title: Combinatorial gene construct and non-viral delivery for anti-obesity in diet-induced obese mice.
abstract: The combinatorial peptidergic therapy of islet amyloid polypeptide (IAPP) and leptin (LEP) analogues was once an optimistic option in treating obese animals and patients. However, the need for frequent administrations and its negative side effects prevent it from being a viable choice. Here, we developed a combinatorial gene therapy of IAPP and LEP, where two genes are inserted into a single plasmid with self-cleaving furin and 2A sites to treat diet-induced obese (DIO) mice. The developed plasmid DNA (pDNA) individually produced both IAPP and LEP peptides in vitro and in vivo. The pDNA was delivered with a non-viral polymeric carrier, and its once-a-week administrations demonstrated a synergistic loss of body weight and significant reductions of fat mass, blood glucose, and lipid levels in DIO mice. The results suggest that the combinatorial gene therapy would have higher potential than the peptidergic approach for future translation due to its improved practicability.
authors: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors: Hongsuk
authors: H
authors: Park
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT 84132, USA.
authors: Sungpil
authors: S
authors: Cho
authors: Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA.
authors: Yong Hwan
authors: YH
authors: Han
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT 84132, USA.
authors: Margit M
authors: MM
authors: Janat-Amsbury
authors: Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA.
authors: Sihem
authors: S
authors: Boudina
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Utah-Inha Drug Delivery Systems and Advanced Therapeutics Research Center, Incheon, Republic of Korea. Electronic address: you.bae@utah.edu.
authors: You Han
authors: YH
authors: Bae
mesh_terms: D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004435:Eating; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000096:biosynthesis / Q000235:genetics; D020738:Leptin / Q000096:biosynthesis* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D013997:Time Factors; D014162:Transfection; D015431:Weight Loss
chemical_list: D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D008055:Lipids; D011108:Polymers
keywords: Combinatorial gene therapy; Islet amyloid polypeptide; Leptin; Non-viral gene carrier; Obesity