Translating the therapeutic potential of neurotrophic factors to clinical 'proof of concept': A personal saga achieving a career-long quest

Neurobiology of Disease

Volumn 48, Issue 2, 2012, Pages 153-178

  Bartus, Raymond T ^a  

^a Ceregene Inc   (United States)

Author keywords

AAV; CERE 120; Gene therapy; Gene transfer; Neurotrophic factor; Neurturin; Parkinson's disease; Proof of concept; Therapeutic development; Translational research

Indexed keywords

ADENOSINE RECEPTOR STIMULATING AGENT; ADRENALIN; AK 26; BICIFADINE; CALPASTATIN; CENTRAL NERVOUS SYSTEM AGENTS; CERE 110; CERE 120; CHOLINESTERASE INHIBITOR; CI 275838; DIAZEPAM; EXENDIN 4; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; HEXACOSANOL; IBUPROFEN; INDIPLON; LEVODOPA; LOBRADIMIL; NALTREXONE; NERVE GROWTH FACTOR; NEUROTROPHIC FACTOR; NEURTURIN; OCINAPLON; PARVOVIRUS VECTOR; PRAMIRACETAM; RISPERIDONE; TRIPTAN DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZALEPLON; ZOLPIDEM;

ACUTE DISEASE; ALCOHOLISM; ALZHEIMER DISEASE; ANAPHYLAXIS; ANXIETY DISORDER; BIOTECHNOLOGY; BIPOLAR DISORDER; BLOOD BRAIN BARRIER; BRAIN DEGENERATION; BREAKTHROUGH PAIN; CENTRAL NERVOUS SYSTEM DISEASE; CHRONIC DISEASE; CHRONIC PAIN; CONCEPTUAL FRAMEWORK; DEGENERATIVE DISEASE; DEPRESSION; DIABETES MELLITUS; DOSE RESPONSE; DRUG ACTIVITY; DRUG DESIGN; DRUG EFFICACY; DRUG INDUSTRY; DRUG MEGADOSE; DRUG RESEARCH; DRUG SAFETY; DRUG TARGETING; DRUG TRANSPORT; EPILEPSY; GENE PRODUCT; GENE TRANSFER; GLIOMA; HUMAN; INSOMNIA; KINETICS; LIVER TOXICITY; MIGRAINE; MILD COGNITIVE IMPAIRMENT; MOTOR PERFORMANCE; NERVE CELL DEGENERATION; NONHUMAN; OPIATE ADDICTION; PARKINSON DISEASE; PILOT STUDY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SECRETION; PROTEIN TRANSPORT; QUALITY OF LIFE; REVIEW; SCHIZOPHRENIA; SCORING SYSTEM; SHAM PROCEDURE; STROKE; SUBSTANTIA NIGRA; TIGHT JUNCTION; UNIFIED PARKINSON DISEASE RATING SCALE; UNSPECIFIED SIDE EFFECT;

ANIMALS; BIOTECHNOLOGY; DRUG DELIVERY SYSTEMS; DRUG INDUSTRY; GENETIC THERAPY; GENETIC VECTORS; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; NERVE GROWTH FACTORS; NERVOUS SYSTEM DISEASES; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84865537699     PISSN: 09699961     EISSN: 1095953X     Source Type: Journal    
DOI: 10.1016/j.nbd.2012.04.004     Document Type: Review

References (115)

