Abstract
We, and others, have previously achieved high and sustained levels of transgene expression from viral vectors, such as recombinant adeno-associated virus (rAAV). However, regulatable transgene expression may be preferred in gene therapy for diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis (RA), in which the timing and dosing of the therapeutic gene product play critical roles. In the present study, we generated a positive feedback regulation system for human alpha 1 antitrypsin (hAAT) expression in the rAAV vector. We performed quantitative kinetics studies in vitro and in vivo demonstrating that this vector system can mediate high levels of inducible transgene expression. Transgene induction could be tailored to occur rapidly or gradually, depending on the dose of the inducing drug, doxycycline (Dox). Conversely, after withdrawal of Dox, the silencing of transgene expression occurred slowly over the course of several weeks. Importantly, rAAV delivery of inducible hAAT significantly prevented T1D development in non-obese diabetic (NOD) mice. These results indicate that this Dox-inducible vector system may facilitate the fine-tuning of transgene expression, particularly for hAAT treatment of human autoimmune diseases, including T1D.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin-producing islet cells in the endocrine pancreas [1]
Granzymes and caspases are key players in controlling the events leading to cell apoptosis, and their inhibition by proteinase inhibitors can protect against islet cell apoptosis [14]
We found that human alpha antitrypsin (hAAT) (SERPINA1) gene therapy prevented T1D in the non-obese diabetic (NOD) mouse model [22]
Summary
Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin-producing islet cells in the endocrine pancreas [1]. Substantial evidence demonstrates that both CD4+ T helper and CD8+ T cytotoxic lymphocytes play a role in the development of the disorder [3,4,5,6,7,8]. Recent studies have shown that increases of CD4+CD25+ regulatory T cells (Tregs) can prevent autoimmune diabetes in the non-obese diabetic (NOD) mouse model of T1D [9,10,11,12]. Gene therapy with the anti-inflammatory cytokine interleukin-10 (IL-10) induces Tregs and prevents T1D in NOD mice [15,16], setting the stage for the development of other immunoregulatory therapies to prevent or reverse autoimmunity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
