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Targeting adipose tissue via systemic gene therapy

Gene Therapy volume 21, pages 653–661 (2014)Cite this article

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Abstract

Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

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Acknowledgements

We thank the University of Pennsylvania Vector Core for providing the vectors and conducting the biodistribution analyses. This work was supported by research awards from the National Institutes of Health (NIH) to the University of Pennsylvania including R01-DK-090505 (to Muredach Reilly), a NIDDK Diabetes and Endocrine Research Center award (P20-DK 019525) and a NIDDK Molecular Therapy P30 Center Grant (P30-DK-047757). Sean O’Neill received support from a NRSA grant 5-T32-HL07748 funded by the National Heart, Lung and Blood Institute. We acknowledge the Diabetes Research Center Mouse Phenotyping Core for their work supported by P30-DK19525. Muredach Reilly is supported also by R01-HL-113147, R01-HL-111694, U01-HL108636 and K24-HL107643 from the NIH.

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Authors and Affiliations

  1. Cardiovascular Institute, Translational Research Center, University of Pennsylvania, Philadelphia, PA, USA,

    S M O'Neill, C Hinkle, S Stephan & M P Reilly

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Gene Therapy Program, Philadelphia, PA, USA,

    S-J Chen, A Sandhu, R Hovhannisyan & J C Johnston

  3. Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA,

    W R Lagor

  4. Division of Endocrinology, Department of Medicine, University of Pennsylvania, Diabetes and Metabolism, Philadelphia, PA, USA,

    R S Ahima

  5. The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    R S Ahima

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  1. S M O'Neill
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Correspondence to M P Reilly.

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O'Neill, S., Hinkle, C., Chen, SJ. et al. Targeting adipose tissue via systemic gene therapy. Gene Ther 21, 653–661 (2014). https://doi.org/10.1038/gt.2014.38

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