Upregulation of FGF21 to Prevent Visceral Fat Gain and Consequent Diabetes

Telling people to eat less doesn't work, as demonstrated by the vast number of overweight individuals with metabolic syndrome and type 2 diabetes. Both of those are preventable, reversible conditions, even in their later stages. All the patient has to do is eat less and lose the weight. Instead most people keep the weight, undergo largely palliative treatments that produce unpleasant side-effects, suffer many more medical complications with aging, and die younger than their peers. We don't live in a particularly rational world. Medical science may yet rescue the obese from themselves, however; certainly a very large amount of funding and effort goes into building potential treatments. Upregulation of FGF21 via gene therapy is an example of the type, a replication of one of the effects of calorie restriction that might have quite broad benefits in many organs, even for people of normal weight.

A research team has managed to cure obesity and type 2 diabetes in mice using gene therapy. A single administration of an adeno-associated viral vector (AAV) carrying the FGF21 (Fibroblast Growth Factor 21) gene, resulted in genetic manipulation of the liver, adipose tissue, or skeletal muscle to continuously produce the FGF21 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, which causes the development of type 2 diabetes.

The therapy has been tested successfully in two different mouse models of obesity, induced either by diet or genetic mutations. In addition, the authors observed that when administered to healthy mice, the gene therapy promoted healthy ageing and prevented age-associated weight gain and insulin resistance. After treatment with AAV-FGF21, mice lost weight and reduced fat accumulation and inflammation in adipose tissue; fat content (steatosis), inflammation, and fibrosis of the liver were also reversed; this led to an increase in insulin sensitivity and in healthy ageing, without any adverse side effects.

The native FGF21 protein has a short half-life when administered using conventional procedures. For this reason, the pharmaceutical industry has developed FGF21 analogues/mimetics and has already conducted clinical trials. FGF21 analogues/mimetics, however, require periodic administration to mediate clinical benefits, but may raise immunological issues associated to the administration of exogenous proteins. The gene therapy vectors, however, induce the mice to produce for many years the same FGF21 hormone naturally produced by the body, after a single administration.

Link: https://www.eurekalert.org/pub_releases/2018-07/uadb-urc070918.php

Comments

Can the same protein be injected in humans as daily therapy? If yes, give me another double portion of deep-fried butter. ;)

On a more serious note. Since injections have side effects and the protein has low half life, the gene therapy is an elegant solution. However, for humans I would like to have something less permanent for safety reasons. For example , taking patients cells, applying the gene therapy and reimplanting them back in one location that could be surgically removed , if needed. Ironically, that would be an artificial organ which doesn't exist in the nature. And they could be tiny stop towards enhanced humans...

Posted by: Cuberat at July 12th, 2018 7:25 AM

Yesterday resTORBio reported positive phase IIa clinical trial results for their lead rapalogue candidate in Science Signalling:

http://ir.restorbio.com/news-releases/news-release-details/restorbio-announces-science-translational-medicine-publication

"The data for this publication were gathered in a randomized, double-blinded, placebo-controlled Phase 2a study of 264 elderly volunteers at least 65 years of age without unstable medical conditions. Subjects were treated for 6 weeks with study drug and after a 2-week drug-free interval, were given a seasonal influenza vaccine. The incidence of infections was assessed for one year after initiation of study drug treatment. In the RTB101 monotherapy and RTB101+everolimus combination treatment arms, statistically significant and clinically meaningful reductions in the annual rate of infections of 33% (p=0.008) and 38% (p=0.001), respectively, compared to placebo, were observed. In addition, both RTB101 monotherapy and the RTB101+everolimus combination therapy were observed to reduce the incidence of RTIs at one year by 42% (p=0.006) and 36% (p=0.01), respectively. The combination of RTB101+everolimus was also observed to significantly enhance the response to influenza vaccination and upregulated the expression of critical antiviral genes that play a key role in enabling the immune system to protect the elderly from respiratory tract infections."

Posted by: Chris at July 12th, 2018 8:44 AM

Hi Chris,
i am curious what would be the result if they used good old rapamycin instead of their own proprietary analog.

Anyway, a 30% improvement of vaccination efficiency could save many thousands lives each year (between 3 to 40K).

Posted by: cuberat at July 12th, 2018 10:49 AM

Chris: I'd be very concerned about the effects of RTB101 on interlukin levels and overall mortality and immune system health. If it is truly increasing a gene expression, and not excessively targeting what remains of it at influenza, then great.

Posted by: Tom Schaefer at July 12th, 2018 10:56 AM

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