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Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice

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Abstract

Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic β 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.

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Acknowledgements

This study was supported by the grants from the NIH (DK58327, HL59412, RR00082, DK62652), the Juvenile Diabetes Research Foundation, the Alpha 1 Foundation and the Children's Miracle Network.

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Authors and Affiliations

  1. Department of Pharmaceutics, University of Florida, Gainesville, FL, USA

    S Song

  2. Department of Pathology, University of Florida, Gainesville, FL, USA

    K Goudy, M Campbell-Thompson, C Wasserfall, M Scott-Jorgensen, JM Crawford, TM Ellis & MA Atkinson

  3. Department of Pediatrics, University of Florida, Gainesville, FL, USA

    J Wang, Q Tang & TR Flotte

  4. Powell Gene Therapy Center, University of Florida, Gainesville, FL, USA

    S Song & TR Flotte

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  1. S Song
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  2. K Goudy
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  3. M Campbell-Thompson
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  4. C Wasserfall
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  5. M Scott-Jorgensen
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  6. J Wang
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  7. Q Tang
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  8. JM Crawford
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  9. TM Ellis
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  10. MA Atkinson
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  11. TR Flotte
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Song, S., Goudy, K., Campbell-Thompson, M. et al. Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice. Gene Ther 11, 181–186 (2004). https://doi.org/10.1038/sj.gt.3302156

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  • DOI: https://doi.org/10.1038/sj.gt.3302156

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