Adenine base editing and prime editing of chemically derived hepatic progenitors rescue genetic liver disease

Yohan Kim, Sung Ah Hong, Jihyeon Yu, Jeongyun Eom, Kiseok Jang, Sangtae Yoon, Da Hee Hong, Daekwan Seo, Seu Na Lee, Jae Sung Woo, Jaemin Jeong, Sangsu Bae, Dongho Choi

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1614-1624.e5
JournalCell Stem Cell
Volume28
Issue number9
DOIs
Publication statusPublished - 2021 Sep 2

Keywords

  • adenine base editor
  • chemically derived hepatic progenitor
  • ex vivo gene editing therapy
  • genetic disorder
  • prime editing
  • regenerative medicine
  • reprogramming
  • tyrosinemia type 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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