Gene therapy in neurology

Current Opinion in Pediatrics

Volumn 8, Issue 6, 1996, Pages 558-568

  Snyder, Evan Y ^a   Fisher, Lisa J ^b  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

VIRUS VECTOR;

CELL TRANSPLANTATION; CLONING VECTOR; COGNITIVE DEFECT; GENE TECHNOLOGY; GENE THERAPY; GENE TRANSFER; METABOLIC DISORDER; MOTOR DYSFUNCTION; NERVE CELL; PRIORITY JOURNAL; REVIEW;

EID: 0030459702     PISSN: 10408703     EISSN: None     Source Type: Journal    
DOI: 10.1097/00008480-199612000-00004     Document Type: Review

References (128)

1. Suhr S, Gage FH: Gene therapy for neurologic disease. Arch Neurol 1993, 50:1252-1268.
2. Friedmann T: Gene therapy for neurological disorders. Trends Genet 1994, 10:210-214.
3. Breakefield XO, Sena-Esteves M, Pechan P, Kramm C, Yoshimoto Y, Lin Q, Davar G, Livermore J, Isacson O, Chiocca EA, et al.: Gene therapy for the nervous system: status 1994. Gene Ther 1996, in press.
4. Yuen EC, Mobley WC: Therapeutic potential of neurotrophic factors for neurological disorders. Ann Neurol 1996, 40:346-354. Excellent and comprehensive review with an emphasis on relevance to neurologic diseases.
5. Maria BL, Medina CD: Gene therapy: the beginning of a new era in treating neurological disease. Int Pediatr 1996, 11:248-255.
6. McKinnis EJR, Sulzbacher S, Rutledge JC, Sander J, Scott CR: Bone marrow transplantation in Hunter syndrome. J Pediatr 1996, 129:145-148. This study is important because its findings represent those generally obtained following BMT in humans with inherited neurodegenerative metabolic diseases. The paper reports on the 6-year follow-up of a patient with mucopolysaccharidosis type II (Hunters syndrome) who received a BMT at the age of 29 months. Despite sustained engraftment, absence of graft-versus-host disease, normal enzyme levels, reduced urinary excretion and hepatocyte storage of glycosaminoglycans, and physical improvement, this patient continued to decline in his neurologic and intellectual functions. In other words, the BMT alleviated the physical disorder, possibly ensuring a longer lifespan than expected from the natural history of the disease, but raised profound biologic and ethical issues when considering the child's deteriorating mental status and the inability of BMT to halt the neurologic progression. The sustained normal level of enzyme production in conjunction with deteriorating mental condition raises questions regarding the ability of macrophages to penetrate the CNS. The paper also raises the concern that BMT performed after the age of 2 to 3 years for other inherited neurogenerative metabolic diseases may offer less neuropsychologic benefit because of the progressive deterioration in mental ability. Such findings as reported in this paper draw attention to animal studies such as those by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in which migratory neural progenitors integrate through the blood-brain barrier and are used to deliver molecules therapeutic for neurogenetic diseases directly and globally to the CNS.
7. McKinnis EJR, Sulzbacher S, Rutledge JC, Sander J, Scott CR: Bone marrow transplantation in Hunter syndrome. J Pediatr 1996, 129:145-148. This study is important because its findings represent those generally obtained following BMT in humans with inherited neurodegenerative metabolic diseases. The paper reports on the 6-year follow-up of a patient with mucopolysaccharidosis type II (Hunters syndrome) who received a BMT at the age of 29 months. Despite sustained engraftment, absence of graft-versus-host disease, normal enzyme levels, reduced urinary excretion and hepatocyte storage of glycosaminoglycans, and physical improvement, this patient continued to decline in his neurologic and intellectual functions. In other words, the BMT alleviated the physical disorder, possibly ensuring a longer lifespan than expected from the natural history of the disease, but raised profound biologic and ethical issues when considering the child's deteriorating mental status and the inability of BMT to halt the neurologic progression. The sustained normal level of enzyme production in conjunction with deteriorating mental condition raises questions regarding the ability of macrophages to penetrate the CNS. The paper also raises the concern that BMT performed after the age of 2 to 3 years for other inherited neurogenerative metabolic diseases may offer less neuropsychologic benefit because of the progressive deterioration in mental ability. Such findings as reported in this paper draw attention to animal studies such as those by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in which migratory neural progenitors integrate through the blood-brain barrier and are used to deliver molecules therapeutic for neurogenetic diseases directly and globally to the CNS.
