Prevention of diabetes in the NOD mouse by intra-muscular injection of recombinant adeno-associated virus containing the preproinsulin II gene.
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 (i.m.) injected with 10(7) 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<200 mg/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 i.m. 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.
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism*; D017931:DNA Primers; D000229:Dependovirus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D007328:Insulin / Q000097:blood*; D008099:Liver / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009928:Organ Specificity; D010179:Pancreas / Q000473:pathology; D011384:Proinsulin / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D012016:Reference Values; D013997:Time Factors
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D011498:Protein Precursors; C013737:preproinsulin; D011384:Proinsulin