Extracellular vesicle-based delivery of silencing sequences for the treatment of Machado-Joseph disease/spinocerebellar ataxia type 3.

Autor:	Rufino-Ramos D; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal., Albuquerque PR; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal., Leandro K; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal., Carmona V; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Martins IM; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Fernandes R; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Henriques C; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal., Lobo D; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Faro R; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal., Perfeito R; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Mendonça LS; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Pereira D; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Gomes CM; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal., Nobre RJ; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal., Pereira de Almeida L; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: luispa@cnc.uc.pt.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 May 03; Vol. 31 (5), pp. 1275-1292. Date of Electronic Publication: 2023 Apr 06.
DOI:	10.1016/j.ymthe.2023.04.001
Abstrakt:	Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominantly inherited ataxia worldwide. It is caused by an over-repetition of the trinucleotide CAG within the ATXN3 gene, which confers toxic properties to ataxin-3 (ATXN3) species. RNA interference technology has shown promising therapeutic outcomes but still lacks a non-invasive delivery method to the brain. Extracellular vesicles (EVs) emerged as promising delivery vehicles due to their capacity to deliver small nucleic acids, such as microRNAs (miRNAs). miRNAs were found to be enriched into EVs due to specific signal motifs designated as ExoMotifs. In this study, we aimed at investigating whether ExoMotifs would promote the packaging of artificial miRNAs into EVs to be used as non-invasive therapeutic delivery vehicles to treat MJD/SCA3. We found that miRNA-based silencing sequences, associated with ExoMotif GGAG and ribonucleoprotein A2B1 (hnRNPA2B1), retained the capacity to silence mutant ATXN3 (mutATXN3) and were 3-fold enriched into EVs. Bioengineered EVs containing the neuronal targeting peptide RVG on the surface significantly decreased mutATXN3 mRNA in primary cerebellar neurons from MJD YAC 84.2 and in a novel dual-luciferase MJD mouse model upon daily intranasal administration. Altogether, these findings indicate that bioengineered EVs carrying miRNA-based silencing sequences are a promising delivery vehicle for brain therapy. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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