Tessler A, Fischer I. Grafting of genetically modified fibroblasts into the injured spinal cord. Prog Brain Res 2000; 128: 309-319.
91. Murray M, Kim D, Liu Y, Tobias C, Tessler A, Fischer I. Transplantation of genetically modified cells contributes to repair and recovery from spinal injury. Brain Res Brain Res Rev 2002; 40: 292-300.
92. Tuszynski MH, Peterson DA, Ray J, Baird A, Nakahara Y, Gage FH. Fibroblasts genetically modified to produce nerve growth factor induce robust neuritic ingrowth after grafting to the spinal cord. Exp Neurol 1994; 126: 1-14.
93. Tuszynski MH, Gabriel K, Gage FH, Suhr S, Meyer S, Rosetti A. Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory, motor, and noradrenergic neurites after adult spinal cord injury. Exp Neurol 1996; 137: 157-173.
94. Grill RJ, Blesch A, Tuszynski MH. Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF-secreting cells. Exp Neurol 1997; 148: 444-452.
95. Grill R, Murai K, Blesch A, Gage FH, Tuszynski MH. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 1997; 17: 5560-5572.
96. Tuszynski MH, Grill R, Jones LL, et al. NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Exp Neurol 2003; 181: 47-56.
97. Liu Y, Kim D, Himes BT, et al. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J Neurosci 1999; 19: 4370-4387.
98. Jin Y, Tessler A, Fischer I, Houle JD. Fibroblasts genetically modified to produce BDNF support regrowth of chronically injured serotonergic axons. Neurorehabil Neural Repair 2000; 14: 311-317.
99. Jin Y, Fischer I, Tessler A, Houle JD. Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp Neurol 2002; 177: 265-275.
100. Himes BT, Liu Y, Solowska JM, Snyder EY, Fischer I, Tessler A. Transplants of cells genetically modified to express neurotrophin-3 rescue axotomized Clarke's nucleus neurons after spinal cord hemisection in adult rats. J Neurosci Res 2001; 65: 549-564.
101. Liu Y, Himes BT, Murray M, Tessler A, Fischer I. Grafts of BDNF-producing fibroblasts rescue axotomized rubrospinal neurons and prevent their atrophy. Exp Neurol 2002; 178: 150-164.
102. Brock JH, Rosenzweig ES, Blesch A, et al. Local and remote growth factor effects after primate spinal cord injury. J Neurosci 2010; 30: 9728-9737.
103. McTigue DM, Horner PJ, Stokes BT, Gage FH. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 1998; 18: 5354-5365.
104. Blesch A, Yang H, Weidner N, Hoang A, Otero D. Axonal responses to cellularly delivered NT-4/5 after spinal cord injury. Mol Cell Neurosci 2004; 27: 190-201.
105. Blesch A, Uy HS, Grill RJ, Cheng JG, Patterson PH, Tuszynski MH. Leukemia inhibitory factor augments neurotrophin expression and corticospinal axon growth after adult CNS injury. J Neurosci 1999; 19: 3556-3566.
106. Blesch A, Tuszynski MH. Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination. J Comp Neurol 2003; 467: 403-417.
107. Oudega M, Xu XM. Schwann cell transplantation for repair of the adult spinal cord. J Neurotrauma 2006; 23: 453-467.
108. Fortun J, Hill CE, Bunge MB. Combinatorial strategies with Schwann cell transplantation to improve repair of the injured spinal cord. Neurosci Lett 2009; 456: 124-132.
109. Haastert K, Mauritz C, Matthies C, Grothe C. Autologous adult human Schwann cells genetically modified to provide alternative cellular transplants in peripheral nerve regeneration. J Neurosurg 2006; 104: 778-786.
110. Taylor JS, Bampton ET. Factors secreted by Schwann cells stimulate the regeneration of neonatal retinal ganglion cells. J Anat 2004; 204: 25-31.
111. Tuszynski MH, Weidner N, McCormack M, Miller I, Powell H, Conner J. Grafts of genetically modified Schwann cells to the spinal cord: survival, axon growth, and myelination. Cell Transplant 1998; 7: 187-196.
112. Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB. Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur J Neurosci 1998; 10: 607-621.
113. Golden KL, Pearse DD, Blits B, et al. Transduced Schwann cells promote axon growth and myelination after spinal cord injury. Exp Neurol 2007; 207: 203-217.
114. Plant GW, Bates ML, Bunge MB. Inhibitory proteoglycan immunoreactivity is higher at the caudal than the rostral Schwann cell graft-transected spinal cord interface. Mol Cell Neurosci 2001; 17: 471-487.
115. Franklin RJ, Barnett SC. Olfactory ensheathing cells and CNS regeneration: the sweet smell of success? Neuron 2000; 28: 15-18.
116. Lakatos A, Barnett SC, Franklin RJ. Olfactory ensheathing cells induce less host astrocyte response and chondroitin sulphate proteoglycan expression than Schwann cells following transplantation into adult CNS white matter. Exp Neurol 2003; 184: 237-246.
117. Mackay-Sim A, St. John JA. Olfactory ensheathing cells from the nose: Clinical application in human spinal cord injuries. Exp Neurol 2010; Epub on Sep 9.
118. Franssen EH, de Bree FM, Verhaagen J. Olfactory ensheathing glia: their contribution to primary olfactory nervous system regeneration and their regenerative potential following transplantation into the injured spinal cord. Brain Res Rev 2007; 56: 236-258.
