Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin.
The ob/ob mouse is genetically deficient in leptin and exhibits a phenotype that includes obesity and non-insulin-dependent diabetes mellitus. This phenotype closely resembles the morbid obesity seen in humans. In this study, we demonstrate that a single intramuscular injection of a recombinant adeno-associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob/ob mice leads to prevention of obesity and diabetes. The treated animals show normalization of metabolic abnormalities including hyperglycemia, insulin resistance, impaired glucose tolerance, and lethargy. The effects of a single injection have lasted through the 6-month course of the study. At all time points measured the circulating levels of leptin in the serum were similar to age-matched control C57 mice. These results demonstrate that maintenance of normal levels of leptin (2-5 ng/ml) in the circulation can prevent both the onset of obesity and associated non-insulin-dependent diabetes. Thus a single injection of a rAAV vector expressing a therapeutic gene can lead to complete and long-term correction of a genetic disorder. Our study demonstrates the long-term correction of a disease caused by a genetic defect and proves the feasibility of using rAAV-based vectors for the treatment of chronic disorders like obesity.
Murphy
J E
JE
Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608, USA.
Zhou
S
S
Giese
K
K
Williams
L T
LT
Escobedo
J A
JA
Dwarki
V J
VJ
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D004435:Eating; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D007273:Injections, Intramuscular; D007328:Insulin / Q000097:blood; D020738:Leptin; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D015430:Weight Gain
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D020738:Leptin; D011506:Proteins