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Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective

Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective
Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5–10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.
2090-021X
1-11
Fernandes, Stephanie A.
7199cf91-c76c-4215-ba8c-b4e53f8b869d
Douglas, Andrew G.L.
2c789ec4-a222-43bc-a040-522ca64fea42
Varela, Miguel A.
2dc5ecd9-fa40-4f5c-b748-ec368ec02497
Wood, Matthew J.A.
2dd0c89e-a284-4012-a125-72b883df6af8
Aoki, Yoshitsugu
dd02408a-9219-4532-9d0d-48e2c2d010f0
Fernandes, Stephanie A.
7199cf91-c76c-4215-ba8c-b4e53f8b869d
Douglas, Andrew G.L.
2c789ec4-a222-43bc-a040-522ca64fea42
Varela, Miguel A.
2dc5ecd9-fa40-4f5c-b748-ec368ec02497
Wood, Matthew J.A.
2dd0c89e-a284-4012-a125-72b883df6af8
Aoki, Yoshitsugu
dd02408a-9219-4532-9d0d-48e2c2d010f0

Fernandes, Stephanie A., Douglas, Andrew G.L., Varela, Miguel A., Wood, Matthew J.A. and Aoki, Yoshitsugu (2013) Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective. Journal of Nucleic Acids, 2013 (208245), 1-11. (doi:10.1155/2013/208245).

Record type: Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5–10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.

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Accepted/In Press date: 19 September 2013
Published date: 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 394074
URI: http://eprints.soton.ac.uk/id/eprint/394074
ISSN: 2090-021X
PURE UUID: 668d8a42-ec5d-4fb7-9a11-b43143174a3b
ORCID for Andrew G.L. Douglas: ORCID iD orcid.org/0000-0001-5154-6714

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Date deposited: 11 May 2016 09:29
Last modified: 28 Oct 2023 02:02

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Contributors

Author: Stephanie A. Fernandes
Author: Miguel A. Varela
Author: Matthew J.A. Wood
Author: Yoshitsugu Aoki

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