Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of erythropoietic protoporphyria.
Albumins
/ metabolism
Animals
Bone Marrow
/ metabolism
COS Cells
Chlorocebus aethiops
Disease Models, Animal
Ferrochelatase
/ genetics
Humans
K562 Cells
Mice
Oligonucleotides
/ administration & dosage
Polymorphism, Single Nucleotide
Protoporphyria, Erythropoietic
/ genetics
RNA Splice Sites
RNA Splicing
Tissue Distribution
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 05 2020
21 05 2020
Historique:
accepted:
09
04
2020
revised:
25
03
2020
received:
14
02
2020
pubmed:
22
4
2020
medline:
9
9
2020
entrez:
22
4
2020
Statut:
ppublish
Résumé
Erythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase (FECH) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation in trans to an allele bearing a SNP that favors aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.
Identifiants
pubmed: 32313951
pii: 5822958
doi: 10.1093/nar/gkaa229
pmc: PMC7229840
doi:
Substances chimiques
Albumins
0
Oligonucleotides
0
RNA Splice Sites
0
Ferrochelatase
EC 4.99.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4658-4671Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Adv Drug Deliv Rev. 2015 Jun 29;87:46-51
pubmed: 25666165
Blood Cells Mol Dis. 2013 Oct;51(3):151-61
pubmed: 23787363
Nature. 2005 Dec 1;438(7068):685-9
pubmed: 16258535
Nucleic Acid Ther. 2020 Apr;30(2):67-70
pubmed: 32043902
Bioanalysis. 2017 Dec;9(23):1859-1872
pubmed: 29205051
Nat Chem Biol. 2012 Apr 15;8(6):555-61
pubmed: 22504300
Clin Cancer Res. 2011 Oct 15;17(20):6417-27
pubmed: 22003069
Nucleic Acid Ther. 2017 Dec;27(6):335-344
pubmed: 28945147
Oligonucleotides. 2010 Dec;20(6):309-16
pubmed: 21117960
Nat Biotechnol. 2002 Dec;20(12):1228-33
pubmed: 12426578
Blood. 1999 Mar 15;93(6):2105-10
pubmed: 10068685
Nucleic Acids Res. 2013 Aug;41(15):e145
pubmed: 23766292
Stem Cells. 2004;22(6):1030-8
pubmed: 15536193
Blood. 2003 Aug 15;102(4):1458-65
pubmed: 12714494
Expert Opin Drug Metab Toxicol. 2009 Apr;5(4):381-91
pubmed: 19379126
Org Lett. 2011 Aug 19;13(16):4364-7
pubmed: 21790151
Nucleic Acid Ther. 2018 Jun;28(3):128-136
pubmed: 29746209
J Immunol. 2006 Mar 15;176(6):3652-61
pubmed: 16517734
Gut. 2007 Jul;56(7):1009-18
pubmed: 17360790
Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8673-7
pubmed: 8378346
Nucleic Acids Res. 2016 Aug 19;44(14):6549-63
pubmed: 27288447
Nucleic Acids Res. 2017 Apr 7;45(6):3448-3459
pubmed: 27899591
Am J Hum Genet. 2014 Apr 3;94(4):611-7
pubmed: 24680888
J Pharm Sci. 2004 Jan;93(1):48-59
pubmed: 14648635
Hematology Am Soc Hematol Educ Program. 2012;2012:19-27
pubmed: 23233556
Mol Diagn Ther. 2020 Feb;24(1):61-68
pubmed: 31792921
Biochem Pharmacol. 2009 Mar 1;77(5):910-9
pubmed: 19056355
Dis Model Mech. 2017 Mar 1;10(3):225-233
pubmed: 28093505
Clin Kidney J. 2018 Apr;11(2):191-197
pubmed: 29644058
Free Radic Biol Med. 2013 Dec;65:244-253
pubmed: 23747983
Mol Ther. 2013 Mar;21(3):602-9
pubmed: 23319054
Nucleic Acids Res. 2007;35(9):2885-92
pubmed: 17439965
Am J Hum Genet. 2008 Apr;82(4):834-48
pubmed: 18371932
Chem Commun (Camb). 2017 Jan 3;53(3):541-544
pubmed: 27966701
Nucleic Acid Ther. 2020 Feb;30(1):4-13
pubmed: 31618108
J Am Chem Soc. 2014 Dec 10;136(49):16958-61
pubmed: 25434769
Nucleic Acids Res. 2019 Feb 20;47(3):1070-1081
pubmed: 30535404
Nucleic Acids Res. 2018 Nov 30;46(21):11396-11404
pubmed: 30329087
CNS Drugs. 2019 Sep;33(9):919-932
pubmed: 31420846
Nucleic Acid Ther. 2018 Feb;28(1):10-22
pubmed: 29185862
Bioanalysis. 2017 Jun;9(11):861-872
pubmed: 28617037
Chem Commun (Camb). 2016 Jan 4;52(1):156-9
pubmed: 26505838
Nucleic Acids Res. 2012 Nov;40(21):10585-95
pubmed: 22989709
Org Biomol Chem. 2012 Nov 14;10(42):8478-83
pubmed: 23007699
Nat Biotechnol. 2007 Oct;25(10):1149-57
pubmed: 17873866
Am J Hum Genet. 2019 Feb 7;104(2):341-347
pubmed: 30712775
Cold Spring Harb Perspect Med. 2013 Apr 01;3(4):a011601
pubmed: 23545573
Nucleic Acids Res. 2009 May;37(9):e67
pubmed: 19339519
Nat Genet. 2002 Jan;30(1):27-8
pubmed: 11753383
Nucleic Acids Res. 2019 Jul 9;47(12):6029-6044
pubmed: 31127296
Nucleic Acids Res. 2018 Jun 1;46(10):4833-4844
pubmed: 29672717
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5797-802
pubmed: 18391195
Nucleic Acids Res. 2015 May 19;43(9):4627-39
pubmed: 25878036
Genes Dev. 2010 Aug 1;24(15):1634-44
pubmed: 20624852
Am J Hum Genet. 1998 Jun;62(6):1341-52
pubmed: 9585598
Nucleic Acid Ther. 2020 Feb;30(1):50-65
pubmed: 31821107
Drug Discov Today. 2014 Jul;19(7):869-81
pubmed: 24239727
Int J Cancer. 1979 Feb;23(2):143-7
pubmed: 367973
Mol Ther Nucleic Acids. 2012 Jul 31;1:e33
pubmed: 23344149
Nucleic Acids Res. 2019 Feb 20;47(3):1082-1096
pubmed: 30544191
Nat Rev Genet. 2016 Jan;17(1):19-32
pubmed: 26593421
J Pharmacol Exp Ther. 1996 May;277(2):923-37
pubmed: 8627575
Methods Mol Biol. 2018;1828:79-90
pubmed: 30171536
Mol Cell Pediatr. 2018 Feb 6;5(1):3
pubmed: 29411170