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GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models

AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for t...

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Autores principales: Gorgogietas, Vyron, Rajaei, Bahareh, Heeyoung, Chae, Santacreu, Bruno J., Marín-Cañas, Sandra, Salpea, Paraskevi, Sawatani, Toshiaki, Musuaya, Anyishai, Arroyo, María N., Moreno-Castro, Cristina, Benabdallah, Khadija, Demarez, Celine, Toivonen, Sanna, Cosentino, Cristina, Pachera, Nathalie, Lytrivi, Maria, Cai, Ying, Carnel, Lode, Brown, Cris, Urano, Fumihiko, Marchetti, Piero, Gilon, Patrick, Eizirik, Decio L., Cnop, Miriam, Igoillo-Esteve, Mariana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244297/
https://www.ncbi.nlm.nih.gov/pubmed/36995380
http://dx.doi.org/10.1007/s00125-023-05905-8
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author Gorgogietas, Vyron
Rajaei, Bahareh
Heeyoung, Chae
Santacreu, Bruno J.
Marín-Cañas, Sandra
Salpea, Paraskevi
Sawatani, Toshiaki
Musuaya, Anyishai
Arroyo, María N.
Moreno-Castro, Cristina
Benabdallah, Khadija
Demarez, Celine
Toivonen, Sanna
Cosentino, Cristina
Pachera, Nathalie
Lytrivi, Maria
Cai, Ying
Carnel, Lode
Brown, Cris
Urano, Fumihiko
Marchetti, Piero
Gilon, Patrick
Eizirik, Decio L.
Cnop, Miriam
Igoillo-Esteve, Mariana
author_facet Gorgogietas, Vyron
Rajaei, Bahareh
Heeyoung, Chae
Santacreu, Bruno J.
Marín-Cañas, Sandra
Salpea, Paraskevi
Sawatani, Toshiaki
Musuaya, Anyishai
Arroyo, María N.
Moreno-Castro, Cristina
Benabdallah, Khadija
Demarez, Celine
Toivonen, Sanna
Cosentino, Cristina
Pachera, Nathalie
Lytrivi, Maria
Cai, Ying
Carnel, Lode
Brown, Cris
Urano, Fumihiko
Marchetti, Piero
Gilon, Patrick
Eizirik, Decio L.
Cnop, Miriam
Igoillo-Esteve, Mariana
author_sort Gorgogietas, Vyron
collection PubMed
description AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. METHODS: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. RESULTS: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. CONCLUSIONS/INTERPRETATION: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-023-05905-8) contains peer-reviewed but unedited supplementary material.
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spelling pubmed-102442972023-06-08 GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models Gorgogietas, Vyron Rajaei, Bahareh Heeyoung, Chae Santacreu, Bruno J. Marín-Cañas, Sandra Salpea, Paraskevi Sawatani, Toshiaki Musuaya, Anyishai Arroyo, María N. Moreno-Castro, Cristina Benabdallah, Khadija Demarez, Celine Toivonen, Sanna Cosentino, Cristina Pachera, Nathalie Lytrivi, Maria Cai, Ying Carnel, Lode Brown, Cris Urano, Fumihiko Marchetti, Piero Gilon, Patrick Eizirik, Decio L. Cnop, Miriam Igoillo-Esteve, Mariana Diabetologia Article AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. METHODS: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. RESULTS: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. CONCLUSIONS/INTERPRETATION: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-023-05905-8) contains peer-reviewed but unedited supplementary material. Springer Berlin Heidelberg 2023-03-30 2023 /pmc/articles/PMC10244297/ /pubmed/36995380 http://dx.doi.org/10.1007/s00125-023-05905-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gorgogietas, Vyron
Rajaei, Bahareh
Heeyoung, Chae
Santacreu, Bruno J.
Marín-Cañas, Sandra
Salpea, Paraskevi
Sawatani, Toshiaki
Musuaya, Anyishai
Arroyo, María N.
Moreno-Castro, Cristina
Benabdallah, Khadija
Demarez, Celine
Toivonen, Sanna
Cosentino, Cristina
Pachera, Nathalie
Lytrivi, Maria
Cai, Ying
Carnel, Lode
Brown, Cris
Urano, Fumihiko
Marchetti, Piero
Gilon, Patrick
Eizirik, Decio L.
Cnop, Miriam
Igoillo-Esteve, Mariana
GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
title GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
title_full GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
title_fullStr GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
title_full_unstemmed GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
title_short GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models
title_sort glp-1r agonists demonstrate potential to treat wolfram syndrome in human preclinical models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244297/
https://www.ncbi.nlm.nih.gov/pubmed/36995380
http://dx.doi.org/10.1007/s00125-023-05905-8
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