Publications by authors named "Que T La"

2 Publications

  • Page 1 of 1

Use of a Hybrid Adeno-Associated Viral Vector Transposon System to Deliver the Insulin Gene to Diabetic NOD Mice.

Cells 2020 10 2;9(10). Epub 2020 Oct 2.

School of Life Sciences, University of Technology Sydney, 15 Broadway, Ultimo, NSW 2007, Australia.

Previously, we used a lentiviral vector to deliver furin-cleavable human insulin () to the livers in several animal models of diabetes using intervallic infusion in full flow occlusion (FFO), with resultant reversal of diabetes, restoration of glucose tolerance and pancreatic transdifferentiation (PT), due to the expression of beta (β)-cell transcription factors (β-TFs). The present study aimed to determine whether we could similarly reverse diabetes in the non-obese diabetic (NOD) mouse using an adeno-associated viral vector (AAV) to deliver - ± the β-TF to the livers of diabetic mice. The traditional AAV8, which provides episomal expression, and the hybrid AAV8/ that results in transgene integration were used. Diabetic mice that received AAV8- became hypoglycaemic with abnormal intraperitoneal glucose tolerance tests (IPGTTs). Expression of β-TFs was not detected in the livers. Reversal of diabetes was not achieved in mice that received AAV8--FUR and AAV8- and IPGTTs were abnormal. Normoglycaemia and glucose tolerance were achieved in mice that received AAV8/-/FFO. Definitive evidence of PT was not observed. This is the first in vivo study using the hybrid AAV8/ system to treat Type 1 diabetes (T1D). However, further development is required before the system can be used for gene therapy of T1D.
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October 2020

Partial pancreatic transdifferentiation of primary human hepatocytes in the livers of a humanised mouse model.

J Gene Med 2018 05 16;20(5):e3017. Epub 2018 Apr 16.

School of Life Sciences, University of Technology Sydney, Sydney, Australia.

Background: Gene therapy is one treatment that may ultimately cure type 1 diabetes. We have previously shown that the introduction of furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes resulted in the reversal of diabetes and partial pancreatic transdifferentiation of liver cells. The present study investigated whether streptozotocin-diabetes could be reversed in FRG mice in which chimeric mouse-human livers can readily be established and, in addition, whether pancreatic transdifferentiation occurred in the engrafted human hepatocytes.

Methods: Engraftment of human hepatocytes was confirmed by measuring human albumin levels. Following delivery of the empty vector or the INS-FUR vector to diabetic FRG mice, mice were monitored for weight and blood glucose levels. Intraperitoneal glucose tolerance tests (IPGTTs) were performed. Expression levels of pancreatic hormones and transcription factors were determined by a reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry.

Results: Diabetes was reversed for a period of 60 days (experimental endpoint) after transduction with INS-FUR. IPGTTs of the insulin-transduced animals were not significantly different from nondiabetic animals. Immunofluorescence microscopy revealed the expression of human albumin and insulin in transduced liver samples. Quantitative RT-PCR showed expression of human and mouse endocrine hormones and β-cell transcription factors, indicating partial pancreatic transdifferentiation of mouse and human hepatocytes. Nonfasting human C-peptide levels were significantly higher than mouse levels, suggesting that transdifferentiated human hepatocytes made a significant contribution to the reversal of diabetes.

Conclusions: These data show that human hepatocytes can be induced to undergo partial pancreatic transdifferentiation in vivo, indicating that the technology holds promise for the treatment of type 1 diabetes.
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May 2018