Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
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...
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Elsevier,
2019-06-01T00:00:00Z.
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| 042 | |a dc | ||
| 100 | 1 | 0 | |a Raygene Martier |e author |
| 700 | 1 | 0 | |a Jolanda M. Liefhebber |e author |
| 700 | 1 | 0 | |a Ana García-Osta |e author |
| 700 | 1 | 0 | |a Jana Miniarikova |e author |
| 700 | 1 | 0 | |a Mar Cuadrado-Tejedor |e author |
| 700 | 1 | 0 | |a Maria Espelosin |e author |
| 700 | 1 | 0 | |a Susana Ursua |e author |
| 700 | 1 | 0 | |a Harald Petry |e author |
| 700 | 1 | 0 | |a Sander J. van Deventer |e author |
| 700 | 1 | 0 | |a Melvin M. Evers |e author |
| 700 | 1 | 0 | |a Pavlina Konstantinova |e author |
| 245 | 0 | 0 | |a Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy |
| 260 | |b Elsevier, |c 2019-06-01T00:00:00Z. | ||
| 500 | |a 2162-2531 | ||
| 500 | |a 10.1016/j.omtn.2019.02.001 | ||
| 520 | |a 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. Keywords: C9orf72, ALS, FTD, miRNA, gene therapy, AAV | ||
| 546 | |a EN | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Molecular Therapy: Nucleic Acids, Vol 16, Iss , Pp 26-37 (2019) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S2162253119300204 | |
| 787 | 0 | |n https://doaj.org/toc/2162-2531 | |
| 856 | 4 | 1 | |u https://doaj.org/article/7205c963663e4645b6377c073cfd2e0c |z Connect to this object online. |