We, and others, have previously achieved high and sustained levels of transgene expression\nfrom viral vectors, such as recombinant adeno-associated virus (rAAV). However, regulatable\ntransgene expression may be preferred in gene therapy for diseases, such as type 1 diabetes (T1D) and\nrheumatoid arthritis (RA), in which the timing and dosing of the therapeutic gene product play critical\nroles. In the present study, we generated a positive feedback regulation system for human alpha 1\nantitrypsin (hAAT) expression in the rAAV vector. We performed quantitative kinetics studies in vitro\nand in vivo demonstrating that this vector system can mediate high levels of inducible transgene\nexpression. Transgene induction could be tailored to occur rapidly or gradually, depending on the\ndose of the inducing drug, doxycycline (Dox). Conversely, after withdrawal of Dox, the silencing of\ntransgene expression occurred slowly over the course of several weeks. Importantly, rAAV delivery\nof inducible hAAT significantly prevented T1D development in non-obese diabetic (NOD) mice.\nThese results indicate that this Dox-inducible vector system may facilitate the fine-tuning of transgene\nexpression, particularly for hAAT treatment of human autoimmune diseases, including T1D.
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