8. McKinnis EJR, Sulzbacher S, Rutledge JC, Sander J, Scott CR: Bone marrow transplantation in Hunter syndrome. J Pediatr 1996, 129:145-148. This study is important because its findings represent those generally obtained following BMT in humans with inherited neurodegenerative metabolic diseases. The paper reports on the 6-year follow-up of a patient with mucopolysaccharidosis type II (Hunters syndrome) who received a BMT at the age of 29 months. Despite sustained engraftment, absence of graft-versus-host disease, normal enzyme levels, reduced urinary excretion and hepatocyte storage of glycosaminoglycans, and physical improvement, this patient continued to decline in his neurologic and intellectual functions. In other words, the BMT alleviated the physical disorder, possibly ensuring a longer lifespan than expected from the natural history of the disease, but raised profound biologic and ethical issues when considering the child's deteriorating mental status and the inability of BMT to halt the neurologic progression. The sustained normal level of enzyme production in conjunction with deteriorating mental condition raises questions regarding the ability of macrophages to penetrate the CNS. The paper also raises the concern that BMT performed after the age of 2 to 3 years for other inherited neurogenerative metabolic diseases may offer less neuropsychologic benefit because of the progressive deterioration in mental ability. Such findings as reported in this paper draw attention to animal studies such as those by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in which migratory neural progenitors integrate through the blood-brain barrier and are used to deliver molecules therapeutic for neurogenetic diseases directly and globally to the CNS.
9. Shapiro EG, Lockman LA, Balthazor M, Krivit W: Neuropsychological outcome of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis 1995, 18:413-429. This paper reports that, of the 16 children with mucopolysaccharidosis type II who received BMT, treatment failure (defined as intelligence quotient decreasing to < 50) occurred in all but one of the children. All had symptoms of disease and were older than 2 years of age at the time of transplantation. This paper brings out many of the same points illustrated in the paper by McKinnis et al. (J Pediatr 1996, 129:145-148).
10. Shapiro EG, Lockman LA, Balthazor M, Krivit W: Neuropsychological outcome of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis 1995, 18:413-429. This paper reports that, of the 16 children with mucopolysaccharidosis type II who received BMT, treatment failure (defined as intelligence quotient decreasing to < 50) occurred in all but one of the children. All had symptoms of disease and were older than 2 years of age at the time of transplantation. This paper brings out many of the same points illustrated in the paper by McKinnis et al. (J Pediatr 1996, 129:145-148).
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18. Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D: In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996, 272:263-267. Though retroviruses are probably the best choice for gene therapy, most require mitosis of the host cells for viral integration. Many of the targets for gene therapy, especially in the CNS, are noncycling or postmitotic cells. HIV, conversely, is a member of the lentivirus class of retroviruses that can infect nondividing cells. These authors have shown that the injection of an HIV-derived retroviral vector into adult rat brains leads to stable introduction of a marker gene into nondividing astrocytes, neurons, and oligodendrocytes. These authors also obtained high titers of vector stocks by substituting the endogenous HIV envelope proteins with the vesticular stomatitus virus G protein in trans. These authors both broadened the host range of the vector and allowed the viral stock to be better concentrated by ultracentrifugation. Although the potential for HIV-mediated introduction of therapeutic genes into postmitotic CNS and muscle cells is quite exciting, safety must, obviously, still be affirmed.
