A single supervision of an adeno-associated viral vector booming the Fibroblast Growth Factor 21 gene resulted in genetic manipulation of the liver, skeletal muscle or adipose tissue to rapidly enhance Fibroblast Growth Factor 21 protein. This protein is a hormone secreted naturally by several organs that acts on many tissues for the maintenance of correct energy metabolism. By inducing FGF21 production through gene therapy the animal lost weight and decreased insulin resistance, this causes the development of type 2 diabetes.
The therapy has been tested successfully in two different mouse models of obesity, induced either by genetic mutations or diet. Also, the researchers scrutinized that when administered to healthy mice, the gene therapy endorsed healthy aging and prevented age associated weight gain and insulin resistance.
After treatment with adeno-associated viral- Fibroblast Growth Factor 21, mice lost weight and reduced fat accumulation and inflammation in adipose tissue; steatosis, fibrosis and inflammation of the liver were also reversed. This led to an increase in healthy aging and in insulin sensitivity without any adverse side effects.
The results have been reproduced after genetic manipulation of three different tissues to produce the Fibroblast Growth Factor 21. This gives flexibility to the treatment, since it permits to choose each time the most appropriate tissue and in case some impediment prevents manipulating any of the tissues, it can be applied to any of the others. When a tissue produces Fibroblast Growth Factor 21 protein and secretes it into the bloodstream, it will be distributed throughout the body.
The authors highlight the significance of these results, since the prevalence of type 2 diabetes and obesity is growing at alarming rates around the world. Obesity also enhances the risk of mortality and indicates an important risk factor for neurodegenerative disorders, cardiovascular and immune diseases, arthritis, hypertension, and some types of cancer.
The results also reveal that the scrutinization of the gene therapy ensured against the risk of tumor formation in the liver in response to a hyper caloric diet for a prolonged period of time.
The native Fibroblast Growth Factor 21 protein has a short half-life when administered using conventional procedures. For this reason, the pharmaceutical industry has developed Fibroblast Growth Factor 21 analogues and has already conducted clinical trials. Fibroblast Growth Factor 21 mimetics, however require periodic administration to mediate clinical advantages and but may raise immunological issues related to the administration of exogenous proteins. The gene therapy vectors used by researcher, however, induce the mice to produce for many years the same FGF21 hormone naturally produced by the body, after a single administration and without any adverse effects.
For scientist the next step will be to test this therapy in larger animals before moving to clinical trials with patients. AAV-mediated gene therapy has been approved for the treatment of several diseases, due to its efficacy and safety profile. Similarly, there exists extensive clinical experience in applying adeno associated viral-mediated gene transfer to liver and skeletal muscle. Subsequently, the therapy described in this study comprises the basis for the future clinical translation of Fibroblast Growth Factor 21 gene transfer to treat obesity, type 2 diabetes, and related comorbidities.