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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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Autores principales: Martier, Raygene, Liefhebber, Jolanda M., García-Osta, Ana, Miniarikova, Jana, Cuadrado-Tejedor, Mar, Espelosin, Maria, Ursua, Susana, Petry, Harald, van Deventer, Sander J., Evers, Melvin M., Konstantinova, Pavlina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393708/
https://www.ncbi.nlm.nih.gov/pubmed/30825670
http://dx.doi.org/10.1016/j.omtn.2019.02.001
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author Martier, Raygene
Liefhebber, Jolanda M.
García-Osta, Ana
Miniarikova, Jana
Cuadrado-Tejedor, Mar
Espelosin, Maria
Ursua, Susana
Petry, Harald
van Deventer, Sander J.
Evers, Melvin M.
Konstantinova, Pavlina
author_facet Martier, Raygene
Liefhebber, Jolanda M.
García-Osta, Ana
Miniarikova, Jana
Cuadrado-Tejedor, Mar
Espelosin, Maria
Ursua, Susana
Petry, Harald
van Deventer, Sander J.
Evers, Melvin M.
Konstantinova, Pavlina
author_sort Martier, Raygene
collection PubMed
description 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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spelling pubmed-63937082019-03-07 Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy Martier, Raygene Liefhebber, Jolanda M. García-Osta, Ana Miniarikova, Jana Cuadrado-Tejedor, Mar Espelosin, Maria Ursua, Susana Petry, Harald van Deventer, Sander J. Evers, Melvin M. Konstantinova, Pavlina Mol Ther Nucleic Acids Article 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. American Society of Gene & Cell Therapy 2019-02-11 /pmc/articles/PMC6393708/ /pubmed/30825670 http://dx.doi.org/10.1016/j.omtn.2019.02.001 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Martier, Raygene
Liefhebber, Jolanda M.
García-Osta, Ana
Miniarikova, Jana
Cuadrado-Tejedor, Mar
Espelosin, Maria
Ursua, Susana
Petry, Harald
van Deventer, Sander J.
Evers, Melvin M.
Konstantinova, Pavlina
Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
title Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
title_full Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
title_fullStr Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
title_full_unstemmed Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
title_short Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy
title_sort targeting rna-mediated toxicity in c9orf72 als and/or ftd by rnai-based gene therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393708/
https://www.ncbi.nlm.nih.gov/pubmed/30825670
http://dx.doi.org/10.1016/j.omtn.2019.02.001
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