Cell based-gene delivery approaches for the treatment of spinal cord injury and neurodegenerative disorders

Current Stem Cell Research and Therapy

Volumn 5, Issue 1, 2010, Pages 23-36

  Taha, Masoumeh Fakhr ^a  

^a NATIONAL INSTITUTE OF GENETIC ENGINEERING AND BIOTECHNOLOGY   (Iran)

Author keywords

Cell transplantation; Gene delivery; Neurodegenerative disorders; Spinal cord injury

Indexed keywords

LENTIVIRUS VECTOR; RETROVIRUS VECTOR; VIRUS VECTOR;

AGING; ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; CELL BASED GENE THERAPY; DEGENERATIVE DISEASE; DNA MODIFICATION; EXPERIMENTAL STUDY; GENE DELIVERY SYSTEM; GENE TARGETING; HUMAN; NONHUMAN; NONVIRAL GENE DELIVERY SYSTEM; PARKINSON DISEASE; PATIENT SAFETY; PRIORITY JOURNAL; REVIEW; SPINAL CORD INJURY; STEM CELL TRANSPLANTATION; VIRAL GENE DELIVERY SYSTEM;

ANIMALS; CELL TRANSPLANTATION; CYTOPROTECTION; DISEASE MODELS, ANIMAL; GENE THERAPY; GENETIC VECTORS; HUMANS; NERVE GROWTH FACTORS; NEURODEGENERATIVE DISEASES; NEURONS; RECOVERY OF FUNCTION; RETROVIRIDAE; SPINAL CORD INJURIES; STEM CELLS; TRANSGENES;

EID: 77949376588     PISSN: 1574888X     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488810790442778     Document Type: Review

References (105)

