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

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 o...

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Autores principales: Georges, Pauline, Boza-Moran, Maria-Gabriela, Gide, Jacqueline, Pêche, Georges Arielle, Forêt, Benjamin, Bayot, Aurélien, Rustin, Pierre, Peschanski, Marc, Martinat, Cécile, Aubry, Laetitia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787055/
https://www.ncbi.nlm.nih.gov/pubmed/31601825
http://dx.doi.org/10.1038/s41598-019-49870-y
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author Georges, Pauline
Boza-Moran, Maria-Gabriela
Gide, Jacqueline
Pêche, Georges Arielle
Forêt, Benjamin
Bayot, Aurélien
Rustin, Pierre
Peschanski, Marc
Martinat, Cécile
Aubry, Laetitia
author_facet Georges, Pauline
Boza-Moran, Maria-Gabriela
Gide, Jacqueline
Pêche, Georges Arielle
Forêt, Benjamin
Bayot, Aurélien
Rustin, Pierre
Peschanski, Marc
Martinat, Cécile
Aubry, Laetitia
author_sort Georges, Pauline
collection PubMed
description 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.
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spelling pubmed-67870552019-10-17 Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide Georges, Pauline Boza-Moran, Maria-Gabriela Gide, Jacqueline Pêche, Georges Arielle Forêt, Benjamin Bayot, Aurélien Rustin, Pierre Peschanski, Marc Martinat, Cécile Aubry, Laetitia Sci Rep Article 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. Nature Publishing Group UK 2019-10-10 /pmc/articles/PMC6787055/ /pubmed/31601825 http://dx.doi.org/10.1038/s41598-019-49870-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Georges, Pauline
Boza-Moran, Maria-Gabriela
Gide, Jacqueline
Pêche, Georges Arielle
Forêt, Benjamin
Bayot, Aurélien
Rustin, Pierre
Peschanski, Marc
Martinat, Cécile
Aubry, Laetitia
Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787055/
https://www.ncbi.nlm.nih.gov/pubmed/31601825
http://dx.doi.org/10.1038/s41598-019-49870-y
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