119. Ruitenberg MJ, Plant GW, Hamers FP, et al. Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord. J Neurosci 2003; 23: 7045-7058.
120. Ruitenberg MJ, Levison DB, Lee SV, Verhaagen J, Harvey AR, Plant GW. NT-3 expression from engineered olfactory ensheathing glia promotes spinal sparing and regeneration. Brain 2005; 128: 839-853.
121. Cao L, Liu L, Chen ZY, et al. Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. Brain 2004; 127: 535-549.
122. Nandoe Tewarie RS, Hurtado A, Bartels RH, Grotenhuis A, Oudega M. Stem cell-based therapies for spinal cord injury. J Spinal Cord Med 2009; 32: 105-114.
123. Rosser AE, Zietlow R, Dunnett SB. Stem cell transplantation for neurodegenerative diseases. Curr Opin Neurol 2007; 20: 688-692.
124. Jandial R, Singec I, Ames CP, Snyder EY. Genetic modification of neural stem cells. Mol Ther 2008; 16: 450-457.
125. Liu Y, Himes BT, Solowska J, et al. Intraspinal delivery of neurotrophin-3 using neural stem cells genetically modified by recombinant retrovirus. Exp Neurol 1999; 158: 9-26.
126. Lu P, Jones LL, Snyder EY, Tuszynski MH. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 2003; 181: 115-129.
127. Blits B, Kitay BM, Farahvar A, Caperton CV, Dietrich WD, Bunge MB. Lentiviral vector-mediated transduction of neural progenitor cells before implantation into injured spinal cord and brain to detect their migration, deliver neurotrophic factors and repair tissue. Restor Neurol Neurosci 2005; 23: 313-324.
128. Kim HM, Hwang DH, Lee JE, Kim SU, Kim BG. Ex vivo VEGF delivery by neural stem cells enhances proliferation of glial progenitors, angiogenesis, and tissue sparing after spinal cord injury. PLoS One 2009; 4: e4987.
129. Vaquero J, Zurita M. Bone marrow stromal cells for spinal cord repair: a challenge for contemporary neurobiology. Histol Histopathol 2009; 24: 107-116.
130. Nandoe Tewarie RD, Hurtado A, Levi AD, Grotenhuis JA, Oudega M. Bone marrow stromal cells for repair of the spinal cord: towards clinical application. Cell Transplant 2006; 15: 563-577.
131. Lu P, Jones LL, Tuszynski MH. BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 2005; 191: 344-360.
132. Sasaki M, Radtke C, Tan AM, et al. BDNF-hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. J Neurosci 2009; 29: 14932-14941.
133. Hollis ER, Lu P, Blesch A, Tuszynski MH. IGF-I gene delivery promotes corticospinal neuronal survival but not regeneration after adult CNS injury. Exp Neurol 2009; 215: 53-59.
134. Cao Q, Xu XM, Devries WH, et al. Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 2005; 25: 6947-6957.
135. Cao Q, He Q, Wang Y, et al. Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinalcord injury. J Neurosci 2010; 30: 2989-3001.
136. Blits B, Oudega M, Boer GJ, Bartlett Bunge M, Verhaagen J. Adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function. Neuroscience 2003; 118: 271-281.
137. Taylor L, Jones L, Tuszynski MH, Blesch A. Neurotrophin-3 gradients established by lentiviral gene delivery promote shortdistance axonal bridging beyond cellular grafts in the injured spinal cord. J Neurosci 2006; 26: 9713-9721.
138. Bonner JF, Blesch A, Neuhuber B, Fischer I. Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J Neurosci Res 2010; 88: 1182-1192.
139. Kadoya K, Tsukada S, Lu P, et al. Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron 2009; 64: 165-172.
140. Alto LT, Havton LA, Conner JM, Hollis Ii ER, Blesch A, Tuszynski MH. Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury. Nat Neurosci 2009; 12: 1106-1113.
141. Busch SA, Silver J. The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 2007; 17: 120-127.
142. Bradbury EJ, Carter LM. Manipulating the glial scar: Chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 2010; Epub on Jul 10.
143. Massey JM, Amps J, Viapiano MS, et al. Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol 2008; 209: 426-445.
144. Tang XQ, Heron P, Mashburn C, Smith GM. Targeting sensory axon regeneration in adult spinal cord. J Neurosci 2007; 27: 6068-6078.
145. Tang XQ, Tanelian DL, Smith GM. Semaphorin3A inhibits nerve growth factor-induced sprouting of nociceptive afferents in adult rat spinal cord. J Neurosci 2004; 24: 819-827.
146. Okano H, Sakaguchi M, Ohki K, Suzuki N, Sawamoto K. Regeneration of the central nervous system using endogenous repair mechanisms. J Neurochem 2007; 102: 1459-1465.
147. Ohori Y, Yamamoto S, Nagao M, et al. Growth factor treatment and genetic manipulation stimulate neurogenesis and oligodendrogenesis by endogenous neural progenitors in the injured adult spinal cord. J Neurosci 2006; 26: 11948-11960.
148. Muir EM, Fyfe I, Gardiner S, et al. Modification of Nglycosylation sites allows secretion of bacterial chondroitinase ABC from mammalian cells. J Biotechnol 2010; 145: 103-110.
149. Liu Y, Figley S, Spratt SK, et al. An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury. Neurobiol Dis 2010; 37: 384-393.