1. Aebischer P., et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat. Med. 1996, 2:696-699.
2. Apfel S.C. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?. Int. Rev. Neurobiol. 2002, 50:393-413.
3. Apfel S.C., et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. Neurology 1998, 51:695-702. NGF Study Group.
4. Apfel S.C., et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. JAMA 2000, 284:2215-2221. rhNGF Clinical Investigator Group.
5. Apkarian A.V., et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J. Neurosci. 2004, 24:10410-10415.
6. Azmitia E.C., et al. Use of tissue culture models to study neuronal regulatory trophic and toxic factors in the aged brain. Neurobiol. Aging 1988, 9:743-758.
7. Backman C., et al. Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy. J. Neurosci. 1996, 16:5437-5442.
8. Backman C., et al. Carrier mediated delivery of NGF: alterations in basal forebrain neurons in aged rats revealed using antibodies against low and high affinity NGF receptors. J. Comp. Neurol. 1997, 387:1-11.
9. Bankiewicz K.S., et al. Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol. Ther. 2006, 14:564-570.
10. Bartus R.T. The need for common perspectives in the development and use of animal models for age-related cognitive and neurodegenerative disorders. Neurobiol. Aging. 1988, 9:445-451.
11. Bartus R.T. Neurotrophic factors: can the degenerating brain be induced to heal itself?. Neurobiol. Aging. 1989, 10:513.
12. Bartus R.T. Drug delivery to the brain: the problem lurking behind the problem?. Neurobiol. Aging. 1989, 10:621.
13. Bartus R.T. The Calpain hypothesis of neurodegeneration: evidence for a common cytotoxic pathway. Neuroscientist 1997, 314-327.
14. Bartus R.T. The blood-brain barrier as a target for pharmacological modulation. Curr. Opin. Drug Discov. Devel. 1999, 2:152-167.
15. Bartus R.T. On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp. Neurol. 2000, 163:495-529.
16. Bartus R.T., Dean R.L. Pharmaceutical treatment for cognitive deficits in Alzheimer's disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps. Psychopharmacology (Berl) 2009, 202:15-36.
17. Bartus R.T., et al. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982, 217:408-414.
18. Bartus R.T., et al. Behavioral and pharmacological studies using animal models of aging: implications for studying and treating dementia of Alzheimer's type. Banbury Report 1515: Biological Aspects of Alzheimer's Disease 1983, 207-218. Cold Spring Harbor Laboratory.
19. Bartus R.T., et al. Dissociation of p75 receptors and nerve growth factor neurotrophic effects: lack of p75 immunoreactivity in striatum following physical trauma, excitotoxicity and NGF administration. Restor. Neurol. Neurosci. 1996, 10:49-59.
20. Bartus R.T., et al. Permeability of the blood brain barrier by the bradykinin agonist, RMP-7: evidence for a sensitive, auto-regulated, receptor-mediated system. Immunopharmacology 1996, 33:270-278.
21. Bartus R.T., et al. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7. Exp. Neurol. 1996, 142:14-28.
22. Bartus R.T., et al. Sustained delivery of proteins for novel therapeutic agents. Science 1998, 281:1161-1162.
23. Bartus R., et al. Use of Cereport (RMP-7) to increase delivery of carboplatin to gliomas: insight and parameters for intracarotid infusion via a single-lumen cannula. Drug Del. 1999, 6:15-21.
24. Bartus R.T., et al. Evidence that Cereport's ability to increase permeability of rat gliomas is dependent upon extent of tumor growth: implications for treating newly emerging tumor colonies. Exp. Neurol. 2000, 161:234-244.
25. Bartus R.T., et al. Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1month in rats. Neuropsychopharmacology 2003, 28:1973-1982.
26. Bartus R.T., et al. A pulmonary formulation of l-dopa enhances its effectiveness in a rat model of Parkinson's disease. J. Pharmacol. Exp. Ther. 2004, 310:828-835.
27. Bartus R.T., et al. Issues regarding gene therapy products for Parkinson's disease: the development of CERE-120 (AAV-NTN) as one reference point. Parkinsonism Relat. Disord. 2007, 13(Suppl. 3):S469-S477.
28. Bartus R.T., et al. Properly scaled and targeted AAV-NRTN (neurturin) to the substantia nigra is safe, effective and causes no weight loss: support for nigral targeting in Parkinson's disease. Neurobiol. Dis. 2011, 44:38-52.
29. Bartus R.T., et al. Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains. Mov. Disord. 2011, 26:27-36.
30. Benabid A.L. Reflection and reaction: gene therapy for Parkinson's disease: do we have the cure?. Lancet Neurol. 2010, 9:1142-1143.
31. Bensadoun J.C., et al. Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF. Exp. Neurol. 2000, 164:15-24.
32. Bjorklund A., et al. Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res. 2000, 886:82-98.
33. Bohn M.C. A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy. Biochem. Pharmacol. 1999, 57:135-142.
34. Borg J., et al. Peripheral administration of a long-chain fatty alcohol promotes septal cholinergic neurons survival after fimbria-fornix transection. Brain Res. 1990, 518:295-298.
