SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 11 2019
18 11 2019
Historique:
accepted:
28
09
2019
revised:
08
08
2019
received:
21
02
2019
pubmed:
5
10
2019
medline:
19
5
2020
entrez:
5
10
2019
Statut:
ppublish
Résumé
Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.
Identifiants
pubmed: 31584077
pii: 5580914
doi: 10.1093/nar/gkz798
pmc: PMC6847766
doi:
Substances chimiques
Iron-Binding Proteins
0
RNA, Messenger
0
RNA, Untranslated
0
Aconitate Hydratase
EC 4.2.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10728-10743Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Nature. 2014 Mar 27;507(7493):462-70
pubmed: 24670764
J Neurochem. 2013 Aug;126 Suppl 1:53-64
pubmed: 23859341
J Neurol Sci. 2011 Apr 15;303(1-2):1-12
pubmed: 21315377
Science. 2004 Jul 9;305(5681):242-5
pubmed: 15247478
Nat Chem Biol. 2006 Oct;2(10):551-8
pubmed: 16921367
Am J Hum Genet. 1996 Sep;59(3):554-60
pubmed: 8751856
Front Cell Neurosci. 2015 May 13;9:174
pubmed: 26029048
J Neurochem. 2013 Aug;126 Suppl 1:65-79
pubmed: 23859342
Neurobiol Dis. 2015 Mar;75:91-9
pubmed: 25549872
Hum Mol Genet. 1997 Oct;6(11):1771-80
pubmed: 9302253
J Biol Chem. 2017 Aug 4;292(31):12754-12763
pubmed: 28615445
Hum Mol Genet. 2015 Aug 1;24(15):4296-305
pubmed: 25948553
Hum Mol Genet. 2008 Mar 1;17(5):735-46
pubmed: 18045775
Mol Genet Metab. 2010 Oct-Nov;101(2-3):238-45
pubmed: 20675166
Nat Commun. 2016 Feb 04;7:10606
pubmed: 26842135
Hum Mol Genet. 2007 Jul 1;16(13):1534-40
pubmed: 17468497
PLoS One. 2018 Feb 7;13(2):e0183229
pubmed: 29414979
J Biol Chem. 2006 Jun 16;281(24):16750-6
pubmed: 16608849
PLoS Genet. 2014 May 01;10(5):e1004318
pubmed: 24787137
Ann Neurol. 1997 May;41(5):675-82
pubmed: 9153531
Nat Biotechnol. 2014 Mar;32(3):217-9
pubmed: 24727769
J Biol Chem. 2001 Jul 20;276(29):27171-7
pubmed: 11340071
J Neurol Neurosurg Psychiatry. 2004 Jul;75(7):1061-3
pubmed: 15201375
Nat Protoc. 2008;3(6):1101-8
pubmed: 18546601
Science. 1996 Mar 8;271(5254):1423-7
pubmed: 8596916
Nature. 2012 Nov 15;491(7424):454-7
pubmed: 23064229
Hum Mol Genet. 2010 Apr 1;19(7):1221-9
pubmed: 20053667
Nat Biotechnol. 2017 Mar;35(3):222-229
pubmed: 28244992
Biochemistry. 2010 Nov 2;49(43):9132-9
pubmed: 20873749
J Biol Chem. 2004 Jun 18;279(25):25943-6
pubmed: 15123683
Nat Med. 2014 May;20(5):542-7
pubmed: 24705334
Ann Neurol. 2016 Mar;79(3):485-95
pubmed: 26704351
RNA Biol. 2015;12(8):771-9
pubmed: 26259533
PLoS One. 2011 Jan 26;6(1):e16199
pubmed: 21298097
Hum Mol Genet. 2012 Mar 15;21(6):1230-47
pubmed: 22113996
Nucleic Acid Ther. 2018 Feb;28(1):23-33
pubmed: 29341839
Sci Rep. 2018 Feb 16;8(1):3189
pubmed: 29453387
Genomics. 2015 Aug;106(2):76-82
pubmed: 26027909
J Biol Chem. 2017 Aug 4;292(31):12744-12753
pubmed: 28615439
PLoS One. 2010 Oct 04;5(10):null
pubmed: 20957177
PLoS One. 2009 Nov 19;4(11):e7914
pubmed: 19956589
Neurol Neurochir Pol. 2018 Mar;52(2):129-139
pubmed: 29499876
Prog Neurobiol. 2017 Aug;155:194-211
pubmed: 27887908
Biochemistry. 2014 Aug 5;53(30):4904-13
pubmed: 24971490
Sci Rep. 2016 Jun 06;6:27315
pubmed: 27265476
BMC Med. 2011 Oct 11;9:112
pubmed: 21985033
J Child Neurol. 2012 Sep;27(9):1133-7
pubmed: 22752493
Mol Ther. 2007 Feb;15(2):248-54
pubmed: 17235301
J Am Chem Soc. 2003 May 21;125(20):6078-84
pubmed: 12785837
Nat Neurosci. 2017 Apr;20(4):497-499
pubmed: 28192393
J Neurol. 2009 Mar;256 Suppl 1:3-8
pubmed: 19283344
J Neurochem. 2013 Aug;126 Suppl 1:43-52
pubmed: 23859340
Hum Mol Genet. 2011 Apr 1;20(7):1253-61
pubmed: 21216878
PLoS One. 2011 Mar 11;6(3):e17627
pubmed: 21412413
Dis Model Mech. 2018 Jun 25;11(6):
pubmed: 29794127
Methods Enzymol. 2002;346:454-65
pubmed: 11883085
Neurobiol Dis. 2011 Jun;42(3):496-505
pubmed: 21397024
Expert Rev Neurother. 2017 Sep;17(9):895-907
pubmed: 28724340
Hum Mol Genet. 2012 Jul 1;21(13):2855-61
pubmed: 22447512
Mol Ther. 2017 May 3;25(5):1069-1075
pubmed: 28366767
Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):692-7
pubmed: 20080737
Hum Mol Genet. 2014 Dec 20;23(25):6848-62
pubmed: 25113747
Nucleic Acids Res. 2007;35(16):5351-9
pubmed: 17693431
Gene. 2015 Sep 15;569(2):287-93
pubmed: 26045368
Nat Rev Drug Discov. 2014 Aug;13(8):622-38
pubmed: 25011539
RNA. 2008 Sep;14(9):1865-73
pubmed: 18658125
Mol Ther. 2015 Jun;23(6):1055-1065
pubmed: 25758173
Br J Pharmacol. 2014 Apr;171(8):2174-90
pubmed: 24138602
Science. 2017 Dec 22;358(6370):1617-1622
pubmed: 29192133