Non-viral systemic delivery of Fas siRNA suppresses cyclophosphamide-induced diabetes in NOD mice.
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 beta 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 beta 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.
Jeong
Ji Hoon
JH
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. jhjeong@skku.edu
Kim
Sun Hwa
SH
Lee
Minhyung
M
Kim
Won Jong
WJ
Park
Tae Gwan
TG
Ko
Kyung Soo
KS
Kim
Sung Wan
SW
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011094:Polyethyleneimine / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
D001786:Blood Glucose; C491899:Fas protein, mouse; D007328:Insulin; D034741:RNA, Small Interfering; D019014:fas Receptor; D003520:Cyclophosphamide; D011094:Polyethyleneimine