FGF21 gene therapy as treatment for obesity and insulin resistance
2018; Springer Nature; Volume: 10; Issue: 8 Linguagem: Inglês
10.15252/emmm.201708791
ISSN1757-4684
AutoresVerónica Jiménez, Claudia Jambrina, Estefanía Casana, Victor Sacristan, Sergio Muñoz, Sara Darriba, Jordi Rodó, Cristina Mallol, Miquel García, Xavier León, Sara Marcó, Albert Ribera, Ivet Elias, Alba Casellas, Ignasi Grass, Gemma Elias, Tura Ferré, Sandra Motas, Sylvie Franckhauser, Francisca Mulero, Marc Navarro, Virginia Haurigot, Jesús Ruberte, Fàtima Bosch,
Tópico(s)Epigenetics and DNA Methylation
ResumoResearch Article9 July 2018Open Access Source DataTransparent process FGF21 gene therapy as treatment for obesity and insulin resistance Veronica Jimenez Veronica Jimenez Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Claudia Jambrina Claudia Jambrina Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Estefania Casana Estefania Casana Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Victor Sacristan Victor Sacristan Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sergio Muñoz Sergio Muñoz Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sara Darriba Sara Darriba Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Jordi Rodó Jordi Rodó Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Cristina Mallol Cristina Mallol Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Miquel Garcia Miquel Garcia Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Xavier León Xavier León Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sara Marcó Sara Marcó Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Albert Ribera Albert Ribera Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Ivet Elias Ivet Elias Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Alba Casellas Alba Casellas Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Ignasi Grass Ignasi Grass Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Gemma Elias Gemma Elias Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Tura Ferré Tura Ferré Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sandra Motas Sandra Motas Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sylvie Franckhauser Sylvie Franckhauser Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Francisca Mulero Francisca Mulero CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Search for more papers by this author Marc Navarro Marc Navarro Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Search for more papers by this author Virginia Haurigot Virginia Haurigot Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Jesus Ruberte Jesus Ruberte Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Search for more papers by this author Fatima Bosch Corresponding Author Fatima Bosch [email protected] orcid.org/0000-0002-7705-5515 Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Veronica Jimenez Veronica Jimenez Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Claudia Jambrina Claudia Jambrina Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Estefania Casana Estefania Casana Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Victor Sacristan Victor Sacristan Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sergio Muñoz Sergio Muñoz Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sara Darriba Sara Darriba Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Jordi Rodó Jordi Rodó Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Cristina Mallol Cristina Mallol Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Miquel Garcia Miquel Garcia Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Xavier León Xavier León Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sara Marcó Sara Marcó Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Albert Ribera Albert Ribera Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Ivet Elias Ivet Elias Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Alba Casellas Alba Casellas Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Ignasi Grass Ignasi Grass Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Gemma Elias Gemma Elias Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Tura Ferré Tura Ferré Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sandra Motas Sandra Motas Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Sylvie Franckhauser Sylvie Franckhauser Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Francisca Mulero Francisca Mulero CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Search for more papers by this author Marc Navarro Marc Navarro Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Search for more papers by this author Virginia Haurigot Virginia Haurigot Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Jesus Ruberte Jesus Ruberte Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Search for more papers by this author Fatima Bosch Corresponding Author Fatima Bosch [email protected] orcid.org/0000-0002-7705-5515 Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain Search for more papers by this author Author Information Veronica Jimenez1,2,3,‡, Claudia Jambrina1,2,3,‡, Estefania Casana1,2,3, Victor Sacristan1,2,3, Sergio Muñoz1,2,3, Sara Darriba1,2,3, Jordi Rodó1,2,3, Cristina Mallol1,2,3, Miquel Garcia1,2,3, Xavier León1,2,3, Sara Marcó1,2,3, Albert Ribera1,2,3, Ivet Elias1,2,3, Alba Casellas1,2,3, Ignasi Grass1,2,3, Gemma Elias1,2,3, Tura Ferré1,3, Sandra Motas1,2,3, Sylvie