How the gene behind Huntington’s disease could be neutralized

Drew, Liam

doi:10.1038/d41586-018-05176-z

Cited by 2 publications

(3 citation statements)

References 7 publications

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“…To date, clinical use of ASOs within the setting of neurological disease has led to the development of splice-switching oligonucleotides for the treatment of spinal muscular atrophy (nusinersen) and Duchenne muscular dystrophy (eteplirsen), whose primary action lies in binding and blocking critical splicing elements in their target pre-mRNAs [ [121] , [122] , [123] ]. ASOs utilising RNase H-mediated target knockdown have also shown great promise in clinical trials for Huntington disease, where target mRNA is actively degraded [ 124 , 125 ]. In ALS, ASOs targeting knockdown of mutant SOD1 transcripts have also now commenced clinical trials following favourable first-in-man phase I studies [ 126 ].…”

Section: Targeting C9orf72 Non-coding Rna As a Thementioning

confidence: 99%

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

Douglas

2018

Non-coding RNA Research

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A hexanucleotide repeat expansion in the first intron/promoter region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the C9orf72 locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of C9orf72-related ALS/FTD, not only through direct sequestration of important RNA binding proteins but also indirectly through non-ATG dependent translation into dipeptide repeats. Formation of RNA/DNA hybrid R-loops may also play a key role in the pathogenesis of this condition and this mechanism could provide a link between the repeat expansion, DNA damage, repeat instability and deficiency of RNA binding proteins. Non-coding C9orf72 antisense transcripts could also act to epigenetically regulate gene expression at the locus. The potential effects of such non-coding RNAs should be considered in the design of antisense oligonucleotide therapeutics for C9orf72-related ALS/FTD. Furthermore, the mechanisms of RNA dysregulation exemplified by C9orf72-related disease may help illustrate more broadly how a “perfect storm” of dysfunction occurs in ALS/FTD and how targeting these factors could lead to corrective or preventative therapies.

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Section: Targeting C9orf72 Non-coding Rna As a Thementioning

confidence: 99%

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

Douglas

2018

Non-coding RNA Research

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“…Roche anticipate that results of a trial designed to assess clinical efficacy will prove definitive, accelerating FDA-approval of IONIS-HTTRx. Other global leaders in therapeutics -Spark, Voyager, and UniQurehave followed suit with programs targeting the mutant huntingtin (muHTT) mRNA, representing a shift in optimism affording by targeting the 'root cause' of the disease -HTT gene expression [3].Despite a shift in approachfrom downstream to upstream targetsdrug development in HD has adopted a common mentality: searching for a single agent which selectively targets one aspect of HD pathology which would then be universally effective in this condition, regardless of when in the disease course it is administered and in what type of patient [4]. Although such a therapy has proven elusive, the selection of candidate disease-modifying therapies has been grounded in mechanistic insights into HD pathogenesis ( fig.…”

mentioning

confidence: 99%

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confidence: 99%

Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

Jensen

Barker

2019

JHD

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To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss diseasemodifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early onbefore it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processese.g. huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.To date, no disease-modifying therapy exists for Huntington's disease (HD), despite considerable financial investment [1]. Roche pharmaceutics, however, believe that IONIS-HTTRx, a promising new drug candidate, bucks this trend; their milestone payment to IONIS follows completion of a phase 1/2 study of IONIS-HTTRx, an antisense oligonucleotide (ASO), in 46 patients with early-stage HD. The drug was safe and well tolerated, and resulted in dose-dependent reductions in huntingtin protein (HTT) in the cerebrospinal fluid (CSF) of treated participants [2]. Roche anticipate that results of a trial designed to assess clinical efficacy will prove definitive, accelerating FDA-approval of IONIS-HTTRx. Other global leaders in therapeutics -Spark, Voyager, and UniQurehave followed suit with programs targeting the mutant huntingtin (muHTT) mRNA, representing a shift in optimism affording by targeting the 'root cause' of the disease -HTT gene expression [3].Despite a shift in approachfrom downstream to upstream targetsdrug development in HD has adopted a common mentality: searching for a single agent which selectively targets one aspect of HD pathology which would then be universally effective in this condition, regardless of when in the disease course it is administered and in what type of patient [4]. Although such a therapy has proven elusive, the selection of candidate disease-modifying therapies has been grounded in mechanistic insights into HD pathogenesis ( fig. 1). Two potential explanations for such low rates of clinical success have received less consideration, and stem from adopting this mentality. Reason one: combination therapy has been disregardedTo date, it has been assumed that manipulating a single pathogenic process will be sufficient to halt disease progression. Initial attempts at disease modification focussed on counteracting one of the downstream effects of muHTT thought to be a key contributor to neuronal death: mitochondrial dysfunction [5], excitotoxicity [6...

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How the gene behind Huntington’s disease could be neutralized

Cited by 2 publications

References 7 publications

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

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