Curative in vivo hematopoietic stem cell gene therapy of murine thalassemia using large regulatory elements.
Adenoviridae
/ genetics
Animals
Antigens, CD34
/ metabolism
DNA Transposable Elements
Disease Models, Animal
Female
Genetic Therapy
/ methods
Genetic Vectors
/ genetics
Hematopoietic Stem Cell Transplantation
/ methods
Hematopoietic Stem Cells
/ physiology
Humans
Membrane Cofactor Protein
/ genetics
Mice, Inbred C57BL
Mice, Transgenic
Regulatory Sequences, Nucleic Acid
/ genetics
Thalassemia
/ genetics
Transduction, Genetic
beta-Globins
/ genetics
gamma-Globins
/ genetics
Gene therapy
Hematology
Hematopoietic stem cells
Mouse models
Therapeutics
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
20 08 2020
20 08 2020
Historique:
received:
24
04
2020
accepted:
15
07
2020
entrez:
21
8
2020
pubmed:
21
8
2020
medline:
12
6
2021
Statut:
epublish
Résumé
Recently, we demonstrated that hematopoietic stem/progenitor cell (HSPC) mobilization followed by intravenous injection of integrating, helper-dependent adenovirus HDAd5/35++ vectors resulted in efficient transduction of long-term repopulating cells and disease amelioration in mouse models after in vivo selection of transduced HSPCs. Acute innate toxicity associated with HDAd5/35++ injection was controlled by appropriate prophylaxis, making this approach feasible for clinical translation. Our ultimate goal is to use this technically simple in vivo HSPC transduction approach for gene therapy of thalassemia major or sickle cell disease. A cure of these diseases requires high expression levels of the therapeutic protein (γ- or β-globin), which is difficult to achieve with lentivirus vectors because of their genome size limitation not allowing larger regulatory elements to be accommodated. Here, we capitalized on the 35 kb insert capacity of HDAd5/35++ vectors to demonstrate that transcriptional regulatory regions of the β-globin locus with a total length of 29 kb can efficiently be transferred into HSPCs. The in vivo HSPC transduction resulted in stable γ-globin levels in erythroid cells that conferred a complete cure of murine thalassemia intermedia. Notably, this was achieved with a minimal in vivo HSPC selection regimen.
Identifiants
pubmed: 32814708
pii: 139538
doi: 10.1172/jci.insight.139538
pmc: PMC7455141
doi:
pii:
Substances chimiques
Antigens, CD34
0
DNA Transposable Elements
0
Membrane Cofactor Protein
0
beta-Globins
0
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
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL130040
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141781
Pays : United States
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