Parkinson's disease (PD) results primarily from striatal dopamine insufficiency and a secondary degeneration of dopaminergic neurons within the substantial nigra pars compacta. The cause of the dopamine (DA) decline still remains unknown. Depending on the age of onset of the disease different risk factors have been identified. Genetic risk is associated with familial cases with early onset. The spontaneous age-related decline in the number of nigral DA cells in humans and non human primates suggests that age is a risk factor for the development of late onset PD. Independent of the age of appearance, DA replacement therapy is the mainstay of therapy. But as PD progresses, drug -related side effects emerge as well as disabling symptoms that are not responsive to the treatment. Since patients with PD have a normal ]lifespan, they must endure crippling systems for many years, severely impacting their quality of life. Clearly, a therapy aimed at stopping the continual loss of DA neurons is needed in order to cease the progression of the disease. In this regard, two experimental strategies have been demonstrated to be successful in animal models of PD; namely administration of the trophic factor glial derived neurotrophic factor (GDNF2 and the administration of antiapoptotic genes such as Bc1-2. Concomitantly with the discovery of genes and proteins that can augment nigrostriatal circuitry is the need to develop ways to deliver them. Indeed, while GDNF is very potent in animal models, a clinicopathological analysis of a PD patient receiving intraventricular (ICV) GDNF found no clinical or neuroanatomical benefit. The method of GDNF delivery likely never reached the vulnerable neurons. In vivo gene therapy approaches are an exciting way to deliver genes in a site-specific manner. We have recently demonstrated that genes can be delivered to the adult monkey brain in a robust, consistent, and sustained fashion without cytotoxicity using a lentiviral vector. We have also tested lentiviral delivery of GDNF into the nigrostriatal system of normal aged rhesus and we observed that this factor is able to reverse the age-related degeneration by increasing the levels of DA and its metabolites in the target areas. The present proposal aims to test the hypothesis that lentiviral gene transfer of Bc1-2 and GDNF can prevent the structural and functional consequences of nigrostriatal degeneration in young and aged MTP-treated monkeys. These studies will serve as the preclinical foundation to determine whether this in vivo method to deliver these potent trophic factor and antiapoptotic genes will be suitable for testing in patients with PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040578-03
Application #
6540348
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Murphy, Diane
Project Start
2000-06-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$286,000
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Emborg, M E; Moirano, J; Raschke, J et al. (2009) Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF. Neurobiol Dis 36:303-11
Capitanio, John P; Emborg, Marina E (2008) Contributions of non-human primates to neuroscience research. Lancet 371:1126-35
Emborg, Marina E; Carbon, Maren; Holden, James E et al. (2007) Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J Cereb Blood Flow Metab 27:501-9
Stephenson, Diane T; Childs, Mary Abigail; Li, Qiu et al. (2007) Differential loss of presynaptic dopaminergic markers in Parkinsonian monkeys. Cell Transplant 16:229-44
Roitberg, Ben Z; Mangubat, Erwin; Chen, Er-Yun et al. (2006) Survival and early differentiation of human neural stem cells transplanted in a nonhuman primate model of stroke. J Neurosurg 105:96-102
Emborg, M E; Moirano, J; Schafernak, K T et al. (2006) Basal ganglia lesions after MPTP administration in rhesus monkeys. Neurobiol Dis 23:281-9
Stephenson, Diane T; Li, Qiu; Simmons, Carol et al. (2005) Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without L-DOPA administration. Neurobiol Dis 20:347-59
Stephenson, Diane T; Meglasson, Martin D; Connell, Mark A et al. (2005) The effects of a selective dopamine D2 receptor agonist on behavioral and pathological outcome in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys. J Pharmacol Exp Ther 314:1257-66
Emborg, Marina E (2004) Evaluation of animal models of Parkinson's disease for neuroprotective strategies. J Neurosci Methods 139:121-43
Barcia, Carlos; Emborg, Marina E; Hirsch, Etienne C et al. (2004) Blood vessels and parkinsonism. Front Biosci 9:277-82

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