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Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy

Gene Therapy volume 17, pages 1411–1420 (2010)Cite this article

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Abstract

This study uses a novel approach to gene therapy in which plasmid DNA is targeted to the pancreas in vivo using ultrasound-targeted microbubble destruction (UTMD) to achieve islet regeneration. Intravenous microbubbles carrying plasmids are destroyed within the pancreatic microcirculation by ultrasound, achieving local gene expression that is further targeted to β-cells by a modified rat insulin promoter (RIP3.1). A series of genes implicated in endocrine development were delivered to rats 2 days after streptozotocin-induced diabetes. The genes, PAX4, Nkx2.2, Nkx6.1, Ngn3 and Mafa, produced α-cell hyperplasia, but no significant improvement in β-cell mass or blood glucose level 30 days after UTMD. In contrast, RIP3.1-NeuroD1 promoted islet regeneration from surviving β-cells, with normalization of glucose, insulin and C-peptide levels at 30 days. In a longer-term experiment, four of six rats had a return of diabetes at 90 days, accompanied by β-cell apoptosis on Tunel staining. Pretreatment with the JNK inhibitor SP600125 successfully blocked β-cell apoptosis and resulted in restoration of β-cell mass and normalization of blood glucose level for up to 90 days. This technique allows in vivo islet regeneration, restoration of β-cell mass and normalization of blood sugar, insulin and C-peptide in rats without viruses.

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Acknowledgements

This work was supported by the Mark and Mary Alice Shepherd endowment of the Baylor Foundation, and by NIDDK grant P02 DK58398 (Newgard, PI).

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Authors and Affiliations

  1. Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA

    S Chen, M Shimoda, J Ding, H Noguchi, S Matsumoto & P A Grayburn

  2. Baylor Research Institute, Islet Cell Laboratory, Fort Worth, Dallas, TX, USA

    M Shimoda, H Noguchi & S Matsumoto

  3. Department of Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX, USA

    M-Y Wang

  4. Department of Internal Medicine, Baylor Heart and Vascular institute, Baylor University Medical Center, Dallas, TX, USA

    P A Grayburn

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  1. S Chen
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  2. M Shimoda
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  4. J Ding
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  5. H Noguchi
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  6. S Matsumoto
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  7. P A Grayburn
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Correspondence to P A Grayburn.

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Chen, S., Shimoda, M., Wang, MY. et al. Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Ther 17, 1411–1420 (2010). https://doi.org/10.1038/gt.2010.85

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