期刊
MOLECULAR THERAPY
卷 30, 期 1, 页码 119-129出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2021.05.022
关键词
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资金
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI16C1012]
- Bio & Medical Technology Development Program of the National Research Foundation [2020M3A9I4036072]
- National Research Foundation of Korea [2020M3A9I4036072] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
This study successfully increased the expression levels of the ABCD1 gene and reduced the levels of metabolites associated with ADLD using gene editing strategies in cells and mouse models derived from ADLD patients. These findings suggest that gene editing could be a promising therapeutic strategy for treating ADLD.
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.
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