Non-viral systemic delivery of Fas siRNA suppresses cyclophosphamide-induced diabetes in NOD mice

• Published in: Journal of controlled release 2010-04, Vol.143 (1), p.88-94
• Main Authors: Jeong, Ji Hoon, Kim, Sun Hwa, Lee, Minhyung, Kim, Won Jong, Park, Tae Gwan, Ko, Kyung Soo, Kim, Sung Wan
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apoptosis; Biological and medical sciences; Blood Glucose - metabolism; Cell Line, Tumor; Cyclophosphamide; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - prevention & control; Disease Models, Animal; Fas; fas Receptor - genetics; fas Receptor - metabolism; Gene delivery; General pharmacology; Genetic Therapy - methods; Injections, Intravenous; Insulin - metabolism; Insulinoma - genetics; Insulinoma - metabolism; Insulinoma - pathology; Islets of Langerhans - metabolism; Medical sciences; Mice; Mice, Inbred NOD; Non-viral vector; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethyleneimine - chemistry; RNA Interference; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - metabolism; siRNA; Time Factors; Transfection; Type-1 diabetes
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2009.12.005

A membrane receptor, Fas (CD95), and its ligand FasL have been considered as key players in diabetes pathogenesis. They are known to mediate interactions between β cells and cytotoxic T cells, which results in apoptotic cell death. We hypothesized that the interruption of Fas–FasL interactions by suppressing Fas expression in β cells would affect the development of diabetes. The effect of Fas-silencing siRNA (Fas siRNA) on diabetes development was evaluated in a cyclophosphamide (CY)-accelerated diabetes animal model after intravenous administration using a polymeric carrier, polyethylenimine (PEI). The systemic non-viral delivery of Fas siRNA showed significant delay in diabetes incidence up to 40 days, while the control mice treated with naked Fas siRNA, scrambled dsRNA, or PBS were afflicted with diabetes within 20 days. The retardation of diabetes incidence after the treatment of Fas siRNA may be due to the delayed progression of the pancreatic insulitis. In this study, the potential use of a non-viral carrier based siRNA gene therapy for the prevention of type-1 diabetes is demonstrated. Polyethylenimine(PEI)-mediated delivery of Fas siRNA protects NOD mice from cyclophosphamide-induced insulitis and diabetes. [Display omitted]