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Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae...

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Autores principales: Murtada, Sae-Il, Mikush, Nicole, Wang, Mo, Ren, Pengwei, Kawamura, Yuki, Ramachandra, Abhay B, Li, David S, Braddock, Demetrios T, Tellides, George, Gordon, Leslie B, Humphrey, Jay D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10023154/
https://www.ncbi.nlm.nih.gov/pubmed/36930696
http://dx.doi.org/10.7554/eLife.82728
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author Murtada, Sae-Il
Mikush, Nicole
Wang, Mo
Ren, Pengwei
Kawamura, Yuki
Ramachandra, Abhay B
Li, David S
Braddock, Demetrios T
Tellides, George
Gordon, Leslie B
Humphrey, Jay D
author_facet Murtada, Sae-Il
Mikush, Nicole
Wang, Mo
Ren, Pengwei
Kawamura, Yuki
Ramachandra, Abhay B
Li, David S
Braddock, Demetrios T
Tellides, George
Gordon, Leslie B
Humphrey, Jay D
author_sort Murtada, Sae-Il
collection PubMed
description Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.
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spelling pubmed-100231542023-03-18 Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome Murtada, Sae-Il Mikush, Nicole Wang, Mo Ren, Pengwei Kawamura, Yuki Ramachandra, Abhay B Li, David S Braddock, Demetrios T Tellides, George Gordon, Leslie B Humphrey, Jay D eLife Physics of Living Systems Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy. eLife Sciences Publications, Ltd 2023-03-17 /pmc/articles/PMC10023154/ /pubmed/36930696 http://dx.doi.org/10.7554/eLife.82728 Text en © 2023, Murtada et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Physics of Living Systems
Murtada, Sae-Il
Mikush, Nicole
Wang, Mo
Ren, Pengwei
Kawamura, Yuki
Ramachandra, Abhay B
Li, David S
Braddock, Demetrios T
Tellides, George
Gordon, Leslie B
Humphrey, Jay D
Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
title Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
title_full Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
title_fullStr Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
title_full_unstemmed Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
title_short Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome
title_sort lonafarnib improves cardiovascular function and survival in a mouse model of hutchinson-gilford progeria syndrome
topic Physics of Living Systems
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10023154/
https://www.ncbi.nlm.nih.gov/pubmed/36930696
http://dx.doi.org/10.7554/eLife.82728
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