Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson’s disease

• DOI: 10.1073/pnas.96.21.12120
• Publication Date: 2002-07-26T14:41:48Z
• Authors: Olga Corti; Amelia Sánchez-Ca...; Philippe Colin; Naïma Hanoun; Michel Hamon; Jacques Mallet
• Keywords: 0303 health sciences; Time Factors; Apomorphine; Tyrosine 3-Monooxygenase; Dopamine; Gene Transfer Techniques; Parkinson Disease; Immunohistochemistry; Corpus Striatum; Adenoviridae; Anti-Bacterial Agents; Rats; 3. Good health; Antiparkinson Agents; Rats, Sprague-Dawley; Disease Models, Animal; 03 medical and health sciences; Gene Expression Regulation; Doxycycline; Animals; Humans; Female; Oxidopamine

Developments of technologies for delivery foreign genes to the central nervous system are opening field promising treatments human neurodegenerative diseases. Gene vectors need fulfill several criteria efficacy and safety before being applied humans. The ability drive expression a therapeutic gene in an adequate number cells, maintain long-term expression, allow exogenous control over transgene product essential requirements clinical application. We describe use adenovirus vector encoding tyrosine hydroxylase (TH) 1 under negative tetracycline-sensitive regulatory direct injection into dopamine-depleted striatum rat model Parkinson’s disease. This mediated synthesis TH numerous striatal cells was observed large proportion them at least 17 weeks. Furthermore, doxycyline, tetracycline analog, allowed efficient reversible expression. Thus, insertion cassette single provides development successful safe therapies neurological Our results also confirm that future effective replacement approaches disease will have consider concomitant transfer GTP-cyclohydrolase transgenes because cofactor tetrahydrobiopterin may be crucial restoration dopaminergic deficit.