35. Braak H., et al. Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Neurosci. Lett. 1999, 265:67-69.
36. Calcedo R., et al. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 2009, 199:381-390.
37. Charles V., et al. Atrophy of cholinergic basal forebrain neurons following excitotoxic cortical lesions is reversed by intravenous administration of an NGF conjugate. Brain Res. 1996, 728:193-203.
38. Choi-Lundberg D.L., et al. Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor. Exp. Neurol. 1998, 154:261-275.
39. Day-Lollini P.A., et al. Hyperplastic changes within the leptomeninges of the rat and monkey in response to chronic intracerebroventricular infusion of nerve growth factor. Exp. Neurol. 1997, 145:24-37.
40. De Vos K.J., et al. Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 2008, 31:151-173.
41. Deuschl G., et al. Deep brain stimulation: postoperative issues. Mov. Disord. 2006, 21(Suppl. 14):S219-S237.
42. Elliott P.J., et al. Intravenous RMP-7 selectively increases uptake of carboplatin into rat brain tumors. Cancer Res. 1996, 56:3998-4005.
43. Emerich D.F., et al. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin. Pharmacokinet. 2001, 40:105-123.
44. Eriksdotter Jonhagen M., et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 1998, 9:246-257.
45. Fischer W., et al. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 1987, 329:65-68.
46. Friden P.M., et al. Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 1993, 259:373-377.
47. Gash D.M., et al. Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys. J. Comp. Neurol. 1995, 363:345-358.
48. Gash D.M., et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 1996, 380:252-255.
49. Gasmi, M., et al., 2012. Needle assembly for use in delivering precise dosages of proteinaceous pharmaceutical compositions and methods for use of same. US Patent # 8092429 B2 Jan 10, 2012.
50. Gasmi M., et al. AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: long-term efficacy and tolerability of CERE-120 for Parkinson's disease. Neurobiol. Dis. 2007, 27:67-76.
51. Gasmi M., 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, 15:62-68.
52. Georgievska B., et al. Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system. J. Neurosci. 2004, 24:6437-6445.
53. Gill S.S., et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 2003, 9:589-595.
54. Hadaczek P., et al. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol. Ther. 2010, 18:1458-1461.
55. Hefti F., et al. Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol. Aging. 1989, 10:515-533.
56. Herzog C.D., et al. Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys. Mov. Disord. 2007, 22:1124-1132.
57. Herzog C.D., et al. Transgene expression, bioactivity, and safety of CERE-120 (AAV2-neurturin) following delivery to the monkey striatum. Mol. Ther. 2008, 16:1737-1744.
58. Herzog C.D., et al. Expression, bioactivity, and safety 1year after adeno-associated viral vector type 2-mediated delivery of neurturin to the monkey nigrostriatal system support CERE-120 for Parkinson's disease. Neurosurgery 2009, 64:602-612.
59. Herzog C.D., et al. Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically-active neurotrophic factor proteins for neurodegenerative diseases. Drug Deliv. Transl. Res. 2011, 1:361-382.
60. Hoffer B., et al. Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo. Neurosci. Lett. 1994, 182:107-111.
61. Hovland D.N., et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys). Toxicol. Pathol. 2007, 35:676-692.
62. Huang E.J., Reichardt L.F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 2001, 24:677-736.
63. Inamura T., et al. Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors. J. Neurosurg. 1994, 81:752-758.
64. Jacobson K.A., et al. Synthesis and biological activity of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine: water-soluble and peripherally selective adenosine agonists. J. Med. Chem. 1992, 35:4143-4149.
65. Jeste D.V., Lohr J.B. Hippocampal pathologic findings in schizophrenia. A morphometric study. Arch. Gen. Psychiatry 1989, 46:1019-1024.
66. Jonhagen M.E., et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 1998, 9:246-257.
67. Kirik D., et al. Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor. Eur. J. Neurosci. 2000, 12:3871-3882.
68. Kirik D., et al. Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J. Neurosci. 2000, 20:4686-4700.
69. Kohn D.B., et al. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat. Rev. Cancer 2003, 3:477-488.
70. Kordower J.H., et al. Nerve growth factor receptor immunoreactivity in the nonhuman primate (Cebus apella): distribution, morphology, and colocalization with cholinergic enzymes. J. Comp. Neurol. 1988, 277:465-486.
71. Kordower J.H., et al. Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:9077-9080.
72. Kordower J.H., et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. Ann. Neurol. 1999, 46:419-424.
73. Kordower J.H., et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000, 290:767-773.
74. Kordower J.H., et al. Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann. Neurol. 2006, 60:706-715.
