Predicting genotoxicity of viral vectors for stem cell gene therapy using gene expression-based machine learning.
gene expression
gene therapy
genotoxicity
in vitro assay
insertional mutagenesis
integrating viral vectors
machine learning
preclinical risk assessment
safety assay gene therapy
support vector machine
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:
01 12 2021
01 12 2021
Historique:
received:
26
02
2021
revised:
12
05
2021
accepted:
07
06
2021
pubmed:
27
6
2021
medline:
8
4
2022
entrez:
26
6
2021
Statut:
ppublish
Résumé
Hematopoietic stem cell gene therapy is emerging as a promising therapeutic strategy for many diseases of the blood and immune system. However, several individuals who underwent gene therapy in different trials developed hematological malignancies caused by insertional mutagenesis. Preclinical assessment of vector safety remains challenging because there are few reliable assays to screen for potential insertional mutagenesis effects in vitro. Here we demonstrate that genotoxic vectors induce a unique gene expression signature linked to stemness and oncogenesis in transduced murine hematopoietic stem and progenitor cells. Based on this finding, we developed the surrogate assay for genotoxicity assessment (SAGA). SAGA classifies integrating retroviral vectors using machine learning to detect this gene expression signature during the course of in vitro immortalization. On a set of benchmark vectors with known genotoxic potential, SAGA achieved an accuracy of 90.9%. SAGA is more robust and sensitive and faster than previous assays and reliably predicts a mutagenic risk for vectors that led to leukemic severe adverse events in clinical trials. Our work provides a fast and robust tool for preclinical risk assessment of gene therapy vectors, potentially paving the way for safer gene therapy trials.
Identifiants
pubmed: 34174440
pii: S1525-0016(21)00323-3
doi: 10.1016/j.ymthe.2021.06.017
pmc: PMC8636173
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3383-3397Subventions
Organisme : Wellcome Trust
ID : 090233/Z/09/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A patent application has been filed under registration number EP3394286A1 (Analytical process for genotoxicity assessment).
Références
Mol Ther. 2006 Jun;13(6):1050-63
pubmed: 16632409
Biostatistics. 2007 Jan;8(1):118-27
pubmed: 16632515
Cancer Cell. 2016 Jul 11;30(1):43-58
pubmed: 27344946
Blood. 2016 Jul 7;128(1):45-54
pubmed: 27129325
BMC Bioinformatics. 2016 Jan 12;17:27
pubmed: 26753519
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
N Engl J Med. 2003 Jan 16;348(3):255-6
pubmed: 12529469
Trends Biotechnol. 2017 Jun;35(6):498-507
pubmed: 28351613
Cell Stem Cell. 2017 Nov 2;21(5):574-590
pubmed: 29100011
Nature. 2016 Dec 15;540(7633):433-437
pubmed: 27926740
Cancer Cell. 2017 Aug 14;32(2):238-252.e9
pubmed: 28810146
Mol Ther Methods Clin Dev. 2014 Feb 12;1:11
pubmed: 26015947
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Mol Ther Nucleic Acids. 2014 Jul 29;3:e179
pubmed: 25072693
Nat Med. 2010 Feb;16(2):198-204
pubmed: 20098431
Bioinformatics. 2004 Feb 12;20(3):307-15
pubmed: 14960456
Hum Gene Ther. 2013 Feb;24(2):132-42
pubmed: 23311447
Brief Bioinform. 2011 May;12(3):189-202
pubmed: 21300697
Blood. 2006 Oct 15;108(8):2545-53
pubmed: 16825499
Nat Med. 2011 Aug 28;17(9):1086-93
pubmed: 21873988
Leukemia. 2013 Apr;27(5):1127-38
pubmed: 23212151
Curr Gene Ther. 2014;14(6):429-36
pubmed: 25245088
J Virol. 2010 May;84(9):4856-9
pubmed: 20181689
J Clin Invest. 2008 Sep;118(9):3143-50
pubmed: 18688286
Cell. 2019 Feb 7;176(4):897-912.e20
pubmed: 30686579
Mol Ther Methods Clin Dev. 2020 Mar 31;17:666-682
pubmed: 32322605
Mol Ther. 2016 Jun;24(6):1090-1099
pubmed: 26957223
Sci Transl Med. 2014 Mar 12;6(227):227ra33
pubmed: 24622513
Hum Gene Ther. 2017 Oct;28(10):875-885
pubmed: 28825370
Mol Ther Methods Clin Dev. 2017 May 12;5:241-258
pubmed: 28603745
Bioinformatics. 2017 Feb 1;33(3):397-404
pubmed: 27797760
Mol Ther Nucleic Acids. 2017 Jun 16;7:231-245
pubmed: 28624199
Mol Ther. 2014 Apr;22(4):774-85
pubmed: 24441399
Nature. 2006 Aug 17;442(7104):818-22
pubmed: 16862118
Curr Gene Ther. 2015;15(1):64-81
pubmed: 25429463
Gene Ther. 2005 Oct;12 Suppl 1:S146-52
pubmed: 16231047
Hum Gene Ther. 2017 Jan;28(1):112-124
pubmed: 27611239
N Engl J Med. 2010 Nov 11;363(20):1918-27
pubmed: 21067383