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32. Lawrence MS, Ho DY, Sun GH, Steinberg GK, Sapolsky RM: Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo. J Neurosci 1996, 15:486-496.
33. Peele AL, Zolotukhin S, Schrimsher GW, Muzyczka N, Reier PJ: Efficient transduction of green fluorescent protein in spinal cord neurons using adeno-associated virus vectors containing cell-type specific promoters. Gene Ther 1997, in press. This paper reports the capacity of recombinant adeno-associated viral vectors, containing neuron-specific promoters, to transduce neurons in vivo in the normal adult rat spinal cord. The neuron-specific enolase promoter and the platelet-derived growth factor B-chain promoter were used to direct the expression of the reporter gene, green fluorescent protein. Efficiency of infection was high and gene expression persisted for up to 15 weeks. The targeting was apparently successful: only neurons appeared to be transduced. There was no detectable Addison's disease. This study helps lay the groundwork for targeting of more functional and therapeutic genes to host neurons in vivo.
34. Chen S-H, Shine HD, Goodman JC, Grossman RG, Woo SLC: Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci U S A 1994, 91:3054-3057.
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46. Lindner MD, Winn SR, Baetge EE, Hammang JP, Gentile FT, Doherty E, McDermott PE, Frydel B, Ullman MD, Shallert T, et al.: Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and Parkinsonian symptoms. Exp Neurol 1995, 132:62-76.
47. Lanza RP, Hayes JL, Chick WL: Encapsulated cell technology. Nat Biotechnol 1996, 14:1107-1111. Useful review, though not specific for the CNS.
48. Emerich DF, Linder MD, Winn SR, Chen E-Y, Frydel BR, Kordower JH: Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease. J Neurosci 1996, 16:5168-5181. In this study, an expression vector encoding human CNTF was transfected into a baby hamster kidney fibroblast cell line. A polymeric device encapsulating the CNTF-secreting cells was implanted unilaterally into the rat lateral ventricle. Twelve days later, the same animals received unilateral injections of the excitotoxin quinolinic acid into the ipsilateral striatum. Seventy days after implantation, rats receiving capsules containing engineered cells showed significantly increased survival of choline acetyltransferase and glutamic acid decarboxylase-immunoreactive striatal neurons histologically and less apomorphine-induced rotational behavior functionally than animals receiving control encapsulated cells. There appeared to be no morbidity from the implantation procedure. Analysis of retrieved capsules revealed numerous viable and mitotically active fibroblasts that continued to secrete CNTF.
49. Snyder EY: Immortalized neural stem cells: insights into development: prospects for gene therapy & repair. Proc Assoc Am Physicians 1995, 107:195-204.
50. Snyder EY, Wolfe, JH: CNS cell transplantation: a novel therapy for storage diseases? Curr Opin Neurol 1996, 9:126-136.
51. Snyder EY, Park KI, Flax JD, Liu S, Rosario CM, Yandava BD, Aurora S: The potential of neural stem-like cells for gene therapy and repair of the degenerating CNS. In Advances in Neurology: Neuronal Regeneration, Reorganization, and Repair. Edited by Seil FJ. Philadelphia: Lippincott-Raven; 1996:121-132.
52. Fisher LJ, Gage FH: Grafting in the mammalian central nervous system. Physiol Rev 1993, 73:583-616.
53. Dunnett SB, Bjorklund A: Functional Neural Transplantation. New York: Raven; 1994.
54. Kawaja MD, Gage FH: Morphological and neurochemical features of cultured primary skin fibroblasts of fischer 344 rats following striatal implantation. J Comp Neurol 1992, 317:102-116.
55. Tuszynski MH, Senut M-C, Ray J, Roberts J, U H-S, Gage FH: Somatic gene transfer to the adult primate CNS: in vitro and in vivo characterization of cells genetically modified to secrete nerve growth factor. Neurobiol Dis 1994, 1:67-78.
