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Therapeutic correction of hemophilia A using 2D endothelial cells and multicellular 3D organoids derived from CRISPR/Cas9-engineered patient iPSCs

 Jeong Sang Son  ;  Chul-Yong Park  ;  Gyunggyu Lee  ;  Ji Young Park  ;  Hyo Jin Kim  ;  Gyeongmin Kim  ;  Kyun Yoo Chi  ;  Dong-Hun Woo  ;  Choongseong Han  ;  Sang Kyum Kim  ;  Han-Jin Park  ;  Dong-Wook Kim  ;  Jong-Hoon Kim 
 BIOMATERIALS, Vol.283 : 121429, 2022-04 
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Animals ; CRISPR-Cas Systems / genetics ; Endothelial Cells / metabolism ; Hemophilia A* / genetics ; Hemophilia A* / metabolism ; Hemophilia A* / therapy ; Humans ; Induced Pluripotent Stem Cells* / metabolism ; Mice ; Organoids / metabolism
Endothelial cells ; Genome-editing ; Hemophilia A ; Induced pluripotent stem cells
The bleeding disorder hemophilia A (HA) is caused by a single-gene (F8) defect and its clinical symptom can be substantially improved by a small increase in the plasma coagulation factor VIII (FVIII) level. In this study, we used F8-defective human induced pluripotent stem cells from an HA patient (F8d-HA hiPSCs) and F8-corrected (F8c) HA hiPSCs produced by CRISPR/Cas9 genome engineering of F8d-HA hiPSCs. We obtained a highly enriched population of CD157+ cells from CRISPR/Cas9-edited F8c-HA hiPSCs. These cells exhibited multiple cellular and functional phenotypes of endothelial cells (ECs) with significant levels of FVIII activity, which was not observed in F8d-HA hiPSC-ECs. After transplantation, the engineered F8c-HA hiPSC-ECs dramatically changed bleeding episodes in HA animals and restored plasma FVIII activity. Notably, grafting a high dose of ECs substantially reduced the bleeding time during multiple consecutive bleeding challenges in HA mice, demonstrating a robust hemostatic effect (90% survival). Furthermore, the engrafted ECs survived more than 3 months in HA mice and reversed bleeding phenotypes against lethal wounding challenges. We also produced F8c-HA hiPSC-derived 3D liver organoids by assembling three different cell types in microwell devices and confirmed its therapeutic effect in HA animals. Our data demonstrate that the combination of genome-engineering and iPSC technologies represents a novel modality that allows autologous cell-mediated gene therapy for treating HA.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Park, Chul Yong(박철용) ORCID logo https://orcid.org/0000-0002-4467-9268
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