AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease

Abstract Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene...

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Autores principales:	Francesca Gatto, Barbara Rossi, Antonietta Tarallo, Elena Polishchuk, Roman Polishchuk, Alessandra Carrella, Edoardo Nusco, Filomena Grazia Alvino, Francesca Iacobellis, Elvira De Leonibus, Alberto Auricchio, Graciana Diez-Roux, Andrea Ballabio, Giancarlo Parenti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/678d39e7a19b43b9866916b4208c4792
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spelling	oai:doaj.org-article:678d39e7a19b43b9866916b4208c47922021-12-02T11:52:18ZAAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease10.1038/s41598-017-15352-22045-2322https://doaj.org/article/678d39e7a19b43b9866916b4208c47922017-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-15352-2https://doaj.org/toc/2045-2322Abstract Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD. We treated 1-month-old PD mice with an AAV2.9-MCK-TFEB vector. An animal cohort was analyzed at 3 months for muscle and heart pathology. A second cohort was followed at different timepoints for functional analysis. In muscles from TFEB-treated mice we observed reduced PAS staining and improved ultrastructure, with reduced number and increased translucency of lysosomes, while total glycogen content remained unchanged. We also observed statistically significant improvements in rotarod performance in treated animals compared to AAV2.9-MCK-eGFP-treated mice at 5 and 8 months. Cardiac echography showed significant reduction in left-ventricular diameters. These results show that TFEB overexpression and modulation of autophagy result in improvements of muscle pathology and of functional performance in the PD murine model, with delayed disease progression.Francesca GattoBarbara RossiAntonietta TaralloElena PolishchukRoman PolishchukAlessandra CarrellaEdoardo NuscoFilomena Grazia AlvinoFrancesca IacobellisElvira De LeonibusAlberto AuricchioGraciana Diez-RouxAndrea BallabioGiancarlo ParentiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Francesca Gatto Barbara Rossi Antonietta Tarallo Elena Polishchuk Roman Polishchuk Alessandra Carrella Edoardo Nusco Filomena Grazia Alvino Francesca Iacobellis Elvira De Leonibus Alberto Auricchio Graciana Diez-Roux Andrea Ballabio Giancarlo Parenti AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease
description	Abstract Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD. We treated 1-month-old PD mice with an AAV2.9-MCK-TFEB vector. An animal cohort was analyzed at 3 months for muscle and heart pathology. A second cohort was followed at different timepoints for functional analysis. In muscles from TFEB-treated mice we observed reduced PAS staining and improved ultrastructure, with reduced number and increased translucency of lysosomes, while total glycogen content remained unchanged. We also observed statistically significant improvements in rotarod performance in treated animals compared to AAV2.9-MCK-eGFP-treated mice at 5 and 8 months. Cardiac echography showed significant reduction in left-ventricular diameters. These results show that TFEB overexpression and modulation of autophagy result in improvements of muscle pathology and of functional performance in the PD murine model, with delayed disease progression.
format	article
author	Francesca Gatto Barbara Rossi Antonietta Tarallo Elena Polishchuk Roman Polishchuk Alessandra Carrella Edoardo Nusco Filomena Grazia Alvino Francesca Iacobellis Elvira De Leonibus Alberto Auricchio Graciana Diez-Roux Andrea Ballabio Giancarlo Parenti
author_facet	Francesca Gatto Barbara Rossi Antonietta Tarallo Elena Polishchuk Roman Polishchuk Alessandra Carrella Edoardo Nusco Filomena Grazia Alvino Francesca Iacobellis Elvira De Leonibus Alberto Auricchio Graciana Diez-Roux Andrea Ballabio Giancarlo Parenti
author_sort	Francesca Gatto
title	AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease
title_short	AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease
title_full	AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease
title_fullStr	AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease
title_full_unstemmed	AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease
title_sort	aav-mediated transcription factor eb (tfeb) gene delivery ameliorates muscle pathology and function in the murine model of pompe disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/678d39e7a19b43b9866916b4208c4792
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AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease

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