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Long-term, antidiabetogenic effects of GLP-1 gene therapy using a double-stranded, adeno-associated viral vector

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Abstract

Diabetes is characterized by insulin resistance and a reduction in insulin secretion, leading to progressive β-cell failure and loss of β-cell mass. Its central therapeutic issues are how to restore glucose responsiveness of β-cells to normal and counteract defects in insulin secretion. Native glucagon-like peptide-1 (GLP-1), which makes β-cells competent and diabetic β-cells specifically more sensitive to glucose, has a major drawback of rapid inactivation. In this study, we describe the construction and analysis of a GLP-1 plasmid and double-stranded, adeno-associated viral (dsAAV) expression vector to overcome both the rapid degradation of native GLP-1 and limitations of gene therapy using standard single-stranded AAV. Our study results demonstrate that fasting blood glucose levels of db/db obese mice decreased significantly up to 4 months after a single injection of dsAAV GLP-1, and both insulin and circulating GLP-1 levels increased in dsAAV GLP-1-infected mice. These results demonstrate that dsAAV GLP-1 has long-term, efficient transgene expression with minimal toxicity and cellular immune responses. This study suggests that GLP-1 produced by dsAAV may be an alternative to the continuous infusions required for GLP-1 peptide therapy or daily injections of GLP-1.

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Acknowledgements

We thank Dr Wilson who gave the vector pAdΔF6.

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  1. Department of Endocrinology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

    S H Choi & H C Lee

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  1. S H Choi
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Correspondence to H C Lee.

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Choi, S., Lee, H. Long-term, antidiabetogenic effects of GLP-1 gene therapy using a double-stranded, adeno-associated viral vector. Gene Ther 18, 155–163 (2011). https://doi.org/10.1038/gt.2010.119

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