Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A.
Animals
Cell Line
Charcot-Marie-Tooth Disease
/ genetics
Disease Models, Animal
Early Growth Response Protein 2
/ genetics
Gene Transfer Techniques
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity
Myelin Proteins
/ genetics
Nanoconjugates
Nerve Fibers, Myelinated
/ metabolism
Nerve Regeneration
Neurofilament Proteins
/ genetics
RNA Interference
RNA, Small Interfering
/ genetics
RNAi Therapeutics
Recovery of Function
SOXE Transcription Factors
/ genetics
Squalene
/ chemistry
Time Factors
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
09 03 2021
09 03 2021
Historique:
received:
10
10
2020
accepted:
11
02
2021
entrez:
22
3
2021
pubmed:
23
3
2021
medline:
10
8
2021
Statut:
epublish
Résumé
Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment. We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in normalization of Pmp22 protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction, one major step in restoring function of myelin sheaths. The normalization of sciatic nerve Krox20, Sox10 and neurofilament levels reflected the regeneration of both myelin and axons. Importantly, the positive effects of siRNA PMP22-SQ NPs lasted for three weeks, and their renewed administration resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for inherited peripheral neuropathies. They provide the proof of concept for a new precision medicine based on the normalization of disease gene expression by siRNA.
Identifiants
pubmed: 33750896
doi: 10.1038/s42003-021-01839-2
pii: 10.1038/s42003-021-01839-2
pmc: PMC7943818
doi:
Substances chimiques
Early Growth Response Protein 2
0
Myelin Proteins
0
Nanoconjugates
0
Neurofilament Proteins
0
PMP22 protein, human
0
Pmp22 protein, mouse
0
RNA, Small Interfering
0
SOXE Transcription Factors
0
Sox10 protein, mouse
0
Squalene
7QWM220FJH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
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