한빛사논문
Yohan Kim1,2,9, Sung-Ah Hong3,9, Jihyeon Yu3,8,9, Jeongyun Eom4, Kiseok Jang4, Sangtae Yoon1,2, Da Hee Hong1,2, Daekwan Seo5, Seu-Na Lee6, Jae-Sung Woo6, Jaemin Jeong1,2,*, Sangsu Bae3,10,*, Dongho Choi1,2,7,*
1Department of Surgery, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
2HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Seoul 04763, Republic of Korea
3Department of Chemistry and Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul 04763, Republic of Korea
4Department of Pathology, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
5Psomagen, Inc., 1330 Piccard Drive, Suite 103, Rockville, MD 20850, USA
6Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
7Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea
8Present address: Division of Life Science, Korea Polar Research Institute, Incheon 21990, Republic of Korea
9These authors contributed equally
10Lead contact
*Corresponding author
Abstract
DNA base editors and prime editing technology enable therapeutic in situ correction of disease-causing alleles. These techniques could have broad applications for ex vivo editing of cells prior to transplantation in a range of diseases, but it is critical that the target population is efficiently modified and engrafts into the host. Chemically derived hepatic progenitors (CdHs) are a multipotent population capable of robust engraftment and hepatocyte differentiation. Here we reprogrammed hepatocytes from a mouse model of hereditary tyrosinemia type 1 (HT1) into expandable CdHs and successfully corrected the disease-causing mutation using both adenine base editors (ABEs) and prime editors (PEs). ABE- and PE-corrected CdHs repopulated the liver with fumarylacetoacetate hydrolase-positive cells and dramatically increased survival of mutant HT1 mice. These results demonstrate the feasibility of precise gene editing in transplantable cell populations for potential treatment of genetic liver disease.
Keywords : chemically derived hepatic progenitor, adenine base editor, prime editing, ex vivo gene editing therapy, tyrosinemia type 1, regenerative medicine, reprogramming, genetic disorder
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