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