Foriel 2015 Abstract MiP2015

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Drosophila as a model to study therapeutic approaches for mitochondrial diseases.

Link:

Foriel S, Smeitink JAM, Willems PHGM, Schenck A, Beyrath J (2015)

Event: MiP2015

Among the wide range of mitochondrial disorders, defects in the oxidative phosphorylation (OxPhos) are the most prevalent. OxPhos deficiencies often lead to early death and are associated with severe and highly variable clinical symptoms. Despite intense efforts in the comprehension of the mechanisms underlying mitochondrial disorders, patients are still without effective treatment. The need of predictive in vivo models of the pathology is an important issue in the development of new therapeutics in order to study their therapeutic potential, toxicity and pharmacokinetics. Due to the extreme genetic and phenotypic heterogeneity of OxPhos disorders one cannot rely on a single in vivo model.

Here we present the method and strategy we use to create, characterize and validate a set of Drosophila melanogaster models of nuclear DNA-encoded OxPhos subunits and preliminary results of systematic evaluation of Khondrion´s lead compound. We primarily focus on complex I by knocking down the core and accessory subunits the most prone to mutation in patients and selecting phenotypes-readouts suitable for drug screening (death at critical stages of development, survival curves, ROS level).

These models will represent a valuable tool with predictive power to evaluate new potential therapeutics as an initial step in the drug development process.


Labels: MiParea: Instruments;methods, mtDNA;mt-genetics, mt-Medicine, Pharmacology;toxicology 

Stress:Mitochondrial disease 


Enzyme: Complex I 



Event: A3, Poster, P-flash  MiP2015 

Affiliations

1-Khondrion BV; 2-Dept Biochemistry, NCMD, Radboud Univ Med Center; 3-Dept Human Genetics, Donders Inst Brain, Cognition and Behaviour, Radboud Univ Med Center; 4-Dept Pediatrics, NCMD, Radboud Univ Med Center; Nijmegen, The Netherlands. - foriel@khondrion.com

Acknowledgements

This work was supported by a Marie-Curie Initial Training Networks (ITN) grant MEET (Mitochondrial European Educational Training, FP7-PEOPLE-2012-ITN, Grant Agreement No: 317433), a PM-Rare (Priority Medicines Rare disorders and orphan diseases) grant from ZON-MW (Netherlands Organization for Health Research and Development-Medical Sciences, No: 40-41900-98-033) and the Stichting Energy4All (www.energy4all.eu).