Targeted Integration and High-Level Transgene Expression in AAVS1 Transgenic Mice after In Vivo HSC Transduction with HDAd5/35++ Vectors.
Adenoviridae
/ genetics
Animals
CRISPR-Cas Systems
Dependovirus
/ genetics
Female
Genes, Reporter
Genetic Therapy
Genetic Vectors
/ genetics
Hematopoietic Stem Cell Mobilization
Hematopoietic Stem Cells
/ cytology
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Transduction, Genetic
Transgenes
/ physiology
Virus Integration
gamma-Globins
/ antagonists & inhibitors
AAVS1
CRISPR/Cas9
helper-dependent adenovirus
hematopoietic stem cell
targeted integration
transgenic mice
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:
04 12 2019
04 12 2019
Historique:
received:
21
05
2019
revised:
10
08
2019
accepted:
14
08
2019
pubmed:
9
9
2019
medline:
27
6
2020
entrez:
9
9
2019
Statut:
ppublish
Résumé
Our goal is the development of in vivo hematopoietic stem cell (HSC) transduction technology with targeted integration. To achieve this, we modified helper-dependent HDAd5/35++ vectors to express a CRISPR/Cas9 specific to the "safe harbor" adeno-associated virus integration site 1 (AAVS1) locus and to provide a donor template for targeted integration through homology-dependent repair. We tested the HDAd-CRISPR + HDAd-donor vector system in AAVS1 transgenic mice using a standard ex vivo HSC gene therapy approach as well as a new in vivo HSC transduction approach that involves HSC mobilization and intravenous HDAd5/35++ injections. In both settings, the majority of treated mice had transgenes (GFP or human γ-globin) integrated into the AAVS1 locus. On average, >60% of peripheral blood cells expressed the transgene after in vivo selection with low-dose O
Identifiants
pubmed: 31494053
pii: S1525-0016(19)30366-1
doi: 10.1016/j.ymthe.2019.08.006
pmc: PMC6904827
pii:
doi:
Substances chimiques
gamma-Globins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2195-2212Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK101328
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141781
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA193077
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL120888
Pays : United States
Informations de copyright
Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
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