Limited time window for retinal gene therapy in a preclinical model of ciliopathy.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
11 08 2020
11 08 2020
Historique:
received:
13
02
2020
revised:
04
05
2020
accepted:
15
06
2020
pubmed:
23
6
2020
medline:
19
8
2021
entrez:
23
6
2020
Statut:
ppublish
Résumé
Retinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to 'optimally' treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet-Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.
Identifiants
pubmed: 32568387
pii: 5860825
doi: 10.1093/hmg/ddaa124
pmc: PMC7424757
doi:
Substances chimiques
Lztfl1 protein, mouse
0
Transcription Factors
0
Tamoxifen
094ZI81Y45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2337-2352Subventions
Organisme : NEI NIH HHS
ID : P30 EY025580
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY022616
Pays : United States
Organisme : NEI NIH HHS
ID : R21 EY027431
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Hum Gene Ther. 2008 Oct;19(10):979-90
pubmed: 18774912
Clin Genet. 2014 May;85(5):476-81
pubmed: 23692385
Science. 1982 Jul 16;217(4556):265-7
pubmed: 6178160
Biol Cell. 2011 Oct 1;103(10):449-66
pubmed: 21732910
Development. 2007 Jan;134(2):307-16
pubmed: 17166921
Hum Gene Ther. 2013 Mar;24(3):242-4
pubmed: 23458444
Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20678-83
pubmed: 22139371
Proc Natl Acad Sci U S A. 2017 May 16;114(20):5259-5264
pubmed: 28468800
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4400-9
pubmed: 26216965
Cold Spring Harb Perspect Biol. 2017 Oct 3;9(10):
pubmed: 28289063
Am J Anat. 1972 Feb;133(2):179-212
pubmed: 5009246
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):E517-25
pubmed: 23341635
J Med Genet. 2012 May;49(5):317-21
pubmed: 22510444
Hum Mol Genet. 2017 Aug 1;26(R1):R75-R82
pubmed: 28453661
Lancet. 2016 Aug 13;388(10045):661-72
pubmed: 27375040
Lancet. 2009 Nov 7;374(9701):1597-605
pubmed: 19854499
Hum Mol Genet. 2015 Jul 15;24(14):3956-70
pubmed: 25877300
J Comp Neurol. 1985 Mar 22;233(4):429-51
pubmed: 3980779
J Biol Chem. 2019 Dec 13;294(50):19119-19136
pubmed: 31694913
Prog Retin Eye Res. 2011 Jul;30(4):258-74
pubmed: 21477661
Med Res Arch. 2017 Sep;5(9):
pubmed: 29457131
N Engl J Med. 2015 May 14;372(20):1887-97
pubmed: 25938638
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8664-9
pubmed: 15173597
J Comp Neurol. 2000 Oct 2;425(4):545-59
pubmed: 10975879
Mol Cell Biol. 1985 Nov;5(11):3274-9
pubmed: 2427927
Hum Gene Ther. 2009 Sep;20(9):999-1004
pubmed: 19583479
J Cell Biol. 1967 Apr;33(1):61-72
pubmed: 6033942
Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3644-3651
pubmed: 31469404
Cell. 2007 Jun 15;129(6):1201-13
pubmed: 17574030
Nat Genet. 2007 Jul;39(7):889-95
pubmed: 17546029
Hum Mol Genet. 2012 Oct 15;21(R1):R111-24
pubmed: 22843501
Ophthalmology. 2017 Sep;124(9):1314-1331
pubmed: 28559085
Exp Eye Res. 2008 Nov;87(5):415-26
pubmed: 18778702
Eur J Hum Genet. 2013 Jan;21(1):8-13
pubmed: 22713813
Sci Transl Med. 2012 Feb 8;4(120):120ra15
pubmed: 22323828
Dev Cell. 2014 Nov 10;31(3):279-290
pubmed: 25446516
Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3443-50
pubmed: 16123450
Vision Res. 2002 Feb;42(4):517-25
pubmed: 11853768
Cell Rep. 2012 Aug 30;2(2):386-96
pubmed: 22884371
PLoS Genet. 2011 Nov;7(11):e1002358
pubmed: 22072986
Hum Mol Genet. 2018 Jan 15;27(2):283-294
pubmed: 29126234
Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16588-93
pubmed: 15539463
Genesis. 2005 Feb;41(2):73-80
pubmed: 15682388
Mol Ther. 2013 Jun;21(6):1131-41
pubmed: 23568263
Hum Mol Genet. 2005 May 1;14(9):1109-18
pubmed: 15772095
J Clin Invest. 2015 Sep;125(9):3704-13
pubmed: 26301813
Cell. 1985 Apr;40(4):795-803
pubmed: 3879971
N Engl J Med. 2008 May 22;358(21):2240-8
pubmed: 18441370
Vision Res. 2004;44(17):2019-26
pubmed: 15149835
N Engl J Med. 2015 May 14;372(20):1920-6
pubmed: 25936984
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19422-7
pubmed: 18032602
Lancet. 2017 Aug 26;390(10097):849-860
pubmed: 28712537
Dev Cell. 2008 Dec;15(6):854-65
pubmed: 19081074
PLoS Genet. 2017 Oct 19;13(10):e1007057
pubmed: 29049287
Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):E5844-53
pubmed: 26460017
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
N Engl J Med. 2008 May 22;358(21):2231-9
pubmed: 18441371
Dis Model Mech. 2015 Feb;8(2):109-29
pubmed: 25650393
Proc Natl Acad Sci U S A. 1985 Nov;82(21):7270-4
pubmed: 2997780
Mol Ther. 2018 Jun 6;26(6):1581-1593
pubmed: 29673930
Mol Ther. 2013 Mar;21(3):509-19
pubmed: 23358189
Mol Ther. 2018 Aug 1;26(8):1953-1964
pubmed: 30001913
Hum Mol Genet. 2014 Jan 15;23(2):514-23
pubmed: 24101599
Invest Ophthalmol Vis Sci. 2011 Jan 05;52(1):7-15
pubmed: 21169527
Mol Cell Biol. 1986 Oct;6(10):3357-67
pubmed: 3540590
Nat Rev Genet. 2010 Apr;11(4):273-84
pubmed: 20212494
J Cell Sci. 2013 Jun 1;126(Pt 11):2372-80
pubmed: 23572516
J Clin Invest. 2011 Jun;121(6):2169-80
pubmed: 21606596
Mol Ther. 2020 Jan 8;28(1):266-278
pubmed: 31604676
Invest Ophthalmol Vis Sci. 2008 Nov;49(11):5067-76
pubmed: 18658088