한빛사 논문
Sung-Ah Hong1,11, Jung Hwa Seo2,3,11, Soohyun Wi2,3,4, Eul Sik Jung5,6, Jihyeon Yu7, Gue-Ho Hwang1, Ji Hea Yu2,3, Ahreum Baek2,8, Soeon Park3,5, Sangsu Bae1,*, Sung-Rae Cho2,3,9,10,*
1Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, Seoul 04673, South Korea
2Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea
4Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, South Korea
5Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, South Korea
6JES Clinic, Incheon 21550, South Korea
7Division of Life Science, Korea Polar Research Institute, Incheon 21990, Republic of Korea
8Department of Rehabilitation Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, South Korea
9Graduate Program of Nano Science and Technology, Yonsei University, Seoul 03722, South Korea
10Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul 03722, Korea
11These authors contributed equally
*Corresponding author
Abstract
Adrenoleukodystrophy (ALD) is caused by various pathogenic mutations in the X-linked ABCD1 gene, which lead to metabolically abnormal accumulations of very long-chain fatty acids in many organs. However, curative treatment of ALD has not yet been achieved. To treat ALD, we applied two different gene-editing strategies, base editing and homology-independent targeted integration (HITI), in ALD patient-derived fibroblasts. Next, we performed in vivo HITI-mediated gene editing using AAV9 vectors delivered via intravenous administration in the ALD model mice. We found that the ABCD1 mRNA level was significantly increased in HITI-treated mice, and the plasma levels of C24:0-LysoPC (lysophosphatidylcholine) and C26:0-LysoPC, sensitive diagnostic markers for ALD, were significantly reduced. These results suggest that HITI-mediated mutant gene rescue could be a promising therapeutic strategy for human ALD treatment.
Keywords : adrenoleukodystrophy, ABCD1, very long-chain fatty acid, homology-independent targeted integration, base editing, CRISPR, genome editing, gene therapy
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