Targeting adipose tissue via systemic gene therapy.
Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.
Cardiovascular Institute, Translational Research Center, University of Pennsylvania, Philadelphia, PA, USA.
S M
SM
O'Neill
Cardiovascular Institute, Translational Research Center, University of Pennsylvania, Philadelphia, PA, USA.
C
C
Hinkle
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
S-J
SJ
Chen
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
A
A
Sandhu
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
R
R
Hovhannisyan
Cardiovascular Institute, Translational Research Center, University of Pennsylvania, Philadelphia, PA, USA.
S
S
Stephan
Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
W R
WR
Lagor
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
R S
RS
Ahima
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J C
JC
Johnston
Cardiovascular Institute, Translational Research Center, University of Pennsylvania, Philadelphia, PA, USA.
M P
MP
Reilly
D020413:3' Untranslated Regions; D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism* / Q000821:virology; D000818:Animals; D000229:Dependovirus / Q000145:classification* / Q000235:genetics*; D004195:Disease Models, Animal; D018390:Gene Targeting / Q000379:methods*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D020738:Leptin / Q000097:blood / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D009765:Obesity / Q000097:blood / Q000628:therapy; D009928:Organ Specificity
D020413:3' Untranslated Regions; D052242:Adiponectin; D020738:Leptin; D035683:MicroRNAs