56. Mucke L, Rockenstein EL: Prolonged delivery of transgene products to specific brain regions by migratory astrocyte grafts. Transgene 1993, 1:3-9.
57. LaGamma EF, Weisinger G, Lenn NJ, Strecker RE: Genetically modified primary astrocytes as cellular vehicles for gene therapy in the brain. Cell Transplant 1993, 2:207-214.
58. Cunningham LA, Hansen JT, Short MP, Bonn MC: The use of genetically altered astrocytes to provide nerve growth factor to adrenal chromaffin cells grafted into the striatum. Brain Res 1991, 561:192-202.
59. Cunningham LA, Short MP, Breakefield XO, Bonn MC: Nerve growth factor released by transgenic astrocytes enhances the function of adrenal chromaffin cell grafts in a rat model of Parkinson's disease. Brain Res 1994, 658:219-231.
60. Yoshimoto Y, Lin Q, Collier TJ, Frim DM, Breakefield XO, Bonn MC: Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson's disease. Brain Res 1995, 691:25-36.
61. Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL: Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 1992, 68:33-55.
62. Renfranz PJ, Cunningham MG, McKay RDG: Region-specific differentiation of the hippocampal stem cell line HIB5 upon implantation into the developing mammalian brain. Cell 1991, 66:713-719.
63. Snyder EY: Grafting immortalized neurons to the CNS. Curr Opin Neurobiol 1994, 4:742-751.
64. Whittemore SR, Snyder EY: The biologic relevance and functional potential of central nervous system-derived cell lines. Molec Neurobiol 1996, 12:13-38.
65. Gage FH, Ray J, Fisher LJ: Isolation, characterization and use of stem cells from the CNS. Annu Rev Neurosci 1995, 18:159-162. Excellent review of this new field in restorative neurology.
66. Weiss S, Reynolds BA, Vescovi AL, Morshead C, Craig C, van der Kooy D: Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 1996, 19:387-393.
67. Kilpatrick T, Richards LJ, Bartlett PF: The regulation of neural precursor cells within the mammalian brain. Mol Cell Neurosci 1995, 6:2-15. Excellent review of the CNS progenitor field, particularly those cells propagated in basic fibroblast growth factor.
68. Snyder EY, Taylor RM, Wolfe JH: Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995, 374:367-370. This study established the feasibility of using neural progenitors as vehicles for gene therapy for neurogenetic diseases. The report demonstrated that murine multipotent neural progenitors could engraft throughout the host brain and intermingle appropriately with endogenous cells, developing into integral members of multiple brain regions. The donor progenitors could be used to deliver sustained, therapeutic levels of a missing enzyme directly to and throughout the brain in a mouse model of a prototypical genetic neurodegenerative disease. The mucopolysaccharidosis type VII mouse has lysosomal storage lesions disseminated throughout the brain that are refractory to other treatment approaches but that can be cross-corrected by the widespread engraftment of enzyme-producing neural progenitors. The success of this approach was made possible by exploiting the inherent biologic properties of neural progenitors and stem cells, some of which are illuminated in this paper. For instance, delivering progenitors to germinal zones (the ventricular or subventricular zones) is one technique for ensuring their efficient distribution appropriately throughout the CNS for disseminated disease. This work helps affirm the confluence of the two emerging fields of progenitor and stem cell biology with CNS gene therapy and repair. It also helps lay the groundwork for several treatment strategies, such as replacement of degenerated cells, engineering cells to be resistant to toxins, delivery of missing metabolic products, overexpression of molecules, and substitution of alternate metabolic pathways.
69. Anton R, Kordower JH, Maidment NT, Manaster JS, Kane DJ, Rabizadeh S, Schueller SB, Yang J, Rabizadeh S, Edwards RH, Markham CH, Bredesen DE: Neural-targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol 1994, 127:207-218.
70. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J: Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A 1996, 92:11879-11883. This paper demonstrates that neural progenitors propagated in basic fibroblast growth factor and isolated even from adult rodent brains can be successfully reimplanted orthotopically into adult rodent brains, yielding results similar to those reported for genetically immortalized neural progenitors, as reported by Snyder et al. (Cell 1992, 68:33-55), Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475).
71. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J: Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A 1996, 92:11879-11883. This paper demonstrates that neural progenitors propagated in basic fibroblast growth factor and isolated even from adult rodent brains can be successfully reimplanted orthotopically into adult rodent brains, yielding results similar to those reported for genetically immortalized neural progenitors, as reported by Snyder et al. (Cell 1992, 68:33-55), Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475).
72. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J: Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A 1996, 92:11879-11883. This paper demonstrates that neural progenitors propagated in basic fibroblast growth factor and isolated even from adult rodent brains can be successfully reimplanted orthotopically into adult rodent brains, yielding results similar to those reported for genetically immortalized neural progenitors, as reported by Snyder et al. (Cell 1992, 68:33-55), Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475).
73. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J: Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A 1996, 92:11879-11883. This paper demonstrates that neural progenitors propagated in basic fibroblast growth factor and isolated even from adult rodent brains can be successfully reimplanted orthotopically into adult rodent brains, yielding results similar to those reported for genetically immortalized neural progenitors, as reported by Snyder et al. (Cell 1992, 68:33-55), Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475).
74. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 1996, 137:376-388. This paper illustrates that neural progenitors isolated from rodent and human brain and propagated in epidermal growth factor can be transplanted orthotopically into adult rodent brain. The differentiation and engraftment of these cells, as described in this paper, however, are not quite comparable to those reported for genetically immortalized neural progenitors by Snyder et al. (Cell 1992, 68:33-55) , Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475) or for basic fibroblast growth factor-propagated cells as reported by Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883.
75. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 1996, 137:376-388. This paper illustrates that neural progenitors isolated from rodent and human brain and propagated in epidermal growth factor can be transplanted orthotopically into adult rodent brain. The differentiation and engraftment of these cells, as described in this paper, however, are not quite comparable to those reported for genetically immortalized neural progenitors by Snyder et al. (Cell 1992, 68:33-55) , Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475) or for basic fibroblast growth factor-propagated cells as reported by Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883.
76. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 1996, 137:376-388. This paper illustrates that neural progenitors isolated from rodent and human brain and propagated in epidermal growth factor can be transplanted orthotopically into adult rodent brain. The differentiation and engraftment of these cells, as described in this paper, however, are not quite comparable to those reported for genetically immortalized neural progenitors by Snyder et al. (Cell 1992, 68:33-55) , Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475) or for basic fibroblast growth factor-propagated cells as reported by Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883.
77. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 1996, 137:376-388. This paper illustrates that neural progenitors isolated from rodent and human brain and propagated in epidermal growth factor can be transplanted orthotopically into adult rodent brain. The differentiation and engraftment of these cells, as described in this paper, however, are not quite comparable to those reported for genetically immortalized neural progenitors by Snyder et al. (Cell 1992, 68:33-55) , Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475) or for basic fibroblast growth factor-propagated cells as reported by Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883.
78. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 1996, 137:376-388. This paper illustrates that neural progenitors isolated from rodent and human brain and propagated in epidermal growth factor can be transplanted orthotopically into adult rodent brain. The differentiation and engraftment of these cells, as described in this paper, however, are not quite comparable to those reported for genetically immortalized neural progenitors by Snyder et al. (Cell 1992, 68:33-55) , Renfranz et al. (Cell 1991, 66:713-719), and Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475) or for basic fibroblast growth factor-propagated cells as reported by Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883.
