Next Article in Journal
The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes
Next Article in Special Issue
Alpha-1-Antitrypsin Ameliorates Pristane Induced Diffuse Alveolar Hemorrhage in Mice
Previous Article in Journal
Factors Enhancing Serum Syndecan-1 Concentrations: A Large-Scale Comprehensive Medical Examination
Previous Article in Special Issue
Peptide Antagonists for P-selectin Discriminate between Sulfatide-Dependent Platelet Aggregation and PSGL-1-Mediated Cell Adhesion
Open AccessArticle

Regulated hAAT Expression from a Novel rAAV Vector and Its Application in the Prevention of Type 1 Diabetes

1
College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
2
Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA
3
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
*
Author to whom correspondence should be addressed.
H.M. and Y.L. contributed equally.
J. Clin. Med. 2019, 8(9), 1321; https://doi.org/10.3390/jcm8091321
Received: 19 July 2019 / Revised: 14 August 2019 / Accepted: 20 August 2019 / Published: 28 August 2019
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. View Full-Text
Keywords: serine proteinase inhibitor (SERPIN); alpha 1 antitrypsin (AAT); autoimmune disease; type 1 diabetes (T1D); gene therapy; recombinant adeno-associated virus (rAAV); tet-on promoter serine proteinase inhibitor (SERPIN); alpha 1 antitrypsin (AAT); autoimmune disease; type 1 diabetes (T1D); gene therapy; recombinant adeno-associated virus (rAAV); tet-on promoter
Show Figures

Figure 1

MDPI and ACS Style

Ma, H.; Lu, Y.; Lowe, K.; van der Meijden-Erkelens, L.; Wasserfall, C.; Atkinson, M.A.; Song, S. Regulated hAAT Expression from a Novel rAAV Vector and Its Application in the Prevention of Type 1 Diabetes. J. Clin. Med. 2019, 8, 1321.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop