Cargando…

Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice

BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding...

Descripción completa

Detalles Bibliográficos
Autores principales: Schiff, Manuel, Bénit, Paule, El-Khoury, Riyad, Schlemmer, Dimitri, Benoist, Jean-François, Rustin, Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236768/
https://www.ncbi.nlm.nih.gov/pubmed/22174907
http://dx.doi.org/10.1371/journal.pone.0028823
_version_ 1782218783800164352
author Schiff, Manuel
Bénit, Paule
El-Khoury, Riyad
Schlemmer, Dimitri
Benoist, Jean-François
Rustin, Pierre
author_facet Schiff, Manuel
Bénit, Paule
El-Khoury, Riyad
Schlemmer, Dimitri
Benoist, Jean-François
Rustin, Pierre
author_sort Schiff, Manuel
collection PubMed
description BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. METHODS AND FINDINGS: Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. CONCLUSIONS: These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients.
format Online
Article
Text
id pubmed-3236768
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-32367682011-12-15 Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice Schiff, Manuel Bénit, Paule El-Khoury, Riyad Schlemmer, Dimitri Benoist, Jean-François Rustin, Pierre PLoS One Research Article BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. METHODS AND FINDINGS: Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. CONCLUSIONS: These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients. Public Library of Science 2011-12-13 /pmc/articles/PMC3236768/ /pubmed/22174907 http://dx.doi.org/10.1371/journal.pone.0028823 Text en Schiff et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Schiff, Manuel
Bénit, Paule
El-Khoury, Riyad
Schlemmer, Dimitri
Benoist, Jean-François
Rustin, Pierre
Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
title Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
title_full Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
title_fullStr Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
title_full_unstemmed Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
title_short Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
title_sort mouse studies to shape clinical trials for mitochondrial diseases: high fat diet in harlequin mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236768/
https://www.ncbi.nlm.nih.gov/pubmed/22174907
http://dx.doi.org/10.1371/journal.pone.0028823
work_keys_str_mv AT schiffmanuel mousestudiestoshapeclinicaltrialsformitochondrialdiseaseshighfatdietinharlequinmice
AT benitpaule mousestudiestoshapeclinicaltrialsformitochondrialdiseaseshighfatdietinharlequinmice
AT elkhouryriyad mousestudiestoshapeclinicaltrialsformitochondrialdiseaseshighfatdietinharlequinmice
AT schlemmerdimitri mousestudiestoshapeclinicaltrialsformitochondrialdiseaseshighfatdietinharlequinmice
AT benoistjeanfrancois mousestudiestoshapeclinicaltrialsformitochondrialdiseaseshighfatdietinharlequinmice
AT rustinpierre mousestudiestoshapeclinicaltrialsformitochondrialdiseaseshighfatdietinharlequinmice