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

Autor: Jean-Michel Vallat, Didier Desmaële, Laurence Richard, Céline Gracia, Julien Loisel-Duwattez, Marie Caillaud, Mévidette El Madani, David Adams, Alice Rouyer, Liliane Massaad-Massade, Patrick Couvreur, Michael Schumacher, Giorgia Urbinati, Andoni Echaniz-Laguna, Suzan Boutary, Charbel Massaad
Přispěvatelé: Institut Galien Paris-Saclay (IGPS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Maladies et hormones du système nerveux (DHNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Neurologie [CHU Limoges], CHU Limoges, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire Interdisciplinaire Solidarités, Sociétés, Territoires (LISST), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA)-Centre National de la Recherche Scientifique (CNRS), Maintenance Myélinique et Neuropathies Périphériques (MMNP), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Desmaële, Didier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Time Factors
Medicine (miscellaneous)
Nanoconjugates
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Pharmacology
Nerve Fibers
Myelinated
Myelin
0302 clinical medicine
Charcot-Marie-Tooth Disease
Neurofilament Proteins
RNA interference
Medicine
RNA
Small Interfering
Biology (General)
SOXE Transcription Factors
Neurodegenerative diseases
Gene Transfer Techniques
3. Good health
medicine.anatomical_structure
RNA Interference
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Sciatic nerve
General Agricultural and Biological Sciences
Myelin Proteins
Squalene
congenital
hereditary
and neonatal diseases and abnormalities
Neurofilament
QH301-705.5
[CHIM.THER] Chemical Sciences/Medicinal Chemistry
Transgene
SOX10
Mice
Transgenic
Motor Activity
Article
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
Animals
Early Growth Response Protein 2
business.industry
Regeneration (biology)
Recovery of Function
Nerve Regeneration
Mice
Inbred C57BL
Disease Models
Animal
RNAi Therapeutics
030104 developmental biology
nervous system
Preclinical research
Cell culture
business
030217 neurology & neurosurgery
Zdroj: Communications Biology
Communications Biology, Nature Publishing Group, 2021, 4 (1), ⟨10.1038/s42003-021-01839-2⟩
Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021)
Communications Biology, 2021, 4 (1), pp.317. ⟨10.1038/s42003-021-01839-2⟩
ISSN: 2399-3642
Popis: 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.
Boutary et al. describe siRNA based therapy conjugated with squalene nanoparticles as an efficient approach to normalize PMP22 protein levels, restore locomotor activity, electrophysiological parameters and function of myelin sheath in CMT1A mouse models. These findings could be useful to develop therapeutic strategies for inherited peripheral neuropathies.
Databáze: OpenAIRE
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