1. Humes HD. Stem cells: The next therapeutic frontier. Trans Am Clin Climatol Assoc 2005; 116: 167-84.
2. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immuno-deficiency. N Engl J Med 2003; 348(3): 255-56.
3. Lehrman S. Virus treatment questioned after gene therapy death. Nature 1999; 401 (6753): 517-8.
4. Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res 2009; 87(10): 2183-200.
5. Cotrim AP, Baum BJ. Gene therapy: some history, applications, problems, and prospects. Toxicol Pathol 2008; 36(1): 97-103.
6. Zubbler RH. Ex vivo expansion of haematopoietic stem cells and gene therapy development. Swiss Med Wkly 2006; 136: 795-9.
7. Baum C, Kustikova O, Modlich U, Li Z, Fehse B. Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors. Hum Gene Ther 2006; 17(3): 253-63.
8. Conlon TJ, Flotte TR. Recombinant adeno-associated virus vectors for gene therapy. Expert Opin Biol Ther 2004; 4(7): 1093-101.
9. Lowenstein PR, Castro MG. Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences. Gene Ther 2003; 10(11): 946-54.
10. Naldini L, Blömer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272(5259): 263-7.
11. Jones LL, Oudega M, Bunge MB, Tuszynski MH. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol 2001; 533(Pt 1): 83-9.
12. Tuszynski MH, Murai K, Blesch A, Grill R, Miller I. Functional characterization of NGF-secreting cell grafts to the acutely injured spinal cord. Cell Transplant 1997; 6(3): 361-8.
13. 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(2): 607-21.
14. 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(11): 4370-87.
15. 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(2): 150-64.
16. Feng SQ, Kong XH, Guo SF, et al. Treatment of spinal cord injury with co-grafts of genetically modified Schwann cells and fetal spinal cord cell suspension in the rat. Neurotox Res 2005; 7(1-2): 169-77.
17. Zhang X, Zeng Y, Zhang W, Wang J, Wu J, Li J. Cotransplantation of neural stem cells and NT-3-overexpressing Schwann cells in transected spinal cord. J Neurotrauma 2007; 24(12): 1863-77.
18. 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(14): 5560-72.
19. 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(9): 3556-66.
20. 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(5-6): 313-24.
21. Cai PQ, Tang X, Lin YQ, et al. The experimental study of genetic engineering human neural stem cells mediated by lentivirus to express multigene. Chin J Traumatol 2006; 9(1): 43-9.
22. Tang X, Cai PQ, Lin YQ, et al. Genetic engineering neural stem cell modified by lentivirus for repair of spinal cord injury in rats. Chin Med Sci J 2006; 21(2): 120-4.
23. Tuszynski MH, Grill R, Jones LL, McKay HM, Blesch A. Spontaneous and augmented growth of axons in the primate spinal cord: effects of local injury and nerve growth factor-secreting cell grafts. J Comp Neurol 2002; 449(1): 88-101.
24. DiBernardo AB, Cudkowicz ME. Translating preclinical insights into effective human trials in ALS. Biochim Biophys Acta 2006; 1762(11-12): 1139-49.
25. Ryberg H, Bowser R. Protein biomarkers for amyotrophic lateral sclerosis. Expert Rev Proteomics 2008; 5(2): 249-62.
26. Andersen PM, Sims KB, Xin WW, et al. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4(2): 62-73.
27. Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 1998; 23(3): 249-56.
28. Howland DS, Liu J, She Y, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 2002; 99(3): 1604-9.
29. 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(11): 1853-66.
30. Henderson CE, Phillips HS, Pollock RA, et al. GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 1994; 266(5187): 1062-4.
31. Klein SM, Behrstock S, McHugh J, et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 2005; 16(4): 509-21.
32. 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 2006; 13(5): 379-88.
33. Suzuki M, McHugh J, Tork C, et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS ONE 2007; 2(8): e689.
34. Rizvanov AA, Kiyasov AP, Gaziziov IM, et al. Human umbilical cord blood cells transfected with VEGF and L(1)CAM do not differentiate into neurons but transform into vascular endothelial cells and secrete neuro-trophic factors to support neuro-genesis-a novel approach in stem cell therapy. Neurochem Int 2008; 53(6-8): 389-94.
35. Aebischer P, Pochon NA, Heyd B, et al. Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Hum Gene Ther 1996a; 7(7): 851-60.
36. Aebischer P, Schluep M, Déglon N, et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat Med 1996b; 2(6): 696-9.
37. Ye M, Wang XJ, Zhang YH, et al. Transplantation of bone marrow stromal cells containing the neurturin gene in rat model of Parkinson's disease. Brain Res 2007; 1142: 206-16.
38. Nagatsu T, Sawada M. Biochemistry of postmortem brains in Parkinson's disease: historical overview and future prospects. J Neural Transm Suppl 2007; (72): 113-20.
39. Schwarz EJ, Alexander GM, Prockop DJ, Azizi SA. Multipotential marrow stromal cells transduced to produce L-DOPA: engraftment in a rat model of Parkinson disease. Hum Gene Ther 1999; 10(15): 2539-49.
