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. 1. Introduction Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease characterised by degeneration of motor neurons, leading to paralysis of voluntary muscles [1], culminating in respiratory failure and death within five years of disease onset [2, 3]. Frontotemporal dementia (FTD) is a cause of presenile dementia, being the second most common form of dementia in individuals younger than 65 years [4]. It is characterised by degeneration of the frontal and temporal lobes of the brain leading to changes in personality, behavior, and language, though with some preservation of perception and memory [2, 5]. FTD patients die 5–10 years after disease onset [6]. Both diseases are incurable. Recently, a hexanucleotide repeat expansion in the C9orf72 gene has been described that is responsible for what is called the c9FTD/ALS continuum. This repeat expansion is now known to be the most common cause for familial c9FTD/ALS, and it has also been observed in apparently sporadic cases [7, 8]. The mechanism by which the repeat expansion causes disease remains to be clarified and both loss- and gain-of-function mechanisms have been proposed. Using knowledge obtained through research into
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