Franckhauser1,3, Francisca Mulero3,4, Marc Navarro1,3,5, Virginia Haurigot1,2,3, Jesus Ruberte1,3,5 and Fatima Bosch *,1,2,3 1Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain 2Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain 3CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain 4Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 5Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain ‡These authors contributed equally to this work *Corresponding author. Tel: +34 93 581 41 82; E-mail: [email protected] EMBO Mol Med (2018)10:e8791https://doi.org/10.15252/emmm.201708791 See also: CH Sponton & S Kajimura (August 2018) PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D. Synopsis This study describes the use of adeno-associated viral (AAV) vectors to achieve long-term production of fibroblast growth factor 21 (FGF21) to treat obesity and insulin resistance. AAV-FGF21 gene transfer to healthy animals also prevented age-associated weight gain and insulin resistance. A one-time administration of an AAV vector encoding FGF21 counteract obesity and insulin resistance for more than a year. The approach works in two different animal models of obesity, induced either by diet or genetic mutations. Administration of AAV-FGF21 to healthy animals promotes healthy aging. AAV-FGF21 pharmacological effects are demonstrated after genetic engineering of 3 different tissues (liver, adipose tissue and skeletal muscle). FGF21 gene therapy holds great translational potential in the fight against insulin resistance, T2D, obesity and related comorbidities. Introduction The prevalence of type 2 diabetes (T2D) is growing at an alarming rate, and T2D has become a major health problem worldwide. T2D and insulin resistance are very strongly associated with obesity, whose prevalence is also increasing (So & Leung, 2016). Obesity increases the risk of mortality (Peeters et al, 2003) and is also a very significant risk factor for heart disease, immune dysfunction, hypertension, arthritis, neurodegenerative diseases, and certain types of cancer (Spiegelman & Hotamisligil, 1993; Whitmer, 2007; Roberts et al, 2010). Lifestyle intervention and conventional pharmacologic treatments have proven effective for many obese and T2D patients. However, these therapeutic options are not successful in all cases and are not exempt of undesirable side effects. Hence, there is a medical need for novel, well-tolerated treatments for the large and heterogenous population of obese/T2D patients. Fibroblast growth factor 21 (FGF21) has recently emerged as a promising therapeutic agent for the treatment of obesity and T2D (Kharitonenkov & DiMarchi, 2017). This peptide hormone is secreted by several organs and can act on multiple tissues to regulate energy homeostasis (Potthoff et al, 2012; Fisher & Maratos-Flier, 2016). One of the main secretors of FGF21 is the liver (Markan et al, 2014). FGF21 binds specifically to the FGF receptors (FGFR) and needs β-Klotho as an obligate co-receptor (Fisher & Maratos-Flier, 2016). The administration of recombinant FGF21 protein to ob/ob, db/db, or high-fat diet (HFD)-fed mice or to obese Zucker diabetic fatty (ZDF) rats promotes a robust reduction in adiposity, lowers blood glucose and triglycerides, and improves insulin sensitivity (Kharitonenkov et al, 2005; Coskun et al, 2008; Berglund et al, 2009; Xu et al, 2009a; Adams et al, 2012a,b). Similarly, liver-specific overexpression of FGF21 in transgenic mice protects animals from diet-induced obesity and insulin resistance (Kharitonenkov et al, 2005; Inagaki et al, 2007). Moreover, the administration of FGF21 to obese diabetic rhesus monkeys markedly reduces fasting plasma glucose, triglyceride, and insulin levels and induces a small but significant loss of body weight (Kharitonenkov et al, 2007). The native FGF21 protein has, however, poor pharmacokinetic properties, including a short half-life (ranging from 0.5 to 2 h), in part because of increased glomerular filtration in the kidney due to its small size (~22 kDa), and susceptibility to in vivo proteolytic degradation and in vitro aggregation (Zhang & Li, 2015; So & Leung, 2016). The pharmaceutical industry is devoting considerable efforts to overcoming these limitations and improving the yield of production of FGF21 analogues or mimetics to enable the development of potential drug products (Zhang & Li, 2015; So & Leung, 2016). These FGF21-class molecules have been reported to have similar therapeutic efficacy than the native FGF21 protein in small and large animal models of obesity and T2D (Foltz et al, 2012; Hecht et al, 2012; Adams et al, 2013; Talukdar et al, 2016; Stanislaus et al, 2017). Indeed, first-generation FGF21 analogues have already reached the clinical stage, and reports from two phase I clinical trials have shown significant improvement of dyslipidemia, slight body weight loss, and reductions in fasting insulinemia in patients with obesity and T2D (Gaich et al, 2013; Talukdar et al, 2016). Thus, preclinical evidence and clinical evidence corroborate that FGF21 may be an attractive candidate to combat obesity and TD2. Despite the pharmacokinetic improvements, FGF21 analogues/mimetics require periodic administrations to mediate clinical benefit, which may not only be uncomfortable for patients and compromise treatment compliance but may also raise immunological