1. ¹Department of Pharmaceutics, University of Florida, Gainesville, FL, USA
2. ²Department of Pathology, University of Florida, Gainesville, FL, USA
3. ³Department of Pediatrics, University of Florida, Gainesville, FL, USA
4. ⁴Powell Gene Therapy Center, University of Florida, Gainesville, FL, USA

Correspondence: Dr S Song, Department of Pharmaceutics, 1600 SW Archer Road, Box 100494 JHMHC, University of Florida, Gainesville, FL 32610, USA

Received 25 October 2002; Accepted 5 August 2003.

Abstract

Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic cells. Although the exact immunologic processes underlying this disease are unclear, increasing evidence suggests that immunosuppressive, immunoregulatory and anti-inflammatory agents can interrupt the progression of the disease. Alpha 1 antitrypsin (AAT) is a multifunctional serine proteinase inhibitor (serpin) that also displays a wide range of anti-inflammatory properties. To test the ability of AAT to modulate the development of type I diabetes, we performed a series of investigations involving recombinant adeno-associated virus vector (rAAV)-mediated gene delivery of human alpha-1 antitrypsin (hAAT) to nonobese diabetic (NOD) mice. Recombinant AAV-expressing hAAT (rAAV2-CB-AT) was administered intramuscularly to 4-week-old female NOD mice (1 10¹⁰ i.u./mouse). A single injection of this vector reduced the intensity of insulitis, the levels of insulin autoantibodies, and the frequency of overt type I diabetes (30% (3/10) at 32 weeks of age versus 70% (7/10) in controls). Transgene expression at the injection sites was confirmed by immunostaining. Interestingly, antibodies against hAAT were present in a majority of the vector-injected mice and circulating hAAT was undetectable when assessed 10 weeks postinjection. This study suggests a potential therapeutic role for AAT in preventing type I diabetes as well as the ability of AAV gene therapy-based approaches to ameliorate disease effectively.