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

被引：15

作者：

Rufino-Ramos, David ^{[1
,2
,3
]}

Albuquerque, Patricia R. ^{[1
,2
,3
]}

Leandro, Kevin ^{[1
,2
,3
]}

Carmona, Vitor ^{[4
]}

Martins, Ines M. ^{[1
,2
,4
]}

Fernandes, Rita ^{[1
,2
,4
]}

Henriques, Carina ^{[1
,2
,3
]}

Lobo, Diana ^{[1
,2
,4
]}

Faro, Rosario ^{[1
,2
]}

Perfeito, Rita ^{[1
,2
,4
]}

Mendonca, Liliana S. ^{[1
,2
,4
]}

Pereira, Dina ^{[1
,2
,4
]}

Gomes, Celia M. ^{[2
,5
,6
]}

Nobre, Rui Jorge ^{[1
,2
,4
]}

de Almeida, Luis Pereira ^{[1
,2
,3
]}

机构：

[1] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, Rua Larga, P-3004504 Coimbra, Portugal

[2] Univ Coimbra, CIBB Ctr Innovat Biomed & Biotechnol, Coimbra, Portugal

[3] Univ Coimbra, Fac Pharm, Coimbra, Portugal

[4] Univ Coimbra, Inst Interdisciplinary Res, Coimbra, Portugal

[5] Univ Coimbra, Fac Med, Coimbra, Portugal

[6] Clin Acad Ctr Coimbra CACC, Coimbra, Portugal

来源：

MOLECULAR THERAPY | 2023年 / 31卷 / 05期

关键词：

NICOTINIC ACETYLCHOLINE-RECEPTORS; TRIGEMINAL NERVE; RAT MODEL; BRAIN; GENE; DISEASE; SIRNA; RNA; VECTOR; EXPRESSION;

D O I：

10.1016/j.ymthe.2023.04.001

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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 trinu-cleotide 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 contain-ing the neuronal targeting peptide RVG on the surface signif-icantly 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. Alto-gether, these findings indicate that bioengineered EVs carrying miRNA-based silencing sequences are a promising delivery vehicle for brain therapy.

引用

页码：1275 / 1292

页数：18