75. Kotzbauer P.T., et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Lett. Nat. 1996, 384:467-470.
76. Lang A.E., et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 2006, 59:459-466.
77. LaVail M.M., et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest. Ophthalmol. Vis. Sci. 1998, 39:592-602.
78. Lewis T.B., Standaert D.G. Parkinson's disease, primates, and gene therapy: vive la difference?. Mov. Disord. 2011, 26:2-3.
79. Li Z., et al. Peptide alpha-keto ester, alpha-keto amide, and alpha-keto acid inhibitors of calpains and other cysteine proteases. J. Med. Chem. 1993, 36:3472-3480.
80. Maillard M.C., et al. Adenosine receptor prodrugs: synthesis and biological activity of derivatives of potent, A1-selective agonists. J. Pharm. Sci. 1994, 83:46-53.
81. Manfredsson F.P., et al. Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector. Mol. Ther. 2009, 17:1857-1867.
82. Manfredsson F.P., et al. Nigrostriatal rAAV-mediated GDNF overexpression induces robust weight loss in a rat model of age-related obesity. Mol. Ther. 2009, 17:980-991.
83. Marks W.J., et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol. 2008, 7:400-408.
84. Marks W.J., et al. Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2010, 9:1164-1172.
85. McCown T.J. Adeno-associated virus (AAV) vectors in the CNS. Curr. Gene Ther. 2011, 11:181-188.
86. McGrath J., et al. Adeno-associated viral delivery of GDNF promotes recovery of dopaminergic phenotype following a unilateral 6-hydroxydopamine lesion. Cell Transplant. 2002, 11:215-227.
87. McMahon S.B. NGF as a mediator of inflammatory pain. Philos. Trans. R. Soc. Lond. B, Biol. Sci. 1996, 351:431-440.
88. Miller R.G., et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. Ann. Neurol. 1996, 39:256-260. rhCNTF ALS Study Group.
89. Morfini G.A., et al. Axonal transport defects in neurodegenerative diseases. J. Neurosci. 2009, 29:12776-12786.
90. Morrison P.F., et al. Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J. Neurosurg. 2007, 107:74-83.
91. Mufson E.J., et al. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog. Neurobiol. 1999, 57:451-484.
92. Nauta H.J., et al. Intraventricular infusion of nerve growth factor as the cause of sympathetic fiber sprouting in sensory ganglia. J. Neurosurg. 1999, 91:447-453.
93. Nutt J.G., et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003, 60:69-73.
94. Overstreet D.H., et al. Crews FT. Suppression of alcohol intake by chronic Naloxone treatment in P rats: tolerance development and elevation of opiate receptor binding. Alcohol. Clin. Exp. Res. 1999, 23(11):1761-1771.
95. Pardridge W.M., et al. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J. Pharmacol. Exp. Ther. 1991, 259:66-70.
96. Penn R.D., et al. Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial). Neurosurgery 1997, 40:94-99. discussion 99-100.
97. Pezet S., McMahon S.B. Neurotrophins: mediators and modulators of pain. Annu. Rev. Neurosci. 2006, 29:507-538.
98. Raff M.C., et al. Axonal self-destruction and neurodegeneration. Science 2002, 296:868-871.
99. Raper S.E., et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 2003, 80:148-158.
100. Rosenblad C., et al. Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system. Eur. J. Neurosci. 2003, 17:260-270.
101. Roy S., et al. Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 2005, 109:5-13.
102. Salvatore M.F., et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp. Neurol. 2006, 202:497-505.
103. Salzberg-Brenhouse H.C., et al. Inhibitors of cyclooxygenase-2, but not cyclooxygenase-1 provide structural and functional protection against quinolinic-acid induced neurodegeneration. J. Pharmacol. Exp. Ther. 2003, 306(1):218-228.
104. Saporito M.S., et al. Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases. Prog. Med. Chem. 2002, 40:23-62.
105. Seiger A., et al. Intracranial infusion of purified nerve growth factor to an Alzheimer patient: the first attempt of a possible future treatment strategy. Behav. Brain Res. 1993, 57:255-261.
106. Sheline Y.I., et al. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 1999, 19:5034-5043.
107. Sherer T.B., et al. Crossroads in GDNF therapy for Parkinson's disease. Mov. Disord. 2006, 21:136-141.
108. Slevin J.T., et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J. Neurosurg. 2005, 102:216-222.
109. Snider W.D., Johnson E.M. Neurotrophic molecules. Ann. Neurol. 1989, 26:489-506.
110. Sofroniew M.V., et al. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 2001, 24:1217-1281.
111. Su X., et al. Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum. Gene Ther. 2009, 20:1627-1640.
112. Tuszynski M.H., et al. Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther. 1996, 3:305-314.
113. Tuszynski M.H., et al. A phase I clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 2005, 1-5.
114. Wang L.H., Johnson E.M. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology 2008, 71:462. author reply 462-3.
115. Wellmer A., et al. A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J. Peripher. Nerv. Syst. 2001, 6:204-210.