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

S. Chen, M. Shimoda, M. Y. Wang, J. Ding, H. Noguchi, S. Matsumoto, P. A. Grayburn

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1411-1420
Number of pages10
JournalGene Therapy
Volume17
Issue number11
DOIs
StatePublished - Nov 2010

Fingerprint

Islets of Langerhans
Genetic Therapy
Regeneration
Microbubbles
Blood Glucose
C-Peptide
Insulin
Plasmids
Apoptosis
Parvovirus
Experimental Diabetes Mellitus
Microcirculation
Genes
Hyperplasia
Pancreas
Staining and Labeling
Gene Expression
Glucose
DNA

Keywords

  • diabetes
  • islets transcriptional factors
  • microbubble
  • pancreatic islets
  • regeneration
  • ultrasound

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Chen, S., Shimoda, M., Wang, M. Y., Ding, J., Noguchi, H., Matsumoto, S., & Grayburn, P. A. (2010). Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Therapy, 17(11), 1411-1420. https://doi.org/10.1038/gt.2010.85

Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. / Chen, S.; Shimoda, M.; Wang, M. Y.; Ding, J.; Noguchi, H.; Matsumoto, S.; Grayburn, P. A.

In: Gene Therapy, Vol. 17, No. 11, 11.2010, p. 1411-1420.

Research output: Contribution to journalArticle

Chen, S, Shimoda, M, Wang, MY, Ding, J, Noguchi, H, Matsumoto, S & Grayburn, PA 2010, 'Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy', Gene Therapy, vol. 17, no. 11, pp. 1411-1420. https://doi.org/10.1038/gt.2010.85
Chen S, Shimoda M, Wang MY, Ding J, Noguchi H, Matsumoto S et al. Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Therapy. 2010 Nov;17(11):1411-1420. https://doi.org/10.1038/gt.2010.85
Chen, S. ; Shimoda, M. ; Wang, M. Y. ; Ding, J. ; Noguchi, H. ; Matsumoto, S. ; Grayburn, P. A. / Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. In: Gene Therapy. 2010 ; Vol. 17, No. 11. pp. 1411-1420.
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