Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
04 11 2020
04 11 2020
Historique:
accepted:
13
07
2020
revised:
23
06
2020
received:
13
05
2020
pubmed:
11
8
2020
medline:
21
11
2020
entrez:
11
8
2020
Statut:
ppublish
Résumé
Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.
Identifiants
pubmed: 32776089
pii: 5878830
doi: 10.1093/nar/gkaa616
pmc: PMC7641729
doi:
Substances chimiques
Oligonucleotides, Antisense
0
Prion Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
10615-10631Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM127045
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI122592
Pays : United States
Organisme : National Science Foundation
ID : GRFP 2015214731
Pays : International
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Acta Neuropathol. 2013 Jun;125(6):795-813
pubmed: 23604588
J Pharmacol Exp Ther. 2013 Nov;347(2):325-38
pubmed: 23965382
J Comp Pathol. 1963 Apr;73:150-62
pubmed: 14003830
Ann Clin Transl Neurol. 2016 Dec 27;4(2):139-144
pubmed: 28168213
Neurology. 2019 Jul 9;93(2):e125-e134
pubmed: 31171647
FASEB J. 2020 Feb;34(2):2359-2375
pubmed: 31907995
J Pharmacol Exp Ther. 2014 Jul;350(1):46-55
pubmed: 24784568
JAMA Neurol. 2019 Aug 01;76(8):969-977
pubmed: 31058916
Nature. 2020 May;581(7809):459-464
pubmed: 32461653
Antimicrob Agents Chemother. 2006 Mar;50(3):1034-44
pubmed: 16495266
Lancet Neurol. 2020 Apr;19(4):361-368
pubmed: 32199098
Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7793-7798
pubmed: 30936307
Alzheimers Res Ther. 2018 Jan 11;10(1):3
pubmed: 29368621
Nat Med. 2019 Feb;25(2):277-283
pubmed: 30664784
Lancet. 1961 Jun 24;1(7191):1378-9
pubmed: 13692303
Nature. 1996 Jan 25;379(6563):339-43
pubmed: 8552188
Vet Res. 2012 Dec 18;43:87
pubmed: 23249298
Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2403-7
pubmed: 8637886
PLoS One. 2014 Feb 14;9(2):e88797
pubmed: 24551164
Brain. 2004 Oct;127(Pt 10):2348-59
pubmed: 15361416
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1983-8
pubmed: 17261803
BMC Med. 2020 Jun 18;18(1):140
pubmed: 32552681
Science. 2010 Feb 26;327(5969):1132-5
pubmed: 20110469
Science. 2010 Feb 12;327(5967):869-72
pubmed: 20044542
Science. 2003 Oct 31;302(5646):871-4
pubmed: 14593181
PLoS One. 2014 May 27;9(5):e98496
pubmed: 24866748
Nat Neurosci. 2010 Mar;13(3):310-8
pubmed: 20098419
Mol Ther Nucleic Acids. 2017 Jun 16;7:200-210
pubmed: 28624196
PLoS Pathog. 2020 Jun 29;16(6):e1008653
pubmed: 32598380
Mol Syst Biol. 2009;5:252
pubmed: 19308092
Int J Mol Sci. 2017 May 17;18(5):
pubmed: 28513534
Biometrics. 1984 Sep;40(3):601-9
pubmed: 6394063
Mol Med. 2007 Mar-Apr;13(3-4):190-8
pubmed: 17592554
Nature. 1992 Apr 16;356(6370):577-82
pubmed: 1373228
Mol Med. 1994 Nov;1(1):19-30
pubmed: 8790598
Nat Biotechnol. 2007 Jan;25(1):132-8
pubmed: 17195841
J Gen Virol. 1991 Mar;72 ( Pt 3):595-603
pubmed: 1672371
Mol Ther Nucleic Acids. 2012 Feb 07;1:e9
pubmed: 23344724
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
pubmed: 9811807
Lancet Neurol. 2017 Aug;16(8):601-609
pubmed: 28601473
Neuron. 2016 Jul 6;91(1):56-66
pubmed: 27292537
N Engl J Med. 2019 Jun 13;380(24):2307-2316
pubmed: 31059641
J Biol Chem. 2014 Jul 18;289(29):19841-9
pubmed: 24860095
J Virol. 2004 May;78(10):4999-5006
pubmed: 15113880
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14508-13
pubmed: 20699386
Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10608-12
pubmed: 7902565
Mol Ther. 2017 Sep 6;25(9):2075-2092
pubmed: 28663102
J Exp Med. 2016 Mar 7;213(3):313-27
pubmed: 26926995
PLoS One. 2010 Jun 14;5(6):e11085
pubmed: 20559428
Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:81-105
pubmed: 27732800
Ann Neurol. 2017 Jan;81(1):79-92
pubmed: 27893164
Neurosci Lett. 2004 Sep 2;367(2):210-2
pubmed: 15331155
Annu Rev Med. 2019 Jan 27;70:307-321
pubmed: 30691367
Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):E4160-9
pubmed: 24128760
EMBO J. 1996 Mar 15;15(6):1255-64
pubmed: 8635458
PLoS Pathog. 2009 Nov;5(11):e1000673
pubmed: 19956709
Biomolecules. 2019 Dec 18;10(1):
pubmed: 31861275
J Neurol Neurosurg Psychiatry. 2018 Sep;89(9):955-961
pubmed: 29487167
PLoS One. 2015 Dec 30;10(12):e0146021
pubmed: 26717316
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):15002-6
pubmed: 19706444
Nature. 2016 Aug 25;536(7617):464-8
pubmed: 27501152
Brain Pathol. 1995 Jan;5(1):53-9
pubmed: 7767491
J Pharmacol Exp Ther. 2015 Oct;355(1):2-12
pubmed: 26224882
Cell. 1993 Jul 2;73(7):1339-47
pubmed: 8100741
J Gen Virol. 2005 Oct;86(Pt 10):2913-2923
pubmed: 16186247
Nucleic Acid Ther. 2019 Jun;29(3):116-122
pubmed: 30907681
J Virol. 1995 Dec;69(12):7586-92
pubmed: 7494265
Sci Transl Med. 2016 Jan 20;8(322):322ra9
pubmed: 26791950
N Engl J Med. 2020 Jul 9;383(2):109-119
pubmed: 32640130
J Pharmacol Exp Ther. 2016 Sep;358(3):537-47
pubmed: 27317802
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10238-43
pubmed: 18632556
JCI Insight. 2019 Jul 30;5:
pubmed: 31361599
Mol Cell Proteomics. 2019 Dec;18(12):2388-2400
pubmed: 31558565
J Virol. 2007 Dec;81(23):12889-98
pubmed: 17881452
Mamm Genome. 1997 Oct;8(10):711-3
pubmed: 9321461
Nat Commun. 2014 Jul 09;5:4347
pubmed: 25005024
Sci Transl Med. 2015 Aug 5;7(299):299ra123
pubmed: 26246168
Vet Res. 2020 Jan 10;51(1):1
pubmed: 31924264
Sci Rep. 2017 Sep 6;7(1):10655
pubmed: 28878311