한빛사논문
- 조회1,098
Hyun Jung Park1,*, Areum Han1, Ji Yeon Kim1, Jiwoo Choi1, Hee Sook Bae2, Gyu-bon Cho2, Hyejung Shin2, Eun ji Shin2, Kang-in Lee2, Seokjoong Kim2, Jae Young Lee2,* and Jihwan Song1,3,*
1Department of Biomedical Science, CHA Stem Cell Institute, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Korea. 2Toolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-gu, Seoul 08594, Korea. 3iPS Bio, Inc., 3F, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13522, Korea.
*Corresponding author.
Abstract
Huntington’s disease (HD) is a severe inherited neurological disorder caused by a CAG repeat expansion in the huntingtin gene (HTT), leading to the accumulation of mutant huntingtin with polyglutamine repeats. Despite its severity, there is no cure for this debilitating disease. HTT lowering strategies, including antisense oligonucleotides (ASO) showed promising results very recently. Attempts to develop stem cell-based therapeutics have shown efficacy in preclinical HD models. Using an HD patient’s autologous cells, which have genetic defects, may hamper therapeutic efficacy due to mutant HTT. Pretreating these cells to reduce mutant HTT expression and transcription may improve the transplanted cells’ therapeutic efficacy. To investigate this, we targeted the SUPT4H1 gene that selectively supports the transcription of long trinucleotide repeats. Transplanting SUPT4H1-edited HD-induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) into the YAC128 HD transgenic mouse model improved motor function compared to unedited HD iPSC-NPCs. Immunohistochemical analysis revealed reduced mutant HTT expression without compensating wild-type HTT expression. Further, SUPT4H1 editing increased neuronal and decreased reactive astrocyte differentiation in HD iPSC-NPCs compared to the unedited HD iPSC-NPCs. This suggests that ex vivo editing of SUPT4H1 can reduce mutant HTT expression and provide a therapeutic gene editing strategy for autologous stem cell transplantation in HD.
논문정보
- Research article
- 2022년 01월 (BRIC 등록일 2022-02-10)
- 국내 연구진
- 생명과학 > 발생생물학
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