Targeting RNA-mediated toxicity in C9orf72 ALS and/or FTD by RNAi-based gene therapy
Keywords: 
C9orf72
ALS
FTD
miRNA
Gene therapy
AAV
Issue Date: 
2019
Publisher: 
Elsevier BV
ISSN: 
2162-2531
Note: 
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Citation: 
Martier, R. (Raygene); Liefhebber, J.M. (Jolanda M.); Garcia-Osta, A. (Ana); et al. "Targeting RNA-mediated toxicity in C9orf72 ALS and/or FTD by RNAi-based gene therapy". Molecular Therapy - Nucleic Acids. 16, 2019, 26 - 37
Abstract
A hexanucleotide GGGGCC expansion in intron 1 of chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The corresponding repeat-containing sense and antisense transcripts cause a gain of toxicity through the accumulation of RNA foci in the nucleus and deposition of dipeptide-repeat (DPR) proteins in the cytoplasm of the affected cells. We have previously reported on the potential of engineered artificial anti-C9orf72-targeting miRNAs (miC) targeting C9orf72 to reduce the gain of toxicity caused by the repeat-containing transcripts. In the current study, we tested the silencing efficacy of adeno-associated virus (AAV)5-miC in human-derived induced pluripotent stem cell (iPSC) neurons and in an ALS mouse model. We demonstrated that AAV5-miC transduces different types of neuronal cells and can reduce the accumulation of repeat-containing C9orf72 transcripts. Additionally, we demonstrated silencing of C9orf72 in both the nucleus and cytoplasm, which has an added value for the treatment of ALS and/or FTD patients. A proof of concept in an ALS mouse model demonstrated the significant reduction in repeat-containing C9orf72 transcripts and RNA foci after treatment. Taken together, these findings support the feasibility of a gene therapy for ALS and FTD based on the reduction in toxicity caused by the repeat-containing C9orf72 transcripts.

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