Terapia gènica per la diabetis tipus 2 dirigida al sistema nerviós central

Abstract

Type 2 Diabetes (TD2) and obesity are closely related pathologies with an increasing worldwide prevalence. TD2 and obese patients have a higher risk of dementia and loss of cognitive ability. There is currently no effective treatment for the metabolic impairments of these pathologies and the related cognitive deficits can neither be cured nor prevented. Therefore, it is necessary to develop new therapeutic approaches to counteract not only the metabolic but also the neurological problems associated with T2D and obesity. Fibroblast growth factor 21 (FGF21) has become a promising therapeutic agent for the treatment of obesity and TD2. This hormone acts on different peripheral and central tissues. Specifically, the action of FGF21 in different brain regions helps to regulate energy homeostasis and is also able to reduce the cognitive deficits associated with different pathologies. However, the pharmacokinetic properties of the native protein FGF21 make it unsuitable for the use as a drug therapy due to its susceptibility to self-aggregate and its very short half-life in circulation. Although FGF21 analogues and mimetics have been developed, these molecules continue to need periodic administration and, being proteins other than the native one, they can cause immunogenicity problems and do not develop a cellular response exactly like the native form. In consequence, new therapeutic strategies need to be develped. Gene therapy allows the long-term overexpression of the native protein after a single administration of the therapeutic vector, and in particular, the adenoassociated viral vectors (AAV) allow a sustained expression of the transgene while presenting a good safety profile and a very low immunogeneicity. The results presented in this study have demonstrated that the adenoassociated vector of serotype 1 (AAV1) administered intra-CSF (intra-cerebrospinal fluid), through the cisterna magna, is able to widely transduce all the CNS Thus, the therapy based on intra-CSF administration of the vector AAV1-FGF21 allowed an specific increase in CNS FGF21 content, without an increase in the circulating levels of this hormone. In obese high fad died fed mice a high fat diet,this therapy resulted in a reduction in body weight. The treatment with AAV1-FGF21 also reduced the adiposity, the inflammation of the adipose tissue and the ectopic accumulation of fat in the liver that reversed inflammation, fibrosis and the associated hepatocarcinomas. Furthermore, the treated animals had and improved glucose metabolism, with normalized fasted insulin levels and increased insulin sensitivity and glucose tolerance. All these metabolic improvements were related to an increase in energy expenditure produced as a direct consequence of FGF21 signaling in the CNS. Spceifically, the action of FGF21 in the hypothalamus could induce a greater sympathetic outflow and induce the thermogenesis of the brown adipose tissue and the browning of inguinal white adipose tissue. In addition, the treatment with AAV1-FGF21 in the CNS also prevented the cognitive deficits associated with the consumption of the HFD by normalizing memory and learning parameters. Thus, the AAV1-FGF21 gene therapy in the CNS reversed obesity, insulin resistance and the cognitive deficits in HFD-fed mice, and could therefore become a new therapy for the treatment of obesity and T2D.

Date of Award	9 Jun 2022
Original language	Catalan
Supervisor	Maria Fatima Bosch Tubert (Director) & Ivet Elias Puigdomenech (Director)