Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo

被引：7

作者：

Cabrera, Gabriela Toro ^{[1
,2
,3
]}

Meijboom, Katharina E. ^{[1
,2
,3
]}

Abdallah, Abbas ^{[2
,3
]}

Tran, Helene ^{[1
]}

Foster, Zachariah ^{[1
]}

Weiss, Alexandra ^{[1
]}

Wightman, Nicholas ^{[1
]}

Stock, Rachel ^{[2
,3
]}

Gendron, Tania ^{[4
]}

Gruntman, Alisha ^{[2
,3
]}

Giampetruzzi, Anthony ^{[1
]}

Petrucelli, Leonard ^{[4
]}

Brown, Robert H. ^{[1
]}

Mueller, Christian ^{[2
,3
]}

机构：

[1] Univ Massachusetts, Chan Med Sch, Dept Neurol, Worcester, MA 01655 USA

[2] Univ Massachusetts, Dept Pediat, Chan Med Sch, Worcester, MA 01655 USA

[3] Univ Massachusetts, Gene Therapy Ctr, Chan Med Sch, Worcester, MA 01655 USA

[4] Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA

来源：

GENE THERAPY | 2024年 / 31卷 / 3-4期

关键词：

HEXANUCLEOTIDE REPEAT; RNA FOCI; ADENOASSOCIATED VIRUS; ANTISENSE TRANSCRIPTS; ALS; TRANSLATION; EXPANSION; FTD; NEURODEGENERATION; EXPRESSION;

D O I：

10.1038/s41434-023-00418-w

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.

引用

页码：105 / 118

页数：14

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