Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A

• DOI: 10.1038/s42003-021-01839-2
• Publication Date: 2021-03-09T11:03:14Z
• Authors: Suzan Boutary; Marie Caillaud; Mévidette El Madani; Jean-Michel Vallat; Julien Loisel-Duw...; Alice Rouyer; Laurence Richard; Céline Gracia; Giorgia Urbinati; Didier Desmaële; Andoni Echaniz-La...; David Adams; Patrick Couvreur; Michael Schumacher; Charbel Massaad; Liliane Massaad-M...
• Keywords: Squalene; 0301 basic medicine; QH301-705.5; Mice, Transgenic; [CHIM.THER]Chemical Sciences/Medicinal Chemistry; Nanoconjugates; Motor Activity; Nerve Fibers, Myelinated; Article; Cell Line; 03 medical and health sciences; Charcot-Marie-Tooth Disease; Neurofilament Proteins; Animals; Biology (General); RNA, Small Interfering; Early Growth Response Protein 2; SOXE Transcription Factors; Gene Transfer Techniques; Recovery of Function; Nerve Regeneration; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; RNAi Therapeutics; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; RNA Interference; Myelin Proteins

Abstract 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 two transgenic CMT1A mouse models with different severity the disease. Pathological studies demonstrated regeneration myelinated axons myelin compaction, one major step restoring function sheaths. The sciatic nerve Krox20, Sox10 neurofilament levels reflected both axons. Importantly, positive effects NPs lasted three weeks, their renewed full functional recovery. Beyond our findings can be considered as potent therapeutic strategy inherited peripheral neuropathies. They proof concept new precision medicine gene expression by siRNA.