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A novel therapeutic approach to treat pandemic obesity and its comorbidities: A translational project from basic neuroscience research to a pharmaceutical product

English title A novel therapeutic approach to treat pandemic obesity and its comorbidities: A translational project from basic neuroscience research to a pharmaceutical product
Applicant Jordi Josua
Number 177254
Funding scheme Bridge - Proof of Concept
Research institution
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.11.2017 - 30.11.2018
Approved amount 130'000.00
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All Disciplines (4)

Discipline
Neurophysiology and Brain Research
Physiology : other topics
Ethology
Pharmacology, Pharmacy

Keywords (4)

in vivo drug screening; obesity; zebrafish; eating behavior

Lay Summary (German)

Lead
Zurzeit sind therapeutische Massnahmen und Medikamente zur Behandlung von Übergewicht punkto Wirksamkeit und Sicherheit unbefriedigend. Dank einer innovativen Forschungsstrategie an Zebrafischen gelang mir die Identifikation einer neuen Art von anti-adipositas Molekülen, welche mithilfe des Bridge-Stipendiums an Säugetieren erfolgreich getestet wurden - ein wichtiger Schritt in der vorklinischen und kommerziellen Entwicklung.
Lay summary

Fettleibigkeit und ihre Komorbiditäten wie Diabetes Typ 2 und Herz-Kreislauf-Erkrankungen sind eine grosse Herausforderung für unsere Gesellschaft mit unzähligen Erkrankten und unabsehbaren finanziellen Folgekosten. Bisher zielt die ärztliche Behandlung auf eine Reduktion des Körpergewichts, was synergistisch alle Komorbiditäten signifikant reduzieren würde. Doch bislang gibt es keine zufriedenstellenden therapeutische Massnahmen oder Medikamente, welche wirksam und sicher zum Gewichtsverlust des adipösen Patienten führen. Dank einer innovativen Forschungsstrategie gelang mir die Identifikation einer neuen Klasse von anti-adipositas Molekülen in Zebrafischen. Dank des Bridge-fellowships konnten wir die Moleküle erfolgreich in der Maus testen - unter besonderer Berücksichtigung der Sicherheit und Potenz. Diese positive Resultate erhöhen die Wahrscheinlichkeit der Wirksamkeit im Menschen, und legen die Grundlage für die klinische Forschung und Kommerzialisierung der Moleküle. Ein wirksames, sicheres Medikament gegen die Übergewichts-Pandemie und ihre assoziierten Komorbiditäten (Diabetes Typ 2, Herz-Kraislauf-Erkrankungen, Krebs, etc.) würde unser Gesundheitssystem fundamental verändern und entlasten.

Direct link to Lay Summary Last update: 10.04.2019

Responsible applicant and co-applicants

Employees

Publications

Collaboration

Group / person Country
Types of collaboration
Prof. T. Lutz Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Abstract

Obesity and its severe comorbidities remain a major burden for our societies, economy, and the billions of affected individuals. The associated yearly economic cost is about two trillion US-dollar, roughly equivalent to the economic damage caused by war and terrorism. For the affected individual, obesity reduces the quality of life, triggers social prejudice and favors co-morbidities such as diabetes type 2, cardiovascular disease, and cancer, among many others highlighting the necessity of effective treatment. However, the anti-obesity medical therapy is to date unsatisfactory in terms of efficacy and safety.This lack of performance motivated me to research and identify novel anti-obesity agents based on an original scientific strategy. I identified fifty appetite-suppressors out of more than ten-thousand tested in an in vivo multi-behavioral screen performed in zebrafish. Candidate compounds are selective to food intake, do not induce neuronal side-effects and act by a novel mechanism of action. With the Bridge fellowship, I implemented a three-step process of elimination to select one potent and safe anti-obesity agent inspired by reflection on what makes past and present appetite modulators not ideal. First, candidate compounds underwent in vivo toxicity and mutagenesis testing in zebrafish, and off-target in vitro human receptor profiling to identify the most promising candidate for future development. Second, the remaining candidates were tested acutly for behavioral, gastrointestinal and neuronal phenotypes in mice. Third, the most potent compound were tested chronicly in two pre-clinical obesity models representative for the majority of the obese human population. This scientific proof of concept was achieved in the synergistic and excellent scientific environment offered at the University of Zurich and Harvard University.This patented compound is the foundation of the startup EraCal Therapeutics Ltd., which now pursues lead optimization prior IND-safety studies. First in human testing is expected in 2021/2022. Ultimately the goal is to tackle the unmet medical need caused by the obesity pandemic and its comorbidities.
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