دورية أكاديمية
Efficient and sustained FOXP3 locus editing in hematopoietic stem cells as a therapeutic approach for IPEX syndrome
| العنوان: | Efficient and sustained FOXP3 locus editing in hematopoietic stem cells as a therapeutic approach for IPEX syndrome |
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| المؤلفون: | Swati Singh, Cole M. Pugliano, Yuchi Honaker, Aidan Laird, M. Quinn DeGottardi, Ezra Lopez, Stefan Lachkar, Claire Stoffers, Karen Sommer, Iram F. Khan, David J. Rawlings |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 32, Iss 1, Pp 101183- (2024) |
| بيانات النشر: | Elsevier, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Genetics LCC:Cytology |
| مصطلحات موضوعية: | FOXP3, IPEX, hematopoietic stem cell, HSC editing, gene editing, CRISPR, Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder caused by mutations in the FOXP3 gene, required for generation of regulatory T (Treg) cells. Loss of Treg cells leads to immune dysregulation characterized by multi-organ autoimmunity and early mortality. Hematopoietic stem cell (HSC) transplantation can be curative, but success is limited by autoimmune complications, donor availability and/or graft-vs.-host disease. Correction of FOXP3 in autologous HSC utilizing a homology-directed repair (HDR)-based platform may provide a safer alternative therapy. Here, we demonstrate efficient editing of FOXP3 utilizing co-delivery of Cas9 ribonucleoprotein complexes and adeno-associated viral vectors to achieve HDR rates of >40% in vitro using mobilized CD34+ cells from multiple donors. Using this approach to deliver either a GFP or a FOXP3 cDNA donor cassette, we demonstrate sustained bone marrow engraftment of approximately 10% of HDR-edited cells in immune-deficient recipient mice at 16 weeks post-transplant. Further, we show targeted integration of FOXP3 cDNA in CD34+ cells from an IPEX patient and expression of the introduced FOXP3 transcript in gene-edited primary T cells from both healthy individuals and IPEX patients. Our combined findings suggest that refinement of this approach is likely to provide future clinical benefit in IPEX. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2329-0501 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S232905012300222X; https://doaj.org/toc/2329-0501 |
| DOI: | 10.1016/j.omtm.2023.101183 |
| URL الوصول: | https://doaj.org/article/70f1555ee4fe46088c5297fc8c0bb2a2 |
| رقم الأكسشن: | edsdoj.70f1555ee4fe46088c5297fc8c0bb2a2 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2023.101183 |