title: Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice.
abstract: Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic beta 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 x 10(10) 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.
authors.affiliation: Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: S
authors.initials: S
authors.lastname: Song
authors.forename: K
authors.initials: K
authors.lastname: Goudy
authors.forename: M
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: C
authors.initials: C
authors.lastname: Wasserfall
authors.forename: M
authors.initials: M
authors.lastname: Scott-Jorgensen
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
authors.forename: J M
authors.initials: JM
authors.lastname: Crawford
authors.forename: T M
authors.initials: TM
authors.lastname: Ellis
authors.forename: M A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: T R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D001323:Autoantibodies / Q000097:blood; D000229:Dependovirus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007273:Injections, Intramuscular; D007328:Insulin / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D014161:Transduction, Genetic / Q000379:methods*; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000276:immunology
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D007328:Insulin; D000515:alpha 1-Antitrypsin