The increase of the elderly population in the urban areas of Argentina is comparable to that of many North American and European cities. Consequently, the incidence of age-related neurological pathologies is becoming a problem of significant medical and economic impact for the country. In this context, the overall goal of the present proposal is to establish a long-term collaboration between the American and Argentine applicants, who share an interest in the potential of gene therapy for the treatment of neurodegenerative diseases. Three specific objectives are proposed: 1) To assess the performance of self-regulating adeno associated viral (AAV) vectors in the brain of old rats. These vectors harbor a reporter gene encoding humanized green fluorescent protein (hGFP) under the control of the tet-off or tet-on promoter system which can be turned off or on, respectively by administration of tetracycline (Tet) or certain Tet derivatives. The above vectors will be stereotaxically injected in the paraventricular, periventricular and arcuate nuclei, all of which contain dopaminergic (DA) neurons of known vulnerability to aging. 2) To assess the therapeutic efficacy of a self-regulating tet-off AAV vector harboring the gene for human glial cell line-derived neurotrophic factor (hGDNF), a potent neuroprotective molecule. The vector will be stereotaxically injected in the arcuate nucleus of 24-month old rats and 6 months later, its ability to prevent the normal age-related loss of hypothalamic tuberoinfundibular DA (TIDA) neurons will be assessed by quantitative immuno-histochemistry for DA neurons and ELISA for hGDNF. Serum PRL levels (an index of TIDA neuron function) will be monitored in the animals throughout the experiment. 3) To construct two self-regulating adenoviral vectors (RAd) harboring suicide genes under the control of the tet-off system. One of the RAds will harbor a hybrid suicide gene coding for a fusion protein between hGFP and HSV1 thymidine kinase (HSV1-TK), which retains fluorescence and HSV1-TK suicide activity. The other RAd will harbor the separate genes for HSV1-TK and hGFP under the control of a bi-directional Tet-off regulatory element. These two vectors, which are expected to be safer than non-regulatable counterparts, will be employed to treat experimental rat prolactinomas. Further to the above specific objectives, contacts with basic and clinical neuroscientists are planned in the US and Argentina in order to assemble a follow up research program focused on senile brain disorders.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21TW006665-02S1
Application #
7122720
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Michels, Kathleen M
Project Start
2004-03-01
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$40,800
Indirect Cost
Name
National University of LA Plata
Department
Type
DUNS #
978307978
City
La Plata
State
Country
Argentina
Zip Code
1900
Reggiani, Paula C; Morel, Gustavo R; Cónsole, Gloria M et al. (2009) The thymus-neuroendocrine axis: physiology, molecular biology, and therapeutic potential of the thymic peptide thymulin. Ann N Y Acad Sci 1153:98-106
Sanchez, H L; Silva, L B; Portiansky, E L et al. (2008) Dopaminergic mesencephalic systems and behavioral performance in very old rats. Neuroscience 154:1598-606
Morel, Gustavo R; Reggiani, Paula C; Console, Gloria M et al. (2008) Potential of gene therapy for restoration of endocrine thymic function in thymus-deficient animal models. Curr Gene Ther 8:49-53
Herenu, C B; Cristina, C; Rimoldi, O J et al. (2007) Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction. Gene Ther 14:237-45
Goya, Rodolfo G; Reggiani, Paula C; Vesenbeckh, Silvan M et al. (2007) Thymulin gene therapy prevents the reduction in circulating gonadotropins induced by thymulin deficiency in mice. Am J Physiol Endocrinol Metab 293:E182-7
Bellini, Maria J; Carino, Monica H; Tacconi-Gomez Dumm, Nelva et al. (2007) Fatty acid profiles in hepatic membranes of rats with different levels of circulating estrogen and prolactin. Comp Biochem Physiol A Mol Integr Physiol 146:470-4
Reggiani, P C; Herenu, C B; Rimoldi, O J et al. (2006) Gene therapy for long-term restoration of circulating thymulin in thymectomized mice and rats. Gene Ther 13:1214-21
Portiansky, Enrique Leo; Barbeito, Claudio Gustavo; Gimeno, Eduardo Juan et al. (2006) Loss of NeuN immunoreactivity in rat spinal cord neurons during aging. Exp Neurol 202:519-21
Morel, Gustavo R; Brown, Oscar A; Reggiani, Paula C et al. (2006) Peripheral and mesencephalic transfer of a synthetic gene for the thymic peptide thymulin. Brain Res Bull 69:647-51
Herenu, Claudia B; Brown, Oscar A; Sosa, Yolanda E et al. (2006) The neuroendocrine system as a model to evaluate experimental gene therapy. Curr Gene Ther 6:125-9

Showing the most recent 10 out of 13 publications