issues associated with the administration of exogenous proteins (Gaich et al, 2013; Talukdar et al, 2016; Kim et al, 2017). Here, we took advantage of adeno-associated viral (AAV) vectors and their ability to mediate multi-year production of therapeutic proteins (Mingozzi & High, 2011; Naldini, 2015) to develop a gene therapy strategy for obesity and T2D based on FGF21 gene transfer to the liver, adipose tissue, or skeletal muscle. AAV vectors, derived from non-pathogenic viruses, are predominantly non-integrative vectors that persist for years as episomes in the nucleus of non-dividing cells (Lisowski et al, 2015; Wolf et al, 2015). Multiple studies have reported high transduction efficiencies for in vivo gene transfer with these vectors, as well as excellent safety profiles in clinical studies (Mingozzi & High, 2011; Naldini, 2015). In particular, studies in large animal models (Rivera et al, 2005; Niemeyer et al, 2009; Callejas et al, 2013; Bainbridge et al, 2015), as well as clinical studies (Hauswirth et al, 2008; Maguire et al, 2008; Simonelli et al, 2010; Buchlis et al, 2012; Jacobson et al, 2012; Gaudet et al, 2013; Testa et al, 2013; Nathwani et al, 2014; Bainbridge et al, 2015), have provided strong evidence of AAV-mediated long-term expression for a variety of therapeutic proteins in the absence of clinically significant adverse events. Thus, AAV-mediated gene therapy can potentially overcome the pharmacokinetic limitations of FGF21-class molecules. Here, we demonstrate for the first time that a single administration of AAV vectors encoding FGF21 enabled a long-lasting increase in FGF21 levels in circulation, which resulted in sustained counteraction of obesity, hepatic steatosis, and insulin resistance in two different models of obesity and T2D, the HFD-fed mouse and the ob/ob mouse. In healthy animals, it prevented age-associated weight gain and insulin resistance. Our results underscore the potential of FGF21 gene therapy to treat these conditions. Results Persistent reversion of obesity by liver-specific AAV8-mediated FGF21 overexpression Two-month-old C57Bl6 mice ("young adults") were fed either a chow or a HFD for 10 weeks. During these first 2.5 months of follow-up, while the weight of chow-fed animals increased by 27%, animals fed a HFD became obese (72% body weight gain) (Fig 1A). Obese animals were then administered intravenously (IV) with 1 × 1010 or 5 × 1010 viral genomes (vg) of serotype 8 AAV vectors encoding a murine optimized FGF21 coding sequence, whose expression was under the control of the synthetic liver-specific hAAT promoter (AAV8-hAAT-FGF21). As controls, another cohort of obese mice and the cohort of chow-fed mice received 5 × 1010 vg of non-coding null vectors (AAV8-null). Following AAV delivery, mice were maintained on chow or HFD feeding for about 1 year; that is, up to 16.5 months of age, and body weight and metabolic parameters were monitored regularly. Animals treated with 1 × 1010 vg AAV8-hAAT-FGF21 gained as much weight as AAV8-null-injected HFD-fed mice (Fig 1A). In marked contrast, the cohort of mice treated with 5 × 1010 vg AAV8-hAAT-FGF21 normalized their body weight within a few weeks of AAV delivery (Fig 1A). Indeed, the mean body weight of this group of animals became indistinguishable from that of the chow-fed, AAV8-null-injected cohort for the duration of the follow-up period (~1 year) (Fig 1A and Appendix Fig S1A). Figure 1. AAV8-mediated liver gene transfer of FGF21 counteracts HFD-induced obesity A, B. Evolution of body weight in animals treated with AAV8-hAAT-FGF21 as young adults (A) or as adults (B). C57Bl6 mice were fed a HFD for ˜10 weeks and then administered with 1 × 1010, 2 × 1010, or 5 × 1010 vg/mouse of AAV8-hAAT-FGF21 vectors. Control obese mice and control chow-fed mice received 5 × 1010 vg of AAV8-hAAT-null. C. Weight of the epididymal (eWAT), inguinal (iWAT), and retroperitoneal (rWAT) white adipose tissue depots, the liver, and the quadriceps obtained from mice treated with AAV8-hAAT-FGF21 vectors as young adults (top panel) or as adults (bottom panel). D. Circulating levels of FGF21 at different time points after vector administration. Data information: All values are expressed as mean ± SEM. In (A–D), young adults: AAV8-hAAT-null chow (n = 10 animals), AAV8-hAAT-null HFD (n = 8), AAV8-hAAT-FGF21 HFD 1 × 1010 vg (n = 9), and 5 × 1010 vg (n = 8). Adults: AAV8-hAAT-null chow (n = 7), AAV8-hAAT-null HFD (n = 7), AAV8-hAAT-FGF21 HFD 1 × 1010 vg (n = 7), 2 × 1010 vg (n = 8) and 5 × 1010 vg (n = 7). In (A–D), data were analyzed by one-way ANOVA with Tukey's post hoc correction. *P < 0.05, **P < 0.01, and ***P < 0.001 versus the chow-fed null-injected group. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus the HFD-fed null-injected group. HFD, high-fat diet. Download figure Download PowerPoint Having observed the profound effects on body weight exerted by FGF21 gene transfer to the liver, and taking into account that obesity and T2D are pathologies associated with aging, we set out another study in which animals began HFD feeding when older, at the age of 29 weeks ("adults"). By week 38, older HFD-fed mice had also become obese, with a mean body weight gain of ~40% (Fig 1B). Mice were then administered IV with AAV8-hAAT-FGF21 vectors at three differe
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