Journal
NUCLEIC ACIDS RESEARCH
Volume 48, Issue 1, Pages 130-140Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz1070
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Funding
- Korean Health Technology R&D Project, Ministry of Health Welfare [HI14C3484, HI16C0426]
- Korean Government, NRF [2016R1A5A2007009, 2017R1A2B2004699, 2018R1A4A1024506, 2017M3A9 B4061404, 2018M3A9H3020844]
- National Institute of Health [RO1 NS094388]
- ToolGen Inc.
- National Research Foundation of Korea [2017R1A2B2004699] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A.
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