This project will study the hypothesis that human neural stem cells (hNSCs) implanted into monkeys can normalize parkinsonism resulting from the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). These primordial, uncommitted, pluripotent cells can be propagated in large numbers and then safely differentiated into most cell types of the nervous system, including dopamine-producing neurons. NSCs migrate to populate developing or degenerating brain regions, perhaps allowing a more functionally correct and effective reconstruction. Pilot studies now show engraftment of hNSCs in the brain of fetal, neonatal, infant, and adult monkeys, for at least a month. Dopamine depleted adult monkeys showed graft-derived tyrosine hydroxylase positive cells and appropriate migration from the site of injection to dopamine-depleted areas. This project will test hypotheses in monkeys: (1) that hNSCs will survive, differentiate, and integrate in the brain of normal adult monkeys without immunological rejection or harmful overgrowth; (2) that hNSCs will eliminate parkinsonism after MPTP treatment, and that the presence of dopamine injury will influence their distribution and fate. NSCs will be identified and quantitated using genetic markers, immunohistochemistry, and multi-synaptic tract tracing. The following will be characterized and compared in normal monkeys and monkeys after MPTP: hNSC survival, migration, cell division, differentiation, connectivity, immunogenicity, stability of expression of a transgene (LacZ), apoptosis, and effect of host environment on all of these. In the dopamine-depleted parkinsonian monkey, dopamine and its metabolite concentrations, autoradiography of dopamine transporters, behavioral reversal of parkinsonism, dose effects, and synaptic connections will be studied over time courses of 7 days, 1, 3, 6, and 12 months. Comparisons will also be made with effects of primary fetal ventral mesencephalic tissue transplants in parkinsonian monkeys from prior and parallel studies. These studies will advance our understanding of the neurobiology and safety of human neural stem cells in a well established clinically relevant primate model of Parkinson's disease, and, if successful, support safe clinical studies in patients with Parkinson's disease in the future. The results will also advance understanding of useful methods for studying and treating a broad range of neurodegenerative, genetic, and traumatic conditions of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040822-02
Application #
6620146
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
2002-04-15
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$858,703
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Redmond Jr, D Eugene; McEntire, Caleb R S; Kingsbery, Joseph P et al. (2013) Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced nonhuman primate Parkinson's model. Mol Ther 21:2160-8
Redmond Jr, D Eugene; Evans, Lawrence (2012) Determination of fetal age by ultrasonography in St. Kitts green monkeys. Am J Primatol 74:433-41
Redmond Jr, D Eugene (2012) Using monkeys to understand and cure Parkinson disease. Hastings Cent Rep Suppl:S7-S11
Bloch, Jocelyne; Kaeser, Mélanie; Sadeghi, Yalda et al. (2011) Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. J Comp Neurol 519:775-89
Morrow, B A; Roth, R H; Redmond, D E et al. (2011) Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease. Neuroscience 189:277-85
Redmond Jr, Donald Eugene; Weiss, Stephanie; Elsworth, John D et al. (2010) Cellular repair in the parkinsonian nonhuman primate brain. Rejuvenation Res 13:188-94
Elsworth, J D; Redmond Jr, D E; Leranth, C et al. (2008) AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons. Exp Neurol 211:252-8
Bjugstad, Kimberly B; Teng, Yang D; Redmond Jr, D Eugene et al. (2008) Human neural stem cells migrate along the nigrostriatal pathway in a primate model of Parkinson's disease. Exp Neurol 211:362-9
Redmond Jr, D Eugene; Bjugstad, Kimberly B; Teng, Yang D et al. (2007) Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A 104:12175-80
Frontera, Walter R; Choi, Howard; Krishnan, Gomathi et al. (2006) Single muscle fiber size and contractility after spinal cord injury in rats. Muscle Nerve 34:101-4

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