Development of an adipose-tropic AAV capsid ablating liver tropism

AAV vectors are mainstream delivery platforms in gene therapy, yet AAV-mediated gene transfer to adipose tissue is underdeveloped due to low efficiency of natural AAVs. We previously demonstrated that an engineered capsid Rec2 displayed improved adipo-tropism but with the caveat of liver transduction. To generate highly adipo-tropic capsid, we modified Rec2 capsid by site-specific mutagenesis and found the variant V7 with F503Y, Y708D and K709I substitution to harbor highly selective adipo-tropism while diminishing liver transduction. Intraperitoneal injection favored transduction to visceral fat while intravenous administration favored subcutaneous fat. Intraperitoneal administration of V7 vector harboring human leptin and adiponectin as single transcript normalized the metabolic dysfunction of <i>ob/ob</i> mice at a low dose. Moreover, introducing the same mutagenesis to AAV8 capsid diminished liver transduction suggesting F503, Y708 and K709 critical for liver transduction. The Rec2.V7 vector may provide a powerful tool for basic research and potent vehicle for adipose-targeting gene therapy.