Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression

Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nons...

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Main Authors:	Keeling, Kim M., Wang, Dan, Dai, Yanying, Murugesan, Srinivasan, Chenna, Balachandra, Clark, Jeremy, Belakhov, Valery, Kandasamy, Jeyakumar, Velu, Sadanandan E., Baasov, Timor, Bedwell, David M.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622682/

id	pubmed-3622682
recordtype	oai_dc
spelling	pubmed-36226822013-04-16 Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression Keeling, Kim M. Wang, Dan Dai, Yanying Murugesan, Srinivasan Chenna, Balachandra Clark, Jeremy Belakhov, Valery Kandasamy, Jeyakumar Velu, Sadanandan E. Baasov, Timor Bedwell, David M. Research Article Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the abundance of mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model of the lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS I-H) that carries a PTC in the Idua locus to test whether NMD attenuation can enhance PTC suppression in vivo. Idua encodes alpha-L-iduronidase, an enzyme required for degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. We found that the NMD attenuator NMDI-1 increased the abundance of the PTC-containing Idua transcript. Furthermore, co-administration of NMDI-1 with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamicin alone, leading to a greater reduction of GAG storage in mouse tissues, including the brain. These results demonstrate that NMD attenuation significantly enhances suppression therapy in vivo. Public Library of Science 2013-04-10 /pmc/articles/PMC3622682/ /pubmed/23593225 http://dx.doi.org/10.1371/journal.pone.0060478 Text en © 2013 Keeling et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Keeling, Kim M. Wang, Dan Dai, Yanying Murugesan, Srinivasan Chenna, Balachandra Clark, Jeremy Belakhov, Valery Kandasamy, Jeyakumar Velu, Sadanandan E. Baasov, Timor Bedwell, David M.
spellingShingle	Keeling, Kim M. Wang, Dan Dai, Yanying Murugesan, Srinivasan Chenna, Balachandra Clark, Jeremy Belakhov, Valery Kandasamy, Jeyakumar Velu, Sadanandan E. Baasov, Timor Bedwell, David M. Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression
author_facet	Keeling, Kim M. Wang, Dan Dai, Yanying Murugesan, Srinivasan Chenna, Balachandra Clark, Jeremy Belakhov, Valery Kandasamy, Jeyakumar Velu, Sadanandan E. Baasov, Timor Bedwell, David M.
author_sort	Keeling, Kim M.
title	Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression
title_short	Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression
title_full	Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression
title_fullStr	Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression
title_full_unstemmed	Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression
title_sort	attenuation of nonsense-mediated mrna decay enhances in vivo nonsense suppression
description	Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the abundance of mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model of the lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS I-H) that carries a PTC in the Idua locus to test whether NMD attenuation can enhance PTC suppression in vivo. Idua encodes alpha-L-iduronidase, an enzyme required for degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. We found that the NMD attenuator NMDI-1 increased the abundance of the PTC-containing Idua transcript. Furthermore, co-administration of NMDI-1 with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamicin alone, leading to a greater reduction of GAG storage in mouse tissues, including the brain. These results demonstrate that NMD attenuation significantly enhances suppression therapy in vivo.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622682/
_version_	1611969324657934336

Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression

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