Delivery of GDNF by an E1,E3 E4 deleted adenoviral vector and driven by a GFAP promoter prevents dopaminergic neuron degeneration in a rat model of Parkinson's disease

• Published in: Gene therapy Vol. 11; no. 9; pp. 746 - 756
• Main Authors: DO THI, N. A, SAILLOUR, P, FERRERO, L, DEDIEU, I. F, MALLET, J, PAUNIO, T
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.05.2004
• Subjects: Adenoviridae - genetics; Adenovirus; Adenovirus Early Proteins - genetics; Adenoviruses; Amphetamines; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Astrocytes; Behavior, Animal; Biological and medical sciences; Biotechnology; Body Weight; Care and treatment; Cell Survival; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine receptors; Female; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic aspects; Genetic Therapy - methods; Genetic Vectors - genetics; Glial Cell Line-Derived Neurotrophic Factor; Glial cells; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - genetics; Health aspects; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Injection; Medical sciences; Movement disorders; Neostriatum; Nerve Growth Factors - biosynthesis; Nerve Growth Factors - genetics; Neurodegeneration; Neurodegenerative diseases; Neurology; Neuronal-glial interactions; Neurons - pathology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson Disease - therapy; Parkinson's disease; Physiological aspects; Promoter Regions, Genetic - genetics; Protein folding; Rats; Rats, Sprague-Dawley; Rotational behavior; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; France; Animal model; Nervous system diseases; Adenoviridae; Parkinson's disease; Rat; Glial fibrillary acidic protein; Rodentia; Parkinson disease; DA neurons; Cerebral disorder; Virus; Vertebrata; Mammalia; GDNF; Central nervous system disease; Glial cell line derived neurotrophic factor; Dopaminergic neuron; recombinant adenovirus; Degenerative disease; Degeneration; Gene therapy; Vector; Extrapyramidal syndrome
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302222

A new adenoviral vector (Ad-GFAP-GDNF) (Ad=adenovirus, GFAP=glial fibrillary acidic protein, GDNF=glial cell line-derived neurotrophic factor) was constructed in which (i) the E1,E3/E4 regions of Ad5 were deleted and (ii) the GDNF transgene is driven by the GFAP promoter. We verified, in vitro, that the recombinant GDNF was expressed in primary cultures of astrocytes. In vivo, the Ad-GFAP-GDNF was injected into the striatum of rats 1 week before provoking striatal 6-OHDA lesion. After 1 month, the striatal GDNF levels were 37 pg/microg total protein. This quantity was at least 120-fold higher than in nontransduced striatum or after injection of the empty adenoviral vector. At 3 months after viral injection, GDNF expression decreased, whereas the viral DNA remained unchanged. Furthermore, around 70% of the dopaminergic (DA) neurons were protected from degeneration up to 3 months as compared to about 45% in the control groups. In addition, the amphetamine-induced rotational behavior was decreased. The results obtained in this study on DA neuron protection and rotational behavior are similar to those previously reported using vectors with viral promoters. In addition to these results, we established that a high level of GDNF was present in the striatum and that the period of GDNF expression was prolonged after injection of our adenoviral vector.