AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice.
Animals
Dependovirus
/ genetics
Disease Models, Animal
Gene Expression
Gene Transfer Techniques
Genetic Therapy
Genetic Vectors
/ genetics
Locomotion
Mice
Motor Neurons
/ metabolism
Muscular Atrophy, Spinal
/ drug therapy
Phenotype
Prognosis
Promoter Regions, Genetic
Spinal Cord
/ metabolism
Survival of Motor Neuron 1 Protein
/ genetics
Transduction, Genetic
Treatment Outcome
AAV
SMA
SMN
gene therapy
neurons
peripheral organs
spinal muscular atrophy
synapsin promoter
ubiquitous promoter
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 08 2020
05 08 2020
Historique:
received:
12
03
2020
revised:
30
03
2020
accepted:
12
05
2020
pubmed:
30
5
2020
medline:
13
7
2021
entrez:
30
5
2020
Statut:
ppublish
Résumé
Spinal muscular atrophy (SMA) is a neuromuscular disease mainly caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene and characterized by the degeneration of motor neurons and progressive muscle weakness. A viable therapeutic approach for SMA patients is a gene replacement strategy that restores functional SMN expression using adeno-associated virus serotype 9 (AAV9) vectors. Currently, systemic or intra-cerebrospinal fluid (CSF) delivery of AAV9-SMN is being explored in clinical trials. In this study, we show that the postnatal delivery of an AAV9 that expresses SMN under the control of the neuron-specific promoter synapsin selectively targets neurons without inducing re-expression in the peripheral organs of SMA mice. However, this approach is less efficient in restoring the survival and neuromuscular functions of SMA mice than the systemic or intra-CSF delivery of an AAV9 in which SMN is placed under the control of a ubiquitous promoter. This study suggests that further efforts are needed to understand the extent to which SMN is required in neurons and peripheral organs for a successful therapeutic effect.
Identifiants
pubmed: 32470325
pii: S1525-0016(20)30245-8
doi: 10.1016/j.ymthe.2020.05.011
pmc: PMC7403319
pii:
doi:
Substances chimiques
Survival of Motor Neuron 1 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1887-1901Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Hum Mol Genet. 2014 Jul 1;23(13):3432-44
pubmed: 24497575
Hum Gene Ther. 2014 Jul;25(7):619-30
pubmed: 24617515
Gene Ther. 2009 Jul;16(7):927-32
pubmed: 19458648
Gene Ther. 2013 Apr;20(4):450-9
pubmed: 23303281
Am J Med Genet A. 2010 Jul;152A(7):1608-16
pubmed: 20578137
Neurobiol Dis. 1996 Apr;3(2):97-110
pubmed: 9173917
Hum Mol Genet. 2011 Nov 15;20(22):4334-44
pubmed: 21840928
Ann Neurol. 2016 Feb;79(2):217-30
pubmed: 26506088
Hum Gene Ther. 2012 Apr;23(4):382-9
pubmed: 22201473
Hum Mol Genet. 2017 Feb 15;26(4):801-819
pubmed: 28108555
Hum Mol Genet. 2008 Apr 1;17(7):949-62
pubmed: 18065780
J Neuropathol Exp Neurol. 2009 May;68(5):474-81
pubmed: 19525895
Nat Biotechnol. 2009 Jan;27(1):59-65
pubmed: 19098898
Curr Mol Med. 2016;16(9):779-792
pubmed: 27894243
Mol Ther. 2017 Sep 6;25(9):2038-2052
pubmed: 28663100
