Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis

Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutatio...

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Autores principales:	Antje Banning, Ritva Tikkanen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	RNA splicing splice-modulators xanthines luteolin caffeine splicing defects Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d4e96def2f9f48ecb36882831720c586
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spelling	oai:doaj.org-article:d4e96def2f9f48ecb36882831720c5862021-11-25T17:07:25ZTowards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis10.3390/cells101128132073-4409https://doaj.org/article/d4e96def2f9f48ecb36882831720c5862021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2813https://doaj.org/toc/2073-4409Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing <i>TPP1</i> gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.Antje BanningRitva TikkanenMDPI AGarticleRNA splicingsplice-modulatorsxanthinesluteolincaffeinesplicing defectsBiology (General)QH301-705.5ENCells, Vol 10, Iss 2813, p 2813 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	RNA splicing splice-modulators xanthines luteolin caffeine splicing defects Biology (General) QH301-705.5
spellingShingle	RNA splicing splice-modulators xanthines luteolin caffeine splicing defects Biology (General) QH301-705.5 Antje Banning Ritva Tikkanen Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
description	Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing <i>TPP1</i> gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.
format	article
author	Antje Banning Ritva Tikkanen
author_facet	Antje Banning Ritva Tikkanen
author_sort	Antje Banning
title	Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
title_short	Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
title_full	Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
title_fullStr	Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
title_full_unstemmed	Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
title_sort	towards splicing therapy for lysosomal storage disorders: methylxanthines and luteolin ameliorate splicing defects in aspartylglucosaminuria and classic late infantile neuronal ceroid lipofuscinosis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d4e96def2f9f48ecb36882831720c586
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Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis

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