1. Lentiviral Gene Therapy in HSCs Restores Lineage-Specific Foxp3 Expression and Suppresses Autoimmunity in a Mouse Model of IPEX Syndrome.
- Author
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Masiuk KE, Laborada J, Roncarolo MG, Hollis RP, and Kohn DB
- 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
- 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
mut ) 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
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