Targeting Visceral Fat by Intraperitoneal Delivery of Novel AAV Serotype Vector Restricting Off-Target Transduction in Liver

• Published in: Molecular therapy. Methods & clinical development Vol. 6; no. C; pp. 68 - 78
• Main Authors: Huang, Wei, Liu, Xianglan, Queen, Nicholas J, Cao, Lei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 15.09.2017; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV; Adipose tissue; Animal models; Body composition; Body fat; Deoxyribonucleic acid; DNA; Experiments; Gene therapy; Gene transfer; Homeostasis; Insulin; Leptin; leptin deficiency; Liver; liver restricting; Metabolic syndrome; metabolic syndromes; MicroRNAs; miRNA; Obesity; Original; Plasmids; Software; Vectors (Biology); visceral fat; gene transfer; AAV; metabolic syndromes; leptin deficiency; visceral fat; liver restricting; obesity
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2017.06.002

It is challenging to genetically manipulate fat in adults. We demonstrate that intraperitoneal (i.p.) injection of an engineered adeno-associated virus (AAV) serotype Rec2 leads to high transduction of multiple visceral fat depots at a dose of 1 to 2 orders lower than commonly used doses for systemic gene delivery. To target adipose tissue, we develop a single AAV vector harboring two expression cassettes: one using the CBA promoter to drive transgene expression and one using the liver-specific albumin promoter to drive a microRNA-targeting WPRE sequence that only exists in this AAV vector. This dual-cassette vector achieves highly selective transduction of visceral fat while severely restricting off-target transduction of liver. As proof of efficacy, i.p. administration of an adipose-targeting Rec2 vector harboring the leptin gene corrects leptin deficiency, obesity, and metabolic syndromes of / mice. This study provides a powerful tool to genetically manipulate fat for basic research and gene therapies of genetic and acquired diseases.