Exploring mTOR inhibition as treatment for mitochondrial disease

Abstract Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway...

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Main Authors:	Abigail Sage‐Schwaede, Kristin Engelstad, Rachel Salazar, Angela Curcio, Alexander Khandji, James H. Garvin Jr, Darryl C. De Vivo
Format:	Article
Language:	English
Published:	Wiley 2019-09-01
Series:	Annals of Clinical and Translational Neurology
Online Access:	https://doi.org/10.1002/acn3.50846

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spelling	doaj-853e75a373114360af9361de5cca6d702021-05-02T06:57:41ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-09-01691877188110.1002/acn3.50846Exploring mTOR inhibition as treatment for mitochondrial diseaseAbigail Sage‐Schwaede0Kristin Engelstad1Rachel Salazar2Angela Curcio3Alexander Khandji4James H. Garvin Jr5Darryl C. De Vivo6Department of Neurology Columbia University Irving Medical Center New York New York 10032Department of Neurology Columbia University Irving Medical Center New York New York 10032Department of Neurology Columbia University Irving Medical Center New York New York 10032Department of Neurology Columbia University Irving Medical Center New York New York 10032Neuroradiology Division, Radiology Department Columbia University, New York University Irving Medical Center Milstein Hospital Room 3‐101, 177 Fort Washington Avenue New York New York 10032Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation Columbia University Irving Medical Center New York New York 10032Department of Neurology Columbia University Irving Medical Center New York New York 10032Abstract Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.https://doi.org/10.1002/acn3.50846
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Abigail Sage‐Schwaede Kristin Engelstad Rachel Salazar Angela Curcio Alexander Khandji James H. Garvin Jr Darryl C. De Vivo
spellingShingle	Abigail Sage‐Schwaede Kristin Engelstad Rachel Salazar Angela Curcio Alexander Khandji James H. Garvin Jr Darryl C. De Vivo Exploring mTOR inhibition as treatment for mitochondrial disease Annals of Clinical and Translational Neurology
author_facet	Abigail Sage‐Schwaede Kristin Engelstad Rachel Salazar Angela Curcio Alexander Khandji James H. Garvin Jr Darryl C. De Vivo
author_sort	Abigail Sage‐Schwaede
title	Exploring mTOR inhibition as treatment for mitochondrial disease
title_short	Exploring mTOR inhibition as treatment for mitochondrial disease
title_full	Exploring mTOR inhibition as treatment for mitochondrial disease
title_fullStr	Exploring mTOR inhibition as treatment for mitochondrial disease
title_full_unstemmed	Exploring mTOR inhibition as treatment for mitochondrial disease
title_sort	exploring mtor inhibition as treatment for mitochondrial disease
publisher	Wiley
series	Annals of Clinical and Translational Neurology
issn	2328-9503
publishDate	2019-09-01
description	Abstract Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.
url	https://doi.org/10.1002/acn3.50846
work_keys_str_mv	AT abigailsageschwaede exploringmtorinhibitionastreatmentformitochondrialdisease AT kristinengelstad exploringmtorinhibitionastreatmentformitochondrialdisease AT rachelsalazar exploringmtorinhibitionastreatmentformitochondrialdisease AT angelacurcio exploringmtorinhibitionastreatmentformitochondrialdisease AT alexanderkhandji exploringmtorinhibitionastreatmentformitochondrialdisease AT jameshgarvinjr exploringmtorinhibitionastreatmentformitochondrialdisease AT darrylcdevivo exploringmtorinhibitionastreatmentformitochondrialdisease
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Exploring mTOR inhibition as treatment for mitochondrial disease

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