NEUROPROTECTIVE GENE THERAPY IN THE AGING BRAIN

GOYA RODOLFO G

Behesda, USA

Simposio; Brain Disorders in the Developing World; 2008

Fogarty International Center, NIH, USA

The increase of the elderly population in the urban areas of Argentina is comparable to that of  many North American cities. Consequently, the incidence of age-related neurological pathologies is becoming a problem of significant medical and economic impact for both countries. In this context, the overall goal of our past and current research is to establish a long-term collaboration between American and Argentine scientists, who share an interest in the potential of gene therapy for the treatment of age-realted neurodegenerative diseases. The specific objective of our R21 exploratory project was to determine whether the hypothalamus of the senile female rat, which constitutes a unique animal model of spontaneous dopaminergic (DA) neurodegeneration, would be suitable to implement restorative gene therapy for DA neurons. The therapeutic molecules chosen for these studies were 1) insulin-like growth factor-I (IGF-I), a peptide that had been shown to be neuroprotective in different areas of the brain but which had not been tested on DA neurons and, 2) glial cell line-derived neurotrophic factor (GDNF), a powerful protective factor for DA neurons.  The results of our R21 project were as follows: - Hypothalamic IGF-I gene therapy (implemented using adenoviral vectors constructed at the foreign site) proved to be highly effective in restoring hypothalamic DA neuron function in aging females, thus demonstrating the feasibility of implementing restorative gene therapy in this unexplored animal model of age-related DA neuron degeneration. Our IGF-I data add to the growing evidence pointing to this peptide as a neuroprotective molecule and suggest that it could possess the ability to induce DAergic neurogenesis in the aging hypothalamus.  These studies have been recently published (1). - In collaboration with Dr. Martha Bohn, we could also demonstrate (manuscript in preparation) that GDNF gene therapy is effective in the hypothalamus of senile female rats, significantly reversing the chronic hyperprolactinemia caused by DA neuron dysfunction in the hypothalamus of aging females. The objective of our recently funded R01 project is to expand our studies on the therapeutic potential of GDNF and IGF-I gene therapy to the substantia nigra and hippocampus of senile rats.   Biomedical significance of our research  The increase in life expectancy achieved by modern medicine has led to a progressive rise in the incidence of age-related neurodegenerative diseases like Alzheimer’s and Parkinson’s, with their destructive consequences on cognition and other brain functions. In this context, new biotechnological strategies like gene therapy and potent neuroprotective molecules like GDNF and IGF-I, emerge as promising therapeutic tools for the prevention and treatment of these devastating pathologies. (1) Hereñú CB, Cristina C, Rimoldi OJ, Becú-Villalobos D, Cambiaggi V, Portiansky EL, Goya RG; Restorative effect of Insulin-like Growth Factor-I gene therapy in the hypo- thalamus of senile rats with dopaminergic dysfunction; Gene Therapy; 14: 237-245 (2007).