Blanc SVSE 1 - Blanc - SVSE 1 - Physiologie, physiopathologie, santé publique

Fighting Friedreich's Ataxia: combining multi-organisms screening and chemical optimization to generate new therapeutic molecules for FA – FiFA2

Fighting Friedreich's ataxia

Combining multi-organisms screening and chemical optimization to generate new therapeutic molecules

The urgent need for effective treatment of FA

Friedreich ataxia is a rare but fatal neurodegenerative disease. There is on cure for the disease, and only compounds with limited effectiveness are administrated to the patients. We aim at taking advantage of our previous work, where chemical libraries were screened in model biological systems, to synthesize, test and validate new coumpounds with high therapeutical potential.

The initial steps of the screening procedure were mostly qualitative, based on growth recovery of test strains. We now develop quantitative scales to evaluate the impact of chemical modifications of the lead compounds. We constructed new reporter strains to discriminate the effects of the compounds on the different phenotypes of frataxin deficient strains.

The expected molecular and cellular tools are now available, in the yeast and drosophila models of Friedreich's ataxia. They allow us to quantify the effects of modifications on the structures of the selected lead compounds. We have characterized new phenotypes in frataxin deficient cells and organisms that shed a new light on frataxin function

Better understand the physiopathology of Friedreich's ataxia, and frataxin function; develop active compounds to cure the disease.

work in progress

The major objective of the FiFA2 research project is to develop new drugs efficient to fight Friedreich’s ataxia (FA), the most prevalent form of autosomal recessive spinocerebellar ataxia in Caucasians. It associates 4 groups (Partner #1, Camadro, IJM, Paris, Partner #2, Rustin, H. Robert Debré, Paris, Partner #3, Hibert, Fac Pharmacie, Strasbourg, Partner #4, Tricoire, BFA, Paris) who want to share their complementary expertises on different fields of biology, pathophysiology, genetics and medicinal chemistry.
Besides progressive neurodegenerescence of dorsal root ganglions and associated peripheral nervous system, many FA patients suffer cardiomyopathy, and for 1/3 of them, diabetes. In spite of extensive research and some therapeutic trials, there is currently no efficient treatment to cure or even stop the progression of this complex disease.
In the last few years, within the frame of an ANR “Rare diseases” action, Partners #1 and #2 utilized yeast models and patient’s cultured fibroblasts in order to i) better understand the role of frataxin, the protein involved in FA, in iron metabolism and in oxidative stress response and ii) -identify therapeutic compounds by screening chemical libraries on yeast, in collaboration with Partner #3. 69 compounds were isolated as positive hits (C1G) out of 6880 compounds, for their ability to improve the fitness of frataxin deficient yeast cells. More recently, Partner #4 developed several Drosophila tissue specific inducible FA models in Drosophila flies. These strains were used to evaluate, in a pilot in vivo secondary screen, the efficiency of a subset of 14 C1G compounds on FA pathological features. Strikingly, 4 compounds showed efficiency in partially rescuing some of the phenotypes developed by the frataxin-deficient flies. Thus, our preliminary data validates our strategy of screening, in a multicellular organism, for compounds pre-selected from yeast Fxn depleted cells to identify potential therapeutic drugs for FA.
Following these promising works, the next step at the heart of the FiFA2 project is to synthesize and characterize new optimized chemicals (C2G, derived from validated C1G hits) with properties of druggable molecules, in order to reach pre-clinical assays as therapeutic agents to cure Friedreich’s ataxia. To this aim we will combine chemical expertise with our innovative screening models on three organisms (yeast, drosophila and humans) to further characterize the different chemicals for their ability to restore normal growth, resistance to oxidative stress, proper iron-sulfur clusters synthesis and assembly in frataxine deficient cells and to improve organ functions in Drosophila models. Then, for the most promising compounds, we will develop affinity ligands to characterize their cellular targets.
We will take advantage of the synergies between different models, the yeast S. cerevisiae, patients’ cultured cells and the new drosophila FA models to:
1) Evaluate quantitatively in detail the effect of the C1G and C2G compounds (C1G-C2G) on frataxin deficient yeast cells physiology at different physiological and biochemical levels and different genetic contexts.
2) Explore the therapeutic potential of C1G-C2G on patient’s cells
3) Investigate in the different tissue specific Drosophila models (steroidogenic gland, heart, oenocytes (hepatocytes like), PNS and glial cells) the therapeutic potential of C1G-C2G and the possibility of combinatorial therapies.
4) Identify new pathological mechanisms that may partly mediate the toxicity of a frataxin deficiency and may be targeted by some of the compounds.
A constant crosstalk between our chemist experts (Partner #3) and the biologists involved in FiFA2 will ensure that optimized compounds will be generated at the end of this interdisciplinary project.
Therefore, we expect that the Fifa project will bring significant progress towards improvements in FA therapy, with possible extensions to other neurodegenerative diseases

Project coordinator

Monsieur CAMADRO Jean-Michel (Institut Jacques Monod) –

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM Inserm U676
UPD-BFA Université Paris Diderot, Unité de Biologie fonctionnelle et Adaptative,
Université de Strasbourg Laboratoire d'Innovation Thérapeutique
CNRS - Univ Paris Diderot Institut Jacques Monod

Help of the ANR 485,700 euros
Beginning and duration of the scientific project: October 2012 - 36 Months

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