Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

TATA Box*; Charcot-Marie-Tooth Disease/*therapy ; Molecular Targeted Therapy/*methods ; Myelin Proteins/*genetics ; Myelin Sheath/*metabolism ; Schwann Cells/*metabolism; Animals ; Axons ; CRISPR-Cas Systems ; Charcot-Marie-Tooth Disease/genetics ; Charcot-Marie-Tooth Disease/metabolism ; Charcot-Marie-Tooth Disease/pathology ; Chromosome Duplication ; Chromosomes, Human, Pair 17 ; Disease Models, Animal ; Gene Editing/methods ; Humans ; Injections ; Mice ; Myelin Proteins/metabolism ; Myelin Sheath/pathology ; Primary Cell Culture ; Promoter Regions, Genetic ; Schwann Cells/pathology ; Sciatic Nerve/metabolism ; Sciatic Nerve/pathology

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.
(© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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R01 NS094388 United States NS NINDS NIH HHS

0 (Myelin Proteins)
0 (PMP22 protein, human)

Date Created: 20191113 Date Completed: 20200318 Latest Revision: 20240425

20240425

PMC7145652

10.1093/nar/gkz1070

31713617