Oligonucleotide therapeutics in neurodegenerative diseases

Scoles, Daniel R.; Pulst, Stefan M.

doi:10.1080/15476286.2018.1454812

Cited by 48 publications

(46 citation statements)

References 75 publications

(82 reference statements)

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“…Oligonucleotides target the altered messenger RNA (mRNA) and decrease the synthesis of the causative protein-Huntingtin [16]. ASO can also be used as a therapy for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxias [17].…”

Section: Therapeutic Importance Of Oligonucleotidesmentioning

confidence: 99%

Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases

Mehta

Deeksha

Tewari

et al. 2019

Chemico-Biological Interactions

306

112

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Section: Therapeutic Importance Of Oligonucleotidesmentioning

confidence: 99%

Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases

Mehta

Deeksha

Tewari

et al. 2019

Chemico-Biological Interactions

306

112

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“…The presence of CAT impaction results in the absence of disease, while the absence of CAT interruption forms a mutable normal (36)(37)(38) or full-penetrance allele (39)(40)(41)(42)(43)(44) repeats) [16,17].…”

Section: Sca1mentioning

confidence: 99%

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

Szpisjak

Zádori

Klivényi

et al. 2019

CNSNDDT

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Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year’s promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

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“…Allele-specific RNA silencing has shown therapeutic promise in scenarios where total gene knockdown may be detrimental. In these situations, targeted silencing of a disease-associated allele has shown potential to relieve disease phenotypes, including in some neurodegenerative diseases [12,13]. Allelespecific silencing has also shown promising results in mouse models of cardiovascular disease, including catecholaminergic polymorphic ventricular tachycardia [14] and HCM [15,16].…”

Section: Introductionmentioning

confidence: 99%

Dissociation of disease phenotype and allele silencing in hypertrophic cardiomyopathy

Dainis

Zaleta-Rivera

Ribeiro

et al. 2019

Preprint

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Allele-specific RNA silencing has been shown to be an effective therapeutic treatment in a number of diseases, including neurodegenerative disorders. Studies of allele-specific silencing in hypertrophic cardiomyopathy to date have focused on mouse models of disease. Here, we investigate two methods of allele-specific silencing, short hairpin RNA (shRNA) and antisense oligonucleotide (ASO) silencing, using a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of disease. We used cellular micropatterning devices with traction force microscopy and automated video analysis to examine each strategy's effects on contractile defects underlying disease. We find that shRNA silencing ameliorates contractile phenotypes of disease, reducing disease-associated increases in cardiomyocyte velocity, force, and power. We find that ASO silencing, while better able to target and knockdown a specific disease-associated allele, showed more modest improvements in contractile phenotypes. We find a dissociation between allelic-specificity and functional improvements between the two tested therapeutic strategies, suggesting a more complex method of allelic control underlying HCM-associated transcripts. Author summaryAllele-specific silencing, whereby a therapeutic molecule is used to lower the expression of just one of the two copies or alleles of a gene, may be a potential therapeutic strategy in diseases caused by a single mutation. In this paper, we examine two such strategies in hypertrophic cardiomyopathy, a disease characterized by an overgrowth of the left-ventricular heart muscle as well as contractile dysfunction. We used a human cell model of disease, creating induced pluripotent stem cell derived cardiomyocytes from a patient with HCM caused by a single base pair change in just one allele of the gene MYH7. We used two strategies to silence the disease-associated copy of MYH7, both focused on reducing RNA expression from the mutated allele, as well as state-of-the-art biophysical techniques for measuring contractility. We found that one