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Search for new therapeutic agents against complicated obesity by reprofiling existing drugs

Final Report Summary - REPROBESITY (Search for new therapeutic agents against complicated obesity by reprofiling existing drugs)

Obesity is one of the most serious and fast-growing health problems in the European Union (EU) and a leading cause of diabetes. The main barrier for approval of an anti-obesity drug is the safety requirements that led to marketing prohibition of almost all anti-obesity drugs approved in the latest period of time such a Sibutramine or Rimonabant. This situation has led to a status on which one of the most relevant causes of morbid-mortality in humans is almost devoid of effective pharmacotherapeutic alternatives. There is an urgent need for new drugs against obesity that is reflected in the EU Seventh Framework Programme (FP7) research call for projects under the topic HEALTH-2007-2.4.3-6: Nutritional signals and the development of new diabetes / obesity therapeutic agents. This project will focus on the effects of alternative compounds which improve carbohydrate / lipid metabolism or modify body weight, and could be used in the development of new therapeutics in the treatment of hyperglycaemia and hyperlipidemia. To be successful, any research proposal has to discover novel or improved treatments in the shortest possible timeframe. The FP7 project REPROBESITY (please see online) proposed to overcome the barriers around obesity by discovering;
a) new indications of existing drugs with proven safety profiles as anti-obesity therapies. Since a relevant clinical end-point for an anti-obesity drug is its ability to reduce abdominal fat, the project has focused on approaches targeting directly abdominal fat cells. This is accomplished by a new specific technology that allows ex-vivo monitoring by flow cytometry techniques of adipose cells responses to libraries of approved drugs. This technology developed by VIVIA Biotech, is followed by target selection and pharmacological validation performed by a team of EU researchers specialised on top quality preclinical studies in obesity.
b) phenotypes and biomarkers that identify subsets of patients with safe and efficacious responses to drugs. The biomarker project intend to establish if we can obtain a way of identify the responding patients to a given therapy against obesity, since the experience with formerly approved drugs indicates that its utility is limited to a restricted set of patients. A new phenotype and/or biomarker may identify responsive patients with good safety profiles.

The work performed by the REPROBESITY consortium has allowed the following:
a) Develop for the first time an effective technique for the reprofiling of existing drugs using both, ex vivo samples of human adipose tissue and human cells engineered to express selected pharmacological targets to identify both, new drug indications and new chemical entities. This approach has allowed the filing of nine industrial patents derived of project's outcomes.
b) Develop a new technique of combinatorial cytomic biomarkers capable of identify the contribution of pathological conditions (i.e. obesity) and environmental factors (i.e. consumption of carbohydrates), to an abnormal cellular response (i.e. reactive oxygen species production, expression of the insulin receptor, expression of the glucose transporter or expression of the fatty acid transporter) that may account for the pathological consequences of obesity (i.e. metabolic syndrome, diabetes etc.).
c) Identify the pathophysiological role of biochemical signalling pathways on obesity. This information is useful to develop new therapeutic alternatives. These targets include known receptors such as GLP-1 receptor, peripheral cannabinoid CB1 receptors, ?3-adrenergic receptors, Thyroid hormone, as well as several orphan receptors, including GPR55, nuclear receptors such as PPAR receptors, and signalling pathways such as that of Sirtuin1/p53.
d) Patent and development of new chemical entities interacting with these targets, one of them, an allosteric modulator of GLP-1 receptors, being ready for clinical trials in humans.