79. Martinez-Serrano A, Fischer W, Bjorklund A: Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secretlng neural progenitors grafted to the basal forebrain. Neuron 1995, 15:473-484. This paper complements the studies by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in suggesting that neural progenitors can be effective vehicles for foreign gene expression. It complements the study by Chen and Gage (J Neurosci 1995, 15:2819-2825) in demonstrating that neural progenitors, engineered to express NGF and implanted focally into the basal forebrain of aged rats, could be as successful as NGF-secreting fibroblasts in reversing aging-associated memory. Finally, it complements the study by Winkler et al. (Nature 1995, 375:484-487) in demonstrating that, for some neurologic disorders, even local replacement of some factors (eg, a trophic factor) may positively impact seemingly complex disease processes such as memory impairment.
80. Martinez-Serrano A, Fischer W, Bjorklund A: Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secretlng neural progenitors grafted to the basal forebrain. Neuron 1995, 15:473-484. This paper complements the studies by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in suggesting that neural progenitors can be effective vehicles for foreign gene expression. It complements the study by Chen and Gage (J Neurosci 1995, 15:2819-2825) in demonstrating that neural progenitors, engineered to express NGF and implanted focally into the basal forebrain of aged rats, could be as successful as NGF-secreting fibroblasts in reversing aging-associated memory. Finally, it complements the study by Winkler et al. (Nature 1995, 375:484-487) in demonstrating that, for some neurologic disorders, even local replacement of some factors (eg, a trophic factor) may positively impact seemingly complex disease processes such as memory impairment.
81. Martinez-Serrano A, Fischer W, Bjorklund A: Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secretlng neural progenitors grafted to the basal forebrain. Neuron 1995, 15:473-484. This paper complements the studies by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in suggesting that neural progenitors can be effective vehicles for foreign gene expression. It complements the study by Chen and Gage (J Neurosci 1995, 15:2819-2825) in demonstrating that neural progenitors, engineered to express NGF and implanted focally into the basal forebrain of aged rats, could be as successful as NGF-secreting fibroblasts in reversing aging-associated memory. Finally, it complements the study by Winkler et al. (Nature 1995, 375:484-487) in demonstrating that, for some neurologic disorders, even local replacement of some factors (eg, a trophic factor) may positively impact seemingly complex disease processes such as memory impairment.
82. Martinez-Serrano A, Fischer W, Bjorklund A: Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secretlng neural progenitors grafted to the basal forebrain. Neuron 1995, 15:473-484. This paper complements the studies by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in suggesting that neural progenitors can be effective vehicles for foreign gene expression. It complements the study by Chen and Gage (J Neurosci 1995, 15:2819-2825) in demonstrating that neural progenitors, engineered to express NGF and implanted focally into the basal forebrain of aged rats, could be as successful as NGF-secreting fibroblasts in reversing aging-associated memory. Finally, it complements the study by Winkler et al. (Nature 1995, 375:484-487) in demonstrating that, for some neurologic disorders, even local replacement of some factors (eg, a trophic factor) may positively impact seemingly complex disease processes such as memory impairment.
83. Martinez-Serrano A, Fischer W, Bjorklund A: Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secretlng neural progenitors grafted to the basal forebrain. Neuron 1995, 15:473-484. This paper complements the studies by Snyder et al. (Nature 1995, 374:367-370) and Lacorazza et al. (Nat Med 1996, 2:424-429) in suggesting that neural progenitors can be effective vehicles for foreign gene expression. It complements the study by Chen and Gage (J Neurosci 1995, 15:2819-2825) in demonstrating that neural progenitors, engineered to express NGF and implanted focally into the basal forebrain of aged rats, could be as successful as NGF-secreting fibroblasts in reversing aging-associated memory. Finally, it complements the study by Winkler et al. (Nature 1995, 375:484-487) in demonstrating that, for some neurologic disorders, even local replacement of some factors (eg, a trophic factor) may positively impact seemingly complex disease processes such as memory impairment.
84. Snyder EY: Retroviral vectors for the study of neuroembryology: immortalization of neural cells. In Viral Vectors: Tools for Analysis and Genetic Manipulation of the Nervous System. Edited by Kaplit MG, Loewy AD. New York: Academic Press; 1995:435-475.
85. Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992, 27:1707-1710.
86. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
87. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
88. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
89. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
90. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
91. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
92. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
93. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
94. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
95. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
96. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al. (Mol Cell Neurosci 1995, 6:2-15), Snyder et al. (Nature 1995, 374:367-370), Anton et al. (Exp Neurol 1994, 127:207-218), Gage et al. (Proc Natl Acad Sci U S A 1996, 92:11879-11883), Svendsen et al. (Exp Neurol 1996, 137:367-388), Reynolds and Weiss (Science 1992, 27:1707-1710), Girth et al. (J Neurosci 1996, 16:1091-1100), and Lacorazza et al. (Nat Med 1996, 2:424-429), this paper helps support the findings of Anton et al. (Exp Neurol 1994k, 127:207-218), Snyder (in Viral Vectors, edited by Kaplit and Loewy. New York: Academic Press; 1995:435-475), and Snyder et al. (in Research and Perspectives in Neurosciences, edited by Gage and Christen. Berlin: Springer-Verlag; 1996:173-196), all these groups have shown that neural progenitors, propagated by a variety of techniques and from a variety of CNS regions, nevertheless behave, intriguingly, quite similarly.
97. Palmer TD, Ray J, Gage FH: FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995, 6:474-486. Taken together with the data from Kilpatrick et al.
98. Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vesoovi AL: Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci 1996, 16:1091-1100.
99. Snyder EY, Flax JD, Yandava BD, Park KI, Liu S, Rosario CM, Aurora S: Transplantation and differentiation of neural stem-like cells: possible insights into development end therapeutic potential. In Research and Perspectives in Neurosciences: Isolation, Characterization, and Utilization of CNS Stem Cells. Edited by Gage FH, Christen Y. Berlin: Springer-Verlag; 1996:173-196.
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101. 2 ganglioside accumulation. Although performed in normal mouse brains, this study confirmed that the amount of enzyme expressed would be sufficient to restore normal ganglioside turnover and established the groundwork for using such cells to rescue recently generated mouse models of the gangliosidoses, as described by Yamanaka et al. (Proc Natl Acad Sci U S A 1994, 91:9975-9979), Sango et al. (Nat Genet 1995, 11:170-176), and Phaneuf et al. (Hum Mol Genet 1996, 5:1-14).
102. 2 ganglioside accumulation. Although performed in normal mouse brains, this study confirmed that the amount of enzyme expressed would be sufficient to restore normal ganglioside turnover and established the groundwork for using such cells to rescue recently generated mouse models of the gangliosidoses, as described by Yamanaka et al. (Proc Natl Acad Sci U S A 1994, 91:9975-9979), Sango et al. (Nat Genet 1995, 11:170-176), and Phaneuf et al. (Hum Mol Genet 1996, 5:1-14).
103. 2 ganglioside accumulation. Although performed in normal mouse brains, this study confirmed that the amount of enzyme expressed would be sufficient to restore normal ganglioside turnover and established the groundwork for using such cells to rescue recently generated mouse models of the gangliosidoses, as described by Yamanaka et al. (Proc Natl Acad Sci U S A 1994, 91:9975-9979), Sango et al. (Nat Genet 1995, 11:170-176), and Phaneuf et al. (Hum Mol Genet 1996, 5:1-14).
104. 2 ganglioside accumulation. Although performed in normal mouse brains, this study confirmed that the amount of enzyme expressed would be sufficient to restore normal ganglioside turnover and established the groundwork for using such cells to rescue recently generated mouse models of the gangliosidoses, as described by Yamanaka et al. (Proc Natl Acad Sci U S A 1994, 91:9975-9979), Sango et al. (Nat Genet 1995, 11:170-176), and Phaneuf et al. (Hum Mol Genet 1996, 5:1-14).
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