The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.
Animals
Central Nervous System
/ chemistry
Female
In Situ Hybridization
Injections, Intraventricular
Injections, Spinal
Macaca fascicularis
Male
Mice
/ metabolism
Neuroglia
/ chemistry
Neurons
/ chemistry
Oligonucleotides, Antisense
/ administration & dosage
Organ Specificity
Primates
/ metabolism
RNA, Long Noncoding
/ analysis
Rats
/ metabolism
Rats, Sprague-Dawley
Ribonuclease H
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:
25 01 2021
25 01 2021
Historique:
accepted:
22
12
2020
revised:
23
11
2020
received:
01
08
2020
pubmed:
29
12
2020
medline:
9
2
2021
entrez:
28
12
2020
Statut:
ppublish
Résumé
Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.
Identifiants
pubmed: 33367834
pii: 6047287
doi: 10.1093/nar/gkaa1235
pmc: PMC7826274
doi:
Substances chimiques
MALAT1 long non-coding RNA, human
0
MALAT1 long noncoding RNA, rat
0
Malat1 long non-coding RNA, mouse
0
Oligonucleotides, Antisense
0
RNA, Long Noncoding
0
Ribonuclease H
EC 3.1.26.4
ribonuclease HI
EC 3.1.26.4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
657-673Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
J Transl Med. 2020 Aug 8;18(1):309
pubmed: 32771027
Drug Metab Dispos. 2007 Mar;35(3):460-8
pubmed: 17172312
Sci Transl Med. 2017 Jan 25;9(374):
pubmed: 28123067
J Clin Invest. 2019 Mar 1;129(3):915-925
pubmed: 30688661
Neuron. 2012 Jun 21;74(6):1031-44
pubmed: 22726834
Proc Natl Acad Sci U S A. 1993 May 15;90(10):4665-9
pubmed: 8506315
Ann Neurol. 2018 Jan;83(1):27-39
pubmed: 29226998
Neuropharmacology. 2016 Nov;110(Pt B):539-547
pubmed: 27108096
Ann Neurol. 2018 Jul;84(1):64-77
pubmed: 29908063
MAbs. 2017 Oct;9(7):1210-1215
pubmed: 28682148
J Clin Invest. 2006 Aug;116(8):2290-6
pubmed: 16878173
JCI Insight. 2019 Jul 30;5:
pubmed: 31361599
Nature. 2017 Apr 20;544(7650):367-371
pubmed: 28405022
Anal Biochem. 2002 May 1;304(1):19-25
pubmed: 11969184
J Neurosci Methods. 2017 Mar 15;280:36-46
pubmed: 28163066
Clin Pharmacokinet. 2001;40(12):907-46
pubmed: 11735609
Nat Rev Neurol. 2018 Oct;14(10):590-605
pubmed: 30131520
Nature. 2020 Sep;585(7825):397-403
pubmed: 32610343
Neuron. 2016 May 4;90(3):535-50
pubmed: 27112497
Lancet. 2017 Dec 17;388(10063):3017-3026
pubmed: 27939059
Front Neuroanat. 2014 Dec 15;8:152
pubmed: 25565977
Handb Clin Neurol. 2018;148:693-700
pubmed: 29478608
Mol Ther Nucleic Acids. 2017 Sep 15;8:508-519
pubmed: 28918051
Sci Transl Med. 2018 Oct 3;10(461):
pubmed: 30282695
Radiology. 1985 Nov;157(2):373-7
pubmed: 4048444
N Engl J Med. 2017 Nov 2;377(18):1723-1732
pubmed: 29091570
J Biol Chem. 2004 Apr 23;279(17):17181-9
pubmed: 14960586
N Engl J Med. 2019 Jun 13;380(24):2307-2316
pubmed: 31059641
J Pharmacol Exp Ther. 2014 Jul;350(1):46-55
pubmed: 24784568
J Clin Invest. 2018 Aug 1;128(8):3558-3567
pubmed: 30010620
J Med Chem. 2016 Mar 24;59(6):2718-33
pubmed: 26914862
Cell Metab. 2019 Feb 5;29(2):501
pubmed: 30726759
Nat Rev Neurosci. 2001 Nov;2(11):806-19
pubmed: 11715057
JCI Insight. 2019 Oct 17;4(20):
pubmed: 31619586
Neuron. 2005 Dec 22;48(6):885-96
pubmed: 16364894
J Clin Invest. 2019 Nov 1;129(11):4817-4831
pubmed: 31589162
Neurosci Lett. 2019 Aug 10;707:134310
pubmed: 31158432
Nat Biotechnol. 2019 Aug;37(8):884-894
pubmed: 31375812
Annu Rev Pharmacol Toxicol. 2010;50:259-93
pubmed: 20055705
Cell. 2019 Oct 3;179(2):312-339
pubmed: 31564456
Neuroscience. 1993 Aug;55(3):607-12
pubmed: 8413923
N Engl J Med. 2020 Jul 9;383(2):109-119
pubmed: 32640130
Neuroscience. 2005;131(3):705-15
pubmed: 15730875
Genes Dev. 2010 Aug 1;24(15):1634-44
pubmed: 20624852
Nature. 1993 May 20;363(6426):260-3
pubmed: 8487863
Nature. 2015 Dec 3;528(7580):123-6
pubmed: 26605526
Nat Biotechnol. 2017 Mar;35(3):230-237
pubmed: 28244996
Lancet Neurol. 2013 May;12(5):435-42
pubmed: 23541756
Sci Adv. 2018 Oct 17;4(10):eaat3386
pubmed: 30345352
Nucleic Acid Ther. 2013 Dec;23(6):369-78
pubmed: 24161045
Sci Transl Med. 2018 Oct 31;10(465):
pubmed: 30381411