FGF21 gene therapy as treatment for obesity and insulin resistance,EMBO Molecular Medicine

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FGF21 gene therapy as treatment for obesity and insulin resistance
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2018-07-09 , DOI: 10.15252/emmm.201708791
Veronica Jimenez _{1,

2,

3} , Claudia Jambrina _{1,

2,

3} , Estefania Casana _{1,

2,

3} , Victor Sacristan _{1,

2,

3} , Sergio Muñoz _{1,

2,

3} , Sara Darriba _{1,

2,

3} , Jordi Rodó _{1,

2,

3} , Cristina Mallol _{1,

2,

3} , Miquel Garcia _{1,

2,

3} , Xavier León _{1,

2,

3} , Sara Marcó _{1,

2,

3} , Albert Ribera _{1,

2,

3} , Ivet Elias _{1,

2,

3} , Alba Casellas _{1,

2,

3} , Ignasi Grass _{1,

2,

3} , Gemma Elias _{1,

2,

3} , Tura Ferré _{1,

3} , Sandra Motas _{1,

2,

3} , Sylvie Franckhauser _{1,

3} , Francisca Mulero _{3,

4} , Marc Navarro _{1,

3,

5} , Virginia Haurigot _{1,

2,

3} , Jesus Ruberte _{1,

3,

5} , Fatima Bosch _{1,

2,

3}

Affiliation

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.

中文翻译：

FGF21基因疗法可治疗肥胖和胰岛素抵抗

全球2型糖尿病（T2D）和肥胖的患病率正在上升。当前可用的疗法并不适合异质肥胖/ T2D人群中的所有患者，因此需要新颖的疗法。成纤维细胞生长因子21（FGF21）被认为是治疗T2D /肥胖症的有前途的治疗剂。然而，天然FGF21具有较差的药代动力学特性，使得基因治疗成为实现该蛋白持续循环水平的诱人策略。在这里，腺相关病毒载体（AAV）用于遗传工程化肝脏，脂肪组织或骨骼肌以分泌FGF21。长期高脂饮食喂养的动物或ob / ob小鼠的治疗显着降低了体重，脂肪组织肥大和炎症，肝脂肪变性，炎症和纤维化以及胰岛素抵抗> 1年。尽管血清FGF21持续升高，但在没有副作用的情况下仍可实现该治疗效果。此外，喂食标准饮食的健康动物中FGF21的过量生产可防止体重增加和与衰老相关的胰岛素抵抗。我们的研究强调了FGF21基因疗法在治疗肥胖症，胰岛素抵抗和2型糖尿病方面的潜力。

更新日期：2020-02-18

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