Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide

Abstract Translation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of the phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by...

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Autores principales:	Pauline Georges, Maria-Gabriela Boza-Moran, Jacqueline Gide, Georges Arielle Pêche, Benjamin Forêt, Aurélien Bayot, Pierre Rustin, Marc Peschanski, Cécile Martinat, Laetitia Aubry
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/adf0e1a8e1024a7a8c3f6f7fe9edf703
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spelling	oai:doaj.org-article:adf0e1a8e1024a7a8c3f6f7fe9edf7032021-12-02T15:09:36ZInduced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide10.1038/s41598-019-49870-y2045-2322https://doaj.org/article/adf0e1a8e1024a7a8c3f6f7fe9edf7032019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-49870-yhttps://doaj.org/toc/2045-2322Abstract Translation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of the phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by relying on cells differentiated from human pluripotent stem cells. To analyse the benefits provided by this approach, we chose to focus on Friedreich ataxia, a neurodegenerative condition for which the recent clinical testing of two compounds was not successful. These compounds, namely, resveratrol and nicotinamide, were selected because they had been shown to stimulate the expression of frataxin in fibroblasts and lymphoblastoid cells. Our results indicated that these compounds failed to do so in iPSC-derived neurons generated from two patients with Friedreich ataxia. By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.Pauline GeorgesMaria-Gabriela Boza-MoranJacqueline GideGeorges Arielle PêcheBenjamin ForêtAurélien BayotPierre RustinMarc PeschanskiCécile MartinatLaetitia AubryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-7 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pauline Georges Maria-Gabriela Boza-Moran Jacqueline Gide Georges Arielle Pêche Benjamin Forêt Aurélien Bayot Pierre Rustin Marc Peschanski Cécile Martinat Laetitia Aubry Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
description	Abstract Translation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of the phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by relying on cells differentiated from human pluripotent stem cells. To analyse the benefits provided by this approach, we chose to focus on Friedreich ataxia, a neurodegenerative condition for which the recent clinical testing of two compounds was not successful. These compounds, namely, resveratrol and nicotinamide, were selected because they had been shown to stimulate the expression of frataxin in fibroblasts and lymphoblastoid cells. Our results indicated that these compounds failed to do so in iPSC-derived neurons generated from two patients with Friedreich ataxia. By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.
format	article
author	Pauline Georges Maria-Gabriela Boza-Moran Jacqueline Gide Georges Arielle Pêche Benjamin Forêt Aurélien Bayot Pierre Rustin Marc Peschanski Cécile Martinat Laetitia Aubry
author_facet	Pauline Georges Maria-Gabriela Boza-Moran Jacqueline Gide Georges Arielle Pêche Benjamin Forêt Aurélien Bayot Pierre Rustin Marc Peschanski Cécile Martinat Laetitia Aubry
author_sort	Pauline Georges
title	Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
title_short	Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
title_full	Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
title_fullStr	Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
title_full_unstemmed	Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
title_sort	induced pluripotent stem cells-derived neurons from patients with friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/adf0e1a8e1024a7a8c3f6f7fe9edf703
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Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide

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