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

S Chen, M Shimoda, MY Wang, J Ding, H Noguchi… - Gene therapy, 2010 - nature.com
S Chen, M Shimoda, MY Wang, J Ding, H Noguchi, S Matsumoto, PA Grayburn
Gene therapy, 2010nature.com
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 …
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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