Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome

Abstract Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC...

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Autores principales:	Steven J. Fliesler, Neal S. Peachey, Josi Herron, Kelly M. Hines, Nadav I. Weinstock, Sriganesh Ramachandra Rao, Libin Xu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0f9352eaa4c44a5492915c722acf3157
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spelling	oai:doaj.org-article:0f9352eaa4c44a5492915c722acf31572021-12-02T15:08:14ZPrevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome10.1038/s41598-018-19592-82045-2322https://doaj.org/article/0f9352eaa4c44a5492915c722acf31572018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19592-8https://doaj.org/toc/2045-2322Abstract Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC and 7DHC-derived oxysterols occur in SLOS patients and in rats treated with the DHCR7 inhibitor AY9944. The rat SLOS model exhibits progressive and irreversible retinal dysfunction and degeneration, which is only partially ameliorated by dietary CHOL supplementation. We hypothesized that 7DHC-derived oxysterols are causally involved in this retinal degeneration, and that blocking or reducing their formation should minimize the phenotype. Here, using the SLOS rat model, we demonstrate that combined dietary supplementation with CHOL plus antioxidants (vitamins E and C, plus sodium selenite) provides better outcomes than dietary CHOL supplementation alone with regard to preservation of retinal structure and function and lowering 7DHC-derived oxysterol formation. These proof-of-principle findings provide a translational, pre-clinical framework for designing clinical trials using CHOL-antioxidant combination therapy as an improved therapeutic intervention over the current standard of care for the treatment of SLOS.Steven J. FlieslerNeal S. PeacheyJosi HerronKelly M. HinesNadav I. WeinstockSriganesh Ramachandra RaoLibin XuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Steven J. Fliesler Neal S. Peachey Josi Herron Kelly M. Hines Nadav I. Weinstock Sriganesh Ramachandra Rao Libin Xu Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
description	Abstract Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC and 7DHC-derived oxysterols occur in SLOS patients and in rats treated with the DHCR7 inhibitor AY9944. The rat SLOS model exhibits progressive and irreversible retinal dysfunction and degeneration, which is only partially ameliorated by dietary CHOL supplementation. We hypothesized that 7DHC-derived oxysterols are causally involved in this retinal degeneration, and that blocking or reducing their formation should minimize the phenotype. Here, using the SLOS rat model, we demonstrate that combined dietary supplementation with CHOL plus antioxidants (vitamins E and C, plus sodium selenite) provides better outcomes than dietary CHOL supplementation alone with regard to preservation of retinal structure and function and lowering 7DHC-derived oxysterol formation. These proof-of-principle findings provide a translational, pre-clinical framework for designing clinical trials using CHOL-antioxidant combination therapy as an improved therapeutic intervention over the current standard of care for the treatment of SLOS.
format	article
author	Steven J. Fliesler Neal S. Peachey Josi Herron Kelly M. Hines Nadav I. Weinstock Sriganesh Ramachandra Rao Libin Xu
author_facet	Steven J. Fliesler Neal S. Peachey Josi Herron Kelly M. Hines Nadav I. Weinstock Sriganesh Ramachandra Rao Libin Xu
author_sort	Steven J. Fliesler
title	Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
title_short	Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
title_full	Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
title_fullStr	Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
title_full_unstemmed	Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
title_sort	prevention of retinal degeneration in a rat model of smith-lemli-opitz syndrome
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/0f9352eaa4c44a5492915c722acf3157
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Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome

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