Sci Transl Med. 2010 Jun 9;2(35):35ra42
pubmed: 20538619
Mol Ther. 2009 Jul;17(7):1187-96
pubmed: 19367261
Biochem Biophys Res Commun. 2012 Jan 6;417(1):376-81
pubmed: 22172949
Neuron. 2018 Nov 21;100(4):783-797
pubmed: 30465765
Am J Pathol. 2004 Nov;165(5):1731-41
pubmed: 15509541
Hum Mol Genet. 2011 Feb 15;20(4):681-93
pubmed: 21118896
Hum Mol Genet. 2008 Aug 15;17(16):2552-69
pubmed: 18492800
Drugs. 2019 Jul;79(11):1255-1262
pubmed: 31270752
Lancet. 2017 Dec 17;388(10063):3017-3026
pubmed: 27939059
Neurobiol Dis. 2005 Dec;20(3):943-52
pubmed: 16046140
Cell. 1995 Jan 13;80(1):155-65
pubmed: 7813012
N Engl J Med. 2017 Nov 2;377(18):1713-1722
pubmed: 29091557
Gene Ther. 2001 Aug;8(16):1248-54
pubmed: 11509958
N Engl J Med. 2017 Nov 2;377(18):1723-1732
pubmed: 29091570
Mol Ther. 2013 Feb;21(2):282-90
pubmed: 23295949
Trends Mol Med. 2013 Jan;19(1):40-50
pubmed: 23228902
J Med Genet. 1978 Dec;15(6):409-13
pubmed: 745211
Hum Gene Ther. 2018 Mar;29(3):285-298
pubmed: 29378426
Genet Med. 2010 Mar;12(3):145-52
pubmed: 20057317
Neurol Clin. 2015 Nov;33(4):831-46
pubmed: 26515624
Mol Ther Methods Clin Dev. 2016 Sep 14;3:16060
pubmed: 27652289
Gene Ther. 2003 Feb;10(4):337-47
pubmed: 12595892
Hum Gene Ther. 2018 Jan;29(1):15-24
pubmed: 28806897
Mol Ther. 2015 Mar;23(3):477-87
pubmed: 25358252
Hum Mol Genet. 2015 Jul 15;24(14):4094-102
pubmed: 25911676
Hum Gene Ther Clin Dev. 2017 Jun;28(2):74-79
pubmed: 28279081
J Clin Invest. 2020 Mar 2;130(3):1271-1287
pubmed: 32039917
Hum Mol Genet. 2008 Apr 15;17(8):1063-75
pubmed: 18178576
Nature. 2011 Oct 05;478(7367):123-6
pubmed: 21979052
Hum Mol Genet. 2010 Oct 15;19(20):3895-905
pubmed: 20639395
Ann Neurol. 2012 Aug;72(2):256-68
pubmed: 22926856
J Clin Invest. 2019 Nov 1;129(11):4817-4831
pubmed: 31589162
Nat Biotechnol. 2010 Mar;28(3):271-4
pubmed: 20190738
Front Neurol. 2020 Feb 03;11:45
pubmed: 32117013
Neurosci Lett. 2014 Jul 25;576:73-8
pubmed: 24882721
Hum Mol Genet. 2010 Oct 15;19(20):3906-18
pubmed: 20693262
Hum Mol Genet. 2010 Oct 15;19(20):4059-71
pubmed: 20696672
N Engl J Med. 2014 Nov 20;371(21):1994-2004
pubmed: 25409372
Mol Ther. 2011 Nov;19(11):1971-80
pubmed: 21811247
J Anat. 2014 Jan;224(1):15-28
pubmed: 23876144
Blood. 2005 Feb 15;105(4):1424-30
pubmed: 15507527
Gene Ther. 2012 Aug;19(8):852-9
pubmed: 21918551
Genes Dev. 2010 Aug 1;24(15):1634-44
pubmed: 20624852
Mol Ther. 2017 May 3;25(5):1069-1075
pubmed: 28366767
Hum Mol Genet. 2014 Sep 1;23(17):4559-68
pubmed: 24722206
Mol Ther Methods Clin Dev. 2016 Feb 17;3:15055
pubmed: 26942208
Ann Neurol. 1999 Mar;45(3):337-43
pubmed: 10072048
Front Mol Neurosci. 2016 Nov 04;9:116
pubmed: 27867348
Brain Res. 2012 Jun 26;1462:81-92
pubmed: 22330725
Hum Mol Genet. 2018 Aug 15;27(16):2851-2862
pubmed: 29790918
Dis Model Mech. 2011 Jul;4(4):457-67
pubmed: 21708901
Hum Mol Genet. 2005 Mar 15;14(6):845-57
pubmed: 15703193
J Neurosci. 2010 Sep 8;30(36):12005-19
pubmed: 20826664
J Cell Biol. 2001 Mar 5;152(5):1107-14
pubmed: 11238465
Hum Mol Genet. 2012 Jan 1;21(1):185-95
pubmed: 21968514