40. Schwarz EJ, Reger RL, Alexander GM, Class R, Azizi SA, Prockop DJ. Rat marrow stromal cells rapidly transduced with a self-inactivating retrovirus synthesize L-DOPA in vitro. Gene Ther 2001; 8(16): 1214-23.
41. Lu L, Zhao C, Liu Y, et al. Therapeutic benefit of TH-engineered mesenchymal stem cells for Parkinson's disease. Brain Res Brain Res Protoc 2005; 15(1): 46-51.
42. Zhang S, Zou Z, Jiang X, et al. The therapeutic effects of tyrosine hydroxylase gene transfected hematopoetic stem cells in a rat model of Parkinson's disease. Cell Mol Neurobiol 2008; 28(4): 529-43.
43. Kodama Y, Hida H, Jung CG, et al. High titer retroviral gene transduction to neural progenitor cells for establishment of donor cells for neural transplantation to parkinsonian model rats. Neurol Med Chir (Tokyo) 2004; 44(7): 344-51; discussion 352.
44. Bencsics C, Wachtel SR, Milstien S, Hatakeyama K, Becker JB, Kang UJ. Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts. J Neurosci 1996; 16(14): 4449-56.
45. Kirik D, Georgievska B, Burger C, et al. Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer. Proc Natl Acad Sci USA 2002; 99(7): 4708-13.
46. Kim SU, Park IH, Kim TH, et al. Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Neuropathology 2006; 26(2): 129-40.
47. Kang UJ, Fisher LJ, Joh TH, O'Malley KL, Gage FH. Regulation of dopamine production by genetically modified primary fibroblasts. J Neurosci 1993; 13(12): 5203-11.
48. Kang UJ, Lee WY, Chang JW. Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models. Hum Cell 2001; 14(1): 39-48.
49. Sun M, Zhang GR, Kong L, et al. Correction of a rat model of Parkinson's disease by co-expression of tyrosine hydroxylase and aromatic amino acid decarboxylase from a helper virus-free herpes simplex virus type 1 vector. Hum Gene Ther 2003; 14(5): 415-24.
50. Ozawa K, Fan DS, Shen Y, et al. Gene therapy of Parkinson's disease using adeno-associated virus (AAV) vectors. J Neural Transm Suppl 2000; (58): 181-91.
51. Azzouz M, Martin-Rendon E, Barber RD, et al. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease. J Neurosci 2002; 22(23): 10302-12.
52. Shen Y, Muramatsu SI, Ikeguchi K, et al. Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, and GTP cyclohydrolase I for gene therapy of Parkinson's disease. Hum Gene Ther 2000; 11(11): 1509-19.
53. Muramatsu S, Fujimoto K, Ikeguchi K, et al. Behavioral recovery in a primate model of Parkinson's disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes. Hum Gene Ther 2002; 13(3): 345-54.
54. Lee WY, Chang JW, Nemeth NL, Kang UJ. Vesicular monoamine transporter-2 and aromatic L-amino acid decarboxylase enhance dopamine delivery after L-3, 4-dihydroxyphenylalanine administration in Parkinsonian rats. J Neurosci 1999; 19(8): 3266-74.
55. Liu Y, Peter D, Roghani A, et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 1992; 70(4): 539-51.
56. Sun M, Kong L, Wang X, et al. Co-expression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease. Hum Gene Ther 2004; 15(12): 1177-96.
57. Saavedra A, Baltazar G, Duarte EP. Driving GDNF expression: the green and the red traffic lights. Prog Neurobiol 2008; 86(3): 186-215.
58. Ostenfeld T, Tai YT, Martin P, Déglon 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(6): 955-65.
59. 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: 8108-18.
60. Capowski EE, Schneider BL, Ebert AD, et al. Lentiviral vectormediated genetic modification of human neural progenitor cells for ex vivo gene therapy. J Neurosci Methods 2007; 163(2): 338-49.
61. Ebert AD, Beres AJ, Barber AE, Svendsen CN. Human neural progenitor cells overexpressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease. Exp Neurol 2008; 209(1): 213-23.
62. Gasmi M, Herzog CD, Brandon EP, et al. Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease. Mol Ther 2007; 15(1): 62-8.
63. Akerud P, Alberch J, Eketjäll S, Wagner J, Arenas E. Differential effects of glial cell line-derived neurotrophic factor and neurturin on developing and adult substantia nigra dopaminergic neurons. J Neurochem 1999; 3(1): 70-8.
64. Horger BA, Nishimura MC, Armanini MP, et al. Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. J Neurosci 1998; 18(13): 4929-37.
65. Oiwa Y, Yoshimura R, Nakai K, Itakura T. Dopaminergic neuro-protection and regeneration by neurturin assessed by using behavioral, biochemical and histochemical measurements in a model of progressive Parkinson's disease. Brain Res 2002; 947(2): 271-83.
66. Liu WG, Wang XJ, Lu GQ, Li B, Wang G, Chen SD. Dopaminergic regeneration by neurturin-overexpressing c17.2 neural stem cells in a rat model of Parkinson's disease. Mol Neurodegener 2007a; 1; 2:19.
67. Liu WG, Lu GQ, Li B, Chen SD. Dopaminergic neuroprotection by neurturin-expressing c17.2 neural stem cells in a rat model of Parkinson's disease. Parkinsonism Relat Disord 2007b; 13(2): 77-88.
68. Bernd P. The role of neurotrophins during early development. Gene Expr 2008; 14(4): 241-50.
69. Espejo M, Cutillas B, Arenas TE, Ambrosio S. Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or glial cell line-derived neurotrophic factor. Cell Transplant 2000; 9(1): 45-53.
70. Gu S, Huang H, Bi J, Yao Y, Wen T. Combined treatment of neurotrophin-3 gene and neural stem cells is ameliorative to behavior recovery of Parkinson's disease rat model. Brain Res 2009; 1257: 1-9.
71. Robichaud AJ. Approaches to palliative therapies for Alzheimer's disease. Curr Top Med Chem 2006; 6(6): 553-68.
72. Kubis AM, Janusz M. Alzheimer's disease: new prospects in therapy and applied experimental models. Postepy Hig Med Dosw (Online) 2008; 62: 372-92.
73. Cattaneo A, Capsoni S, Paoletti F. Towards non invasive nerve growth factor therapies for Alzheimer's disease. J Alzheimers Dis 2008; 15(2): 255-83.
74. Rosenberg MB, Friedmann T, Robertson RC, et al. Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science 1988; 242(4885): 1575-8.
75. Chen KS, Gage FH. Somatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration. J Neurosci 1995; 15(4): 2819-25.
76. Martínez-Serrano A, Fischer W, Björklund A. Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain. Neuron 1995; 15(2): 473-84.
77. Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med 2009; 15(3): 331-7.
78. Klein J. Phenserine. Expert Opin Investig Drugs 2007; 16(7): 1087-97.
79. Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proc Natl Acad Sci USA 2007; 104(30): 12506-11.
80. Iwata N, Tsubuki S, Takaki Y, et al. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000; 6(2): 143-50.
81. Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of brain Abeta by neprilysin. Science 2001; 292(5521): 1550-2.
82. Spencer B, Marr RA, Rockenstein E, Crews L. Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice. BMC Neurosci 2008; 9: 109.
83. El-Amouri SS, Zhu H, Yu J, Gage FH, Verma IM, Kindy MS. Neprilysin protects neurons against Abeta peptide toxicity. Brain Res 2007; 1152: 191-200.
84. Conner JM, Darracq MA, Roberts J, Tuszynski MH. Nontropic actions of neurotrophins: subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation. Proc Natl Acad Sci USA 2001; 98(4): 1941-6.
85. Smith DE, Roberts J, Gage FH, Tuszynski MH. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc Natl Acad Sci USA. 1999 Sep 14;96(19):10893-8.
86. Erratum in: Proc Natl Acad Sci USA 1999; 96(25): 14668.
87. Kordower JH, Winn SR, Liu YT, et al. The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor. Proc Natl Acad Sci USA 1994; 91(23): 10898-902.
88. Tuszynski MH, 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.
89. Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987; 237(4819):1154-62.
90. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 1978; 2(6150): 1457-9.
91. Tuszynski MH, Smith DE, Roberts J, McKay H, Mufson E. Targeted intraparenchymal delivery of human NGF by gene transfer to the primate basal forebrain for 3 months does not accelerate beta-amyloid plaque deposition. Exp Neurol 1998; 154(2): 573-82.
92. Tai IT, Sun AM. Microencapsulation of recombinant cells: a new delivery system for gene therapy. FASEB J 1993; 7(11): 1061-9.
93. Winn SR, Hammang JP, Emerich DF, Lee A, Palmiter RD, Baetge EE. Polymer-encapsulated cells genetically modified to secrete human nerve growth factor promote the survival of axotomized septal cholinergic neurons. Proc Natl Acad Sci USA 1994; 91(6): 2324-8.
94. Wu X, Li Y, Crise B, Burgess SM. Transcription start regions in the human genome are favored targets for MLV integration. Science 2003; 300(5626): 1749-51.
95. Mitchell RS, Beitzel BF, Schroder AR, et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2004; 2(8): E234.
96. De Palma M, Montini E, Santoni de Sio FR, et al. Promoter trapping reveals significant differences in integration site selection between MLV and HIV vectors in primary hematopoietic cells. Blood 2005; 105(6): 2307-15.
97. Hematti P, Hong BK, Ferguson C, et al. Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells. PLoS Biol 2004; 2(12) :e423.
98. Laufs S, Nagy KZ, Giordano FA, Hotz-Wagenblatt A, Zeller WJ, Fruehauf S. Insertion of retroviral vectors in NOD/SCID repopulating human peripheral blood progenitor cells occurs preferentially in the vicinity of transcription start regions and in introns. Mol Ther 2004; 10(5): 874-81.
99. Montini E, Cesana D, Schmidt M, et al. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 2006; 24(6): 687-96.
100. Lewinski MK, Yamashita M, Emerman M, et al. Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog 2006; 2(6): e60.
101. Felice B, Cattoglio C, Cittaro D, et al. Transcription factor binding sites are genetic determinants of retroviral integration in the human genome. PLoS ONE 2009; 4(2): e4571.
102. Shujia J, Haider HK, Idris NM, Lu G, Ashraf M. Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair. Cardiovasc Res 2008; 77: 525-33.
103. Johansen J, Rosenblad C, Andsberg K, et al. Evaluation of Tet-on system to avoid transgene down-regulation in ex vivo gene transfer to the CNS. Gene Ther 2002; 9(19): 1291-301.
104. Englund U, Ericson C, Rosenblad C, et al. The use of a recombinant lentiviral vector for ex vivo gene transfer into the rat CNS. Neuroreport 2000; 11(18): 3973-7.
105. Aiuti A, Cassani B, Andolfi G, et al. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest 2007; 117(8): 2233-40.