Abstract
Using the Adeno-associated virus (AAV) as a gene delivery vehicle, we have constructed a recombinant vector containing the full length rat preproinsulin gene (vLP-1). Utilizing the well described non-obese diabetic (NOD) mouse model, an experimental group (n=10) of animals were intramuscularly (IM) injected with 107 rAAV virions containing the insulin gene and compared to a mock-injected control group (n=10). Blood glucose (glc) was then measured weekly for 16 weeks. Data showed that the experimental group contained 70% euglycemic animals (defined as glc <200mg/dL) versus 10% of the control animals (P<.05) at 14 weeks. Mean weight in the treated group was greater than the untreated group. Insulin mRNA was detected at the injection site of all of the treated animals, but not controls. Complete destruction of islets was confirmed by histology ruling out the possibility of spontaneous reversal of insulinitis. We conclude that IM delivery of the insulin gene in the NOD mouse was able to prevent clinical DM up to 14 weeks in a majority of treated animals. Our experimental data suggests that gene therapy may be an alternative treatment for IDDM in the future.
Highlights
Diabetes Mellitus (DM) in humans is the result of either lack of insulin (Type I) or insulin resistance (Type II)
The steps in the construction of recombinant recombinant adeno-associated virus (rAAV) containing the rat preproinsulin II gene gene have been described previously.I51 Briefly, the pLP-1 plasmid incorporating the gene was engineered by releasing the rI2 gene with a Rous sarcoma virus long terminal repeat (RSV-LTR) promoter from pBC I2BI
We investigated the effe4t of IM injection on rAAV containing the rI2 into 11 week old female Non-obese diabetic (NOD) mice
Summary
Diabetes Mellitus (DM) in humans is the result of either lack of insulin (Type I) or insulin resistance (Type II). The impact of DM on morbidity and mortality is considerable. Since the discovery of insulin, DM is considered a manageable disease, secondary complications of DM are considerable and lead to significant morbidity and mortality. Alternative strategies for insulin delivery and the long-term treatment for type I DM are being actively investigated. Implantable insulin pumps have been tried, but technical complications and cost are prohibitive. [1] Pancreatic islet cell transplants have had mixed results; I21 the results of whole organ pancreas transplants have improved in the last few years, the severe shortage of cadaver organs will be a limiting factor along with additional problems associated with life-long immunosuppression. The prospects of xenotransplantation of islets appears to have serious immunological, ethical and infectious problems
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