Adipose Tissue: An Emerging Target for Adeno-associated Viral Vectors

Abstract

Adipose tissue is one of the largest organs, playing important roles in physiology and pathologies of multiple diseases. However, research related to adeno-associated virus (AAV) targeting adipose tissue has been left far behind studies carried out in the liver, brain, heart, and muscle. Despite initial reports indicating poor performance, AAV-mediated gene delivery to adipose tissue has continued to rise during the past two decades. AAV8 and a novel engineered hybrid serotype, Rec2, have been shown to transduce adipose tissue more efficiently than other serotypes so far tested and have been applied in most of the in vivo studies. The Rec2 serotype displays high efficacy of gene transfer to both brown and white fat via local and systemic administration. This review summarizes the advances in developing AAV vectors with enhanced adipose tropism and restricting off-target transgene expression. We discuss the challenges and strategies to search for and generate novel serotypes with tropism tailoring for adipose tissue and develop AAV vector systems to improve adipose transgene expression for basic research and translational studies.

ADGRG6 promotes adipogenesis and is involved in sex-specific fat distribution

“…mCherry levels were detected in all adipose tissues with the highest level in BAT and pWAT ( Fig. S6D ), consistent with tissue distribution of AAV9 ( 77 ). Adgrg6 expression levels were significantly reduced in pWAT, iWAT and BAT in promoter targeted mice and only significantly reduced in pWAT in enhancer targeted mice (the reduction in iWAT and BAT was not significant), fitting with its Adgrg6 enhancer knockout expression ( Fig.…”

“…S6A ). The gRNAs along with dCas9-KRAB were packaged into AAV serotype 9, which is known to effectively express transgenes in mouse adipose depots ( 77 ). AAV9 co-infection of individual gRNA along with dCas9-KRAB into 3T3-L1 cells found all three gRNAs to significantly reduce Adgrg6 expression ( fig.…”

GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β‐catenin and ALK5/SMAD2/3 pathways

“…Further studies are essential for the development of GDF11‐ and other metabotrophins‐based systemic therapies for obesity and related cardio‐ and neurometabolic diseases, including Alzheimer's disease. 1 , 3 We envisage that these therapies should overcome side effects in other organs—such as liver fibrosis, 85 , 86 targeting the adipose tissue in a tissue‐specific manner 87 …”

Visceral adipose tissue-directed FGF21 gene therapy improves metabolic and immune health in BTBR mice

“…The recent development of AAV vectors with improved adipose tropism and restriction of off-target transduction paves ways to investigate the long-term transgene expression, local and systemic immune responses, therapeutic efficacy, and safety profile of these vectors in adipose tissue. 75 New AAV administration techniques and bioengineering projects will be essential to increase specificity and efficacy of targeted gene therapies. 74 , 76 …”