Diabetes reversal via gene transfer: building on successes in animal models

Abstract:

Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic β-cells. People with T1D manage their hyperglycemia using daily insulin injections; however, this does not prevent the development of long-term diabetic complications such as retinopathy, nephropathy, neuropathy, and various macrovascular disorders. Currently, the only “cure” for T1D is pancreas transplantation or islet-cell transplantation; however, this is hampered by the limited number of donors and the requirement for life-long immunosuppression. As a result, the need for alternative therapies is vital. One of the strategies employed to correct T1D is the use of gene transfer to generate the production of an “artificial” β-cell that is capable of secreting insulin in response to fluctuating glucose concentrations that normally occurs in people without T1D. The treatment of many diseases using cell and gene therapy is generating significant attention in the T1D research community; however, for a cell therapy to enter clinical trials, success and safety must first be shown in an appropriate animal model. Animal models have been used in diabetes research for over a century, have improved our understanding of the pathophysiology of diabetes, and have led to the discovery of useful drugs for the treatment of the disease. Currently, the nonobese diabetic mouse is the animal model of choice for the study of T1D as it most closely reflects disease development in humans. The aim of this review is to evaluate the success of cell and gene therapy to reverse T1D in animal models for future clinical application.

Keywords::

• β-cell transcription factors
• animal models
• gene therapy
• insulin

Acknowledgments

Dario Gerace is supported by an Australian Postgraduate Award and the Arrow Bone Marrow Transplant Foundation/Hawkesbury Canoe Classic Scholarship. Research conducted by Ann M Simpson and Dario Gerace was supported by the National Health and Medical Research Council of Australia Project Grants (352909, 513100). Ann M Simpson and Rosetta Martiniello-Wilks also received grants from Diabetes Australia Research Trust and Rebecca L Cooper Medical Research Foundation. The authors would like to thank Richard Limburg for IT support.

Disclosure

Ann M Simpson is an inventor in the patent “Cells genetically modified to comprise pancreatic islet glucokinase and uses thereof”; WO 2009021276 A1, Ann M Simpson and Chang Tao, European patent: EP20080782908, Australian patent: AU 2008/001160, United States of America patent: US12/672,832. The authors declare no other conflicts of interest.