Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein.
Antisense oligonucleotide
Frataxin
Friedreich’s Ataxia
Gene activation
RNA
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
22
01
2020
revised:
24
03
2020
accepted:
26
03
2020
pubmed:
14
4
2020
medline:
2
6
2021
entrez:
14
4
2020
Statut:
ppublish
Résumé
Friedreich's Ataxia (FRDA) is an incurable genetic disease caused by an expanded trinucleotide AAG repeat within intronic RNA of the frataxin (FXN) gene. We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN and return levels of FXN protein to near normal. The potency of these compounds, however, was too low to encourage vigorous pre-clinical development. We now report testing of "gapmer" oligonucleotides consisting of a central DNA portion flanked by chemically modified RNA that increases binding affinity. We find that gapmer antisense oligonucleotides are several fold more potent activators of FXN expression relative to previously tested compounds. The potency of FXN activation is similar to a potent benchmark gapmer targeting the nuclear noncoding RNA MALAT-1, suggesting that our approach has potential for developing more effective compounds to regulate FXN expression in vivo.
Identifiants
pubmed: 32279920
pii: S0968-0896(20)30286-8
doi: 10.1016/j.bmc.2020.115472
pmc: PMC7217746
mid: NIHMS1583645
pii:
doi:
Substances chimiques
Iron-Binding Proteins
0
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115472Subventions
Organisme : NINDS NIH HHS
ID : R01 NS081366
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118103
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest DRC has filed a patent application related to early work on this topic.
Références
Nat Biotechnol. 2009 Mar;27(3):275-80
pubmed: 19252484
Fundam Clin Pharmacol. 2008 Dec;22(6):633-48
pubmed: 19049668
Nat Biotechnol. 2019 Jun;37(6):640-650
pubmed: 31036929
RNA. 2019 Sep;25(9):1118-1129
pubmed: 31151992
Nat Commun. 2016 Feb 04;7:10606
pubmed: 26842135
Neurobiol Dis. 2019 Dec;132:104606
pubmed: 31494282
N Engl J Med. 2019 Jun 13;380(24):2307-2316
pubmed: 31059641
Nucleic Acids Res. 2018 Feb 28;46(4):1584-1600
pubmed: 29240946
Nucleic Acid Ther. 2018 Feb;28(1):23-33
pubmed: 29341839
Bioorg Med Chem Lett. 2018 Sep 15;28(17):2850-2855
pubmed: 30076049
Nucleic Acids Res. 2017 Mar 17;45(5):2294-2306
pubmed: 28158620
Nucleic Acids Res. 2010 Aug;38(15):5242-59
pubmed: 20403811
Annu Rev Neurosci. 2019 Jul 8;42:385-406
pubmed: 31283897
N Engl J Med. 2019 Aug 8;381(6):531-542
pubmed: 31390500
N Engl J Med. 2019 Oct 24;381(17):1644-1652
pubmed: 31597037
PLoS Genet. 2014 May 01;10(5):e1004318
pubmed: 24787137
Nat Neurosci. 2017 Apr;20(4):497-499
pubmed: 28192393
Nat Nanotechnol. 2019 Dec;14(12):1084-1087
pubmed: 31802031
Pharmacol Res. 2019 Dec;150:104413
pubmed: 31449975
N Engl J Med. 2019 Feb 7;380(6):549-558
pubmed: 30726693
N Engl J Med. 2019 Jan 3;380(1):57-70
pubmed: 30601736
Nucleic Acid Ther. 2019 Dec;29(6):302-304
pubmed: 31804155
Mol Ther. 2015 Jun;23(6):1055-1065
pubmed: 25758173