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

Autor:	Queen NJ; Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Bates R; Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Huang W; Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Xiao R; Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Appana B; Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Cao L; Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Dec 25; Vol. 20, pp. 409-422. Date of Electronic Publication: 2020 Dec 25 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2020.12.011
Abstrakt:	Fibroblast growth factor 21 (FGF21) is a peptide hormone that serves as a potent effector of energy homeostasis. Increasingly, FGF21 is viewed as a promising therapeutic agent for type 2 diabetes, fatty liver disease, and other metabolic complications. Exogenous administration of native FGF21 peptide has proved difficult due to unfavorable pharmacokinetic properties. Here, we utilized an engineered serotype adeno-associated viral (AAV) vector coupled with a dual-cassette design to selectively overexpress FGF21 in visceral adipose tissue of insulin-resistant BTBR T+Itpr3tf/J (BTBR) mice. Under high-fat diet conditions, a single, low-dose intraperitoneal injection of AAV-FGF21 resulted in sustained benefits, including improved insulin sensitivity, glycemic processing, and systemic metabolic function and reduced whole-body adiposity, hepatic steatosis, inflammatory cytokines, and adipose tissue macrophage inflammation. Our study highlights the potential of adipose tissue as a FGF21 gene-therapy target and the promise of minimally invasive AAV vectors as therapeutic agents for metabolic diseases. Competing Interests: L.C. and W.H. are inventors of a provisional patent application related to the liver-restricting AAV vector. All other authors declare no conflicts of interest. (© 2020 The Author(s).)
Databáze:	MEDLINE
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