Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases

Nonsense mutations are quite prevalent in inherited diseases. Readthrough drugs could provide a therapeutic option for any disease caused by this type of mutation. Geneticin (G418) and gentamicin were among the first to be described. Novel compounds have been generated, but only a few have shown imp...

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Autores: Gómez Grau, Marta, Garrido Fernández, Elena, Cozar, Mónica, Rodríguez Sureda, Víctor, Domínguez, Carmen, Arenas Solà, Concepción, Gatti, Richard A, Cormand Rifà, Bru, Grinberg Vaisman, Daniel Raúl, Vilageliu i Arqués, Lluïsa
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/104382
Acesso em linha:https://hdl.handle.net/2445/104382
Access Level:acceso abierto
Palavra-chave:Lisosomes
Antibiòtics
Lysosomes
Antibiotics
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spelling Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseasesGómez Grau, MartaGarrido Fernández, ElenaCozar, MónicaRodríguez Sureda, VíctorDomínguez, CarmenArenas Solà, ConcepciónGatti, Richard ACormand Rifà, BruGrinberg Vaisman, Daniel RaúlVilageliu i Arqués, LluïsaLisosomesAntibiòticsLysosomesAntibioticsNonsense mutations are quite prevalent in inherited diseases. Readthrough drugs could provide a therapeutic option for any disease caused by this type of mutation. Geneticin (G418) and gentamicin were among the first to be described. Novel compounds have been generated, but only a few have shown improved results. PTC124 is the only compound to have reached clinical trials. Here we first investigated the readthrough effects of gentamicin on fibroblasts from one patient with Sanfilippo B, one with Sanfilippo C, and one with Maro- teaux-Lamy. We found that ARSB activity (Maroteaux-Lamy case) resulted in an increase of 2 - 3 folds and that the amount of this enzyme within the lysosomes was also increased, after treatment. Since the other two cases (Sanfilippo B and Sanfilippo C) did not respond to gentamicin, the treatments were extended with the use of geneticin and five non-aminogly- coside (PTC124, RTC13, RTC14, BZ6 and BZ16) readthrough compounds (RTCs). No recovery was observed at the enzyme activity level. However, mRNA recovery was observed in both cases, nearly a two-fold increase for Sanfilippo B fibroblasts with G418 and around 1.5 fold increase for Sanfilippo C cells with RTC14 and PTC124. Afterwards, some of the products were assessed through in vitro analyses for seven mutations in genes responsible for those diseases and, also, for Niemann-Pick A/B. Using the coupled tran- scription/translation system (TNT), the best results were obtained for SMPD1 mutations with G418, reaching a 35% recovery at 0.25 μ g/ml, for the p.W168X mutation. The use of COS cells transfected with mutant cDNAs gave positive results for most of the mutations with some of the drugs, although to a different extent. The higher enzyme activity recovery, of around two-fold increase, was found for gentamicin on the ARSB p.W146X mutation. Our results are promising and consistent with those of other groups. Further studies of novelcompounds are necessary to find those with more consistent efficacy and fewer toxic effectsPublic Library of Science (PLoS)2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/104382Articles publicats en revistes (Genètica, Microbiologia i Estadística)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1371/journal.pone.0135873PLoS One, 2015, vol. 10, num. 8, p. e0135873https://doi.org/10.1371/journal.pone.0135873cc-by (c) Gomez Grau, Marta et al., 2015http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1043822026-05-27T06:46:51Z
dc.title.none.fl_str_mv Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
title Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
spellingShingle Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
Gómez Grau, Marta
Lisosomes
Antibiòtics
Lysosomes
Antibiotics
title_short Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
title_full Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
title_fullStr Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
title_full_unstemmed Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
title_sort Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases
dc.creator.none.fl_str_mv Gómez Grau, Marta
Garrido Fernández, Elena
Cozar, Mónica
Rodríguez Sureda, Víctor
Domínguez, Carmen
Arenas Solà, Concepción
Gatti, Richard A
Cormand Rifà, Bru
Grinberg Vaisman, Daniel Raúl
Vilageliu i Arqués, Lluïsa
author Gómez Grau, Marta
author_facet Gómez Grau, Marta
Garrido Fernández, Elena
Cozar, Mónica
Rodríguez Sureda, Víctor
Domínguez, Carmen
Arenas Solà, Concepción
Gatti, Richard A
Cormand Rifà, Bru
Grinberg Vaisman, Daniel Raúl
Vilageliu i Arqués, Lluïsa
author_role author
author2 Garrido Fernández, Elena
Cozar, Mónica
Rodríguez Sureda, Víctor
Domínguez, Carmen
Arenas Solà, Concepción
Gatti, Richard A
Cormand Rifà, Bru
Grinberg Vaisman, Daniel Raúl
Vilageliu i Arqués, Lluïsa
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Lisosomes
Antibiòtics
Lysosomes
Antibiotics
topic Lisosomes
Antibiòtics
Lysosomes
Antibiotics
description Nonsense mutations are quite prevalent in inherited diseases. Readthrough drugs could provide a therapeutic option for any disease caused by this type of mutation. Geneticin (G418) and gentamicin were among the first to be described. Novel compounds have been generated, but only a few have shown improved results. PTC124 is the only compound to have reached clinical trials. Here we first investigated the readthrough effects of gentamicin on fibroblasts from one patient with Sanfilippo B, one with Sanfilippo C, and one with Maro- teaux-Lamy. We found that ARSB activity (Maroteaux-Lamy case) resulted in an increase of 2 - 3 folds and that the amount of this enzyme within the lysosomes was also increased, after treatment. Since the other two cases (Sanfilippo B and Sanfilippo C) did not respond to gentamicin, the treatments were extended with the use of geneticin and five non-aminogly- coside (PTC124, RTC13, RTC14, BZ6 and BZ16) readthrough compounds (RTCs). No recovery was observed at the enzyme activity level. However, mRNA recovery was observed in both cases, nearly a two-fold increase for Sanfilippo B fibroblasts with G418 and around 1.5 fold increase for Sanfilippo C cells with RTC14 and PTC124. Afterwards, some of the products were assessed through in vitro analyses for seven mutations in genes responsible for those diseases and, also, for Niemann-Pick A/B. Using the coupled tran- scription/translation system (TNT), the best results were obtained for SMPD1 mutations with G418, reaching a 35% recovery at 0.25 μ g/ml, for the p.W168X mutation. The use of COS cells transfected with mutant cDNAs gave positive results for most of the mutations with some of the drugs, although to a different extent. The higher enzyme activity recovery, of around two-fold increase, was found for gentamicin on the ARSB p.W146X mutation. Our results are promising and consistent with those of other groups. Further studies of novelcompounds are necessary to find those with more consistent efficacy and fewer toxic effects
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/104382
url https://hdl.handle.net/2445/104382
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0135873
PLoS One, 2015, vol. 10, num. 8, p. e0135873
https://doi.org/10.1371/journal.pone.0135873
dc.rights.none.fl_str_mv cc-by (c) Gomez Grau, Marta et al., 2015
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Gomez Grau, Marta et al., 2015
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Genètica, Microbiologia i Estadística)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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