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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253119300204 |
| _version_ | 1819258986688413696 |
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| author | Raygene Martier Jolanda M. Liefhebber Ana García-Osta Jana Miniarikova Mar Cuadrado-Tejedor Maria Espelosin Susana Ursua Harald Petry Sander J. van Deventer Melvin M. Evers Pavlina Konstantinova |
| author_facet | Raygene Martier Jolanda M. Liefhebber Ana García-Osta Jana Miniarikova Mar Cuadrado-Tejedor Maria Espelosin Susana Ursua Harald Petry Sander J. van Deventer Melvin M. Evers Pavlina Konstantinova |
| author_sort | Raygene Martier |
| collection | DOAJ |
| 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. Keywords: C9orf72, ALS, FTD, miRNA, gene therapy, AAV |
| first_indexed | 2024-12-23T19:02:50Z |
| format | Article |
| id | doaj.art-7205c963663e4645b6377c073cfd2e0c |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-23T19:02:50Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-7205c963663e4645b6377c073cfd2e0c2022-12-21T17:34:40ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-06-01162637Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene TherapyRaygene Martier0Jolanda M. Liefhebber1Ana García-Osta2Jana Miniarikova3Mar Cuadrado-Tejedor4Maria Espelosin5Susana Ursua6Harald Petry7Sander J. van Deventer8Melvin M. Evers9Pavlina Konstantinova10Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands; Corresponding author: Raygene Martier, Department of Research & Development, uniQure Biopharma B.V., P.O. 22506, 1100 DA Amsterdam, the Netherlands.Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the NetherlandsNeurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, SpainDepartment of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the NetherlandsNeurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, SpainNeurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, SpainNeurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, SpainDepartment of Research & Development, uniQure Biopharma B.V., Amsterdam, the NetherlandsDepartment of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Research & Development, uniQure Biopharma B.V., Amsterdam, the NetherlandsDepartment of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands; Corresponding author: Pavlina Konstantinova, Department of Research & Development, uniQure Biopharma B.V., P.O. 22506, 1100 DA Amsterdam, the Netherlands.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, AAVhttp://www.sciencedirect.com/science/article/pii/S2162253119300204 |
| spellingShingle | Raygene Martier Jolanda M. Liefhebber Ana García-Osta Jana Miniarikova Mar Cuadrado-Tejedor Maria Espelosin Susana Ursua Harald Petry Sander J. van Deventer Melvin M. Evers Pavlina Konstantinova Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy Molecular Therapy: Nucleic Acids |
| 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 |
| url | http://www.sciencedirect.com/science/article/pii/S2162253119300204 |
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