한빛사논문 | BRIC

한빛사 논문

조회573

서울대학교

CV File 285 kb

Biomaterials, Available online 17 February 2022, 121419 | https://doi.org/10.1016/j.biomaterials.2022.121419 Multiple isogenic GNE-myopathy modeling with mutation specific phenotypes from human pluripotent stem cells by base editors

Ju-Chan Park^a,1, Jumee Kim^a,1, Hyun-Ki Jang^b,f, Seung-Yeon Lee^a, Keun-Tae Kim^a, Eun-Ji Kwon^a, Seokwoo Park^c, Hyun Sik Lee^d, Hyewon Choi^e, Seung-Yeol Park^e, Hee-Jung Choi^d, Soon-Jung Park^f, Sung-Hwan Moon^f, Sangsu Bae^b,g, Hyuk-Jin Cha^a,*

^aCollege of Pharmacy, Seoul National University, Seoul, Republic of Korea
^bInstitute for Convergence of Basic Sciences, Hanyang University, Seoul, Republic of Korea
^cDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
^dDepartment of Biological Sciences, Seoul National University, Seoul, Republic of Korea
^eDepartment of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
^fStem Cell Research Institute, T&R Biofab Co. Ltd, Siheung, Republic of Korea
^gDepartment of Chemistry, Hanyang University, Seoul, Republic of Korea

¹These authors contributed equally.

^*Corresponding author.

Abstract

Despite the great potential of disease modeling using human pluripotent stem cells (hPSCs) derived from patients with mutations, lack of an appropriate isogenic control hinders a precise phenotypic comparison due to the bias arising from the dissimilar genetic backgrounds between the control and diseased hPSCs. Herein, we took advantage of currently available base editors (BEs) to epitomize the isogenic disease model from hPSCs. Using this method, we established multiple isogenic GNE myopathy disease models that harbor point mutations on the GNE gene, including four different mutations found in GNE myopathy patients. Four different mutations in the epimerase or kinase domains of GNE revealed mutation-specific hyposialylation, which was closely correlated to pathological clinical phenotypes. GNE protein structure modeling based on the mutations, addressed these mutation-specific hyposialylation patterns. Furthermore, treatment with a drug candidate currently under clinical trials showed a mutation-specific drug response in GNE myopathy disease models, showing hyposialylation dependent gene signature. These data suggest that derivation of multiple isogenic disease models from hPSCs by using genome editing can enable translationally relevant studies on the pathophysiology of GNE myopathy and drug responses.

Keywords : Genome editing, Base editor, Human pluripotent stem cells, Disease modeling, GNE myopathy, Hyposialylation, Isogenic pair, Myoblast

논문정보

형식Research article
게재일2022년 02월 (BRIC 등록일 2022-02-18)
연구진국내 연구진
분야 의약학 > 약학

댓글 작성 로그인

CV 열람하기

연락처 보기