Use of PTC124 for nonsense suppression therapy targeting BMP4 nonsense variants in vitro and the bmp4st72 allele in zebrafish.


Journal

PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081

Informations de publication

Date de publication:
2019
Historique:
received: 23 08 2018
accepted: 07 04 2019
entrez: 25 4 2019
pubmed: 25 4 2019
medline: 24 12 2019
Statut: epublish

Résumé

Nonsense suppression therapy (NST) utilizes compounds such as PTC124 (Ataluren) to induce translational read-through of stop variants by promoting the insertion of near cognate, aminoacyl tRNAs that yield functional proteins. We used NST with PTC124 to determine if we could successfully rescue nonsense variants in human Bone Morphogenetic Protein 4 (BMP4) in vitro and in a zebrafish bmp4 allele with a stop variant in vivo. We transfected 293T/17 cells with wildtype or mutant human BMP4 cDNA containing p.Arg198* and p.Glu213* and exposed cells to 0-20 μM PTC124. Treatment with 20 μM PTC124 produced a small, non-significant increase in BMP4 when targeting the p.Arg198* allele, but not the p.Glu213* allele, as measured with an In-cell ELISA assay. We then examined the ability of PTC124 to rescue the ventral tail fin defects associated with homozygosity for the p.Glu209* allele of bmp4 (bmp4st72/st72) in Danio rerio. We in-crossed bmp4st72/+ heterozygous fish and found a statistically significant increase in homozygous larvae without tail fin and ventroposterior defects, consistent with phenotypic rescue, after treatment of dechorionated larvae with 0.5 μM PTC124. We conclude that treatment with PTC124 can rescue bmp4 nonsense variants, but that the degree of rescue may depend on sequence specific factors and the amount of RNA transcript available for rescue. Our work also confirms that zebrafish show promise as a useful animal model for assessing the efficacy of PTC124 treatment on nonsense variants.

Identifiants

pubmed: 31017898
doi: 10.1371/journal.pone.0212121
pii: PONE-D-18-24808
pmc: PMC6481805
doi:

Substances chimiques

BMP4 protein, human 0
Bone Morphogenetic Protein 4 0
Codon, Nonsense 0
Oxadiazoles 0
Zebrafish Proteins 0
bmp4 protein, zebrafish 0
ataluren K16AME9I3V

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e0212121

Déclaration de conflit d'intérêts

The authors have declared that no competing interests exist.

Références

FASEB J. 2014 Apr;28(4):1593-9
pubmed: 24371125
Hum Mol Genet. 2016 Aug 15;25(16):3416-3431
pubmed: 27329764
Eur J Hum Genet. 2007 Nov;15(11):1156-62
pubmed: 17625509
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2064-9
pubmed: 18272502
J Invest Dermatol. 2013 Dec;133(12):2672-2677
pubmed: 23702584
Dev Biol. 2007 Oct 1;310(1):71-84
pubmed: 17727832
Cell Mol Life Sci. 2016 Feb;73(4):841-57
pubmed: 26341094
Am J Respir Cell Mol Biol. 2013 Sep;49(3):403-9
pubmed: 23590310
Hum Mol Genet. 2008 Dec 15;17(24):3987-4000
pubmed: 18809619
Dev Biol. 2007 May 15;305(2):577-88
pubmed: 17395172
J Clin Invest. 2014 Jan;124(1):111-6
pubmed: 24355924
Exp Eye Res. 2017 Feb;155:24-37
pubmed: 28065590
Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3764-73
pubmed: 20130285
Exp Eye Res. 2013 Apr;109:98-106
pubmed: 23428741
Hum Gene Ther. 2011 May;22(5):537-47
pubmed: 21235327
Trends Genet. 2008 Nov;24(11):552-63
pubmed: 18937996
Hum Mol Genet. 2015 Feb 15;24(4):972-86
pubmed: 25292197
Eur J Oral Sci. 2013 Aug;121(4):313-8
pubmed: 23841782
RNA. 2000 Jul;6(7):1044-55
pubmed: 10917599
Lancet. 2017 Sep 23;390(10101):1489-1498
pubmed: 28728956
Cell Mol Life Sci. 2015 May;72(10):1931-8
pubmed: 25651836
Eur Respir J. 2011 Jul;38(1):59-69
pubmed: 21233271
Muscle Nerve. 2014 Oct;50(4):477-87
pubmed: 25042182
Expert Opin Pharmacother. 2017 Sep;18(13):1363-1371
pubmed: 28730885
Mol Ther Nucleic Acids. 2017 Jun 16;7:417-428
pubmed: 28624217
Hum Genet. 2011 Oct;130(4):495-504
pubmed: 21340693
BioDrugs. 2009;23(3):165-74
pubmed: 19627168
Nature. 2007 May 3;447(7140):87-91
pubmed: 17450125
Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12508-12513
pubmed: 27702906
J Clin Pharmacol. 2007 Apr;47(4):430-44
pubmed: 17389552
Ann Neurol. 2000 Aug;48(2):164-9
pubmed: 10939566
Paediatr Respir Rev. 2017 Sep;24:32-34
pubmed: 28566196
Gene Ther. 2004 Apr;11(7):619-27
pubmed: 14973546

Auteurs

Max Krall (M)

Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States of America.

Stephanie Htun (S)

Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States of America.

Anne Slavotinek (A)

Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States of America.

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Classifications MeSH