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Lentiviral Gene Therapy in HSCs Restores Lineage-Specific Foxp3 Expression and Suppresses Autoimmunity in a Mouse Model of IPEX Syndrome.
- Source :
-
Cell stem cell [Cell Stem Cell] 2019 Feb 07; Vol. 24 (2), pp. 309-317.e7. Date of Electronic Publication: 2019 Jan 10. - Publication Year :
- 2019
-
Abstract
- Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a devastating autoimmune disease caused by mutations in FoxP3, a transcription factor required for the development and function of regulatory T cells (Treg cells). Allogeneic hematopoietic stem cell transplant (HSCT) can be curative, but suitable donors are often unavailable. Here, we demonstrate a strategy for autologous HSCT and gene therapy utilizing a lentiviral vector (LV) to restore FoxP3 expression under the control of endogenous human FOXP3 regulatory elements. Both murine transplant models and humanized mice engrafted with LV-modified HSCs show high levels of LV expression selective for CD4+CD25+FoxP3+ Treg cells. LV transduction of scurfy (FoxP3 <superscript>mut</superscript> ) HSCs restores development of functional FoxP3+ Treg cells that suppress T cell proliferation in vitro and rescue the scurfy autoimmune phenotype in vivo. These findings demonstrate preclinical efficacy for the treatment of IPEX patients by autologous HSC transplant and may provide valuable insights into new cell therapies for autoimmunity.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Diabetes Mellitus, Type 1 genetics
Diabetes Mellitus, Type 1 immunology
Diabetes Mellitus, Type 1 therapy
Diarrhea genetics
Disease Models, Animal
Forkhead Transcription Factors genetics
Genes, Reporter
Genetic Diseases, X-Linked genetics
Humans
Immune System Diseases genetics
Immune System Diseases immunology
Immune System Diseases therapy
Mice
T-Lymphocytes, Regulatory immunology
Autoimmunity
Cell Lineage
Diabetes Mellitus, Type 1 congenital
Diarrhea immunology
Diarrhea therapy
Forkhead Transcription Factors therapeutic use
Genetic Diseases, X-Linked immunology
Genetic Diseases, X-Linked therapy
Genetic Therapy
Hematopoietic Stem Cells metabolism
Immune System Diseases congenital
Lentivirus genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1875-9777
- Volume :
- 24
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell stem cell
- Publication Type :
- Academic Journal
- Accession number :
- 30639036
- Full Text :
- https://doi.org/10.1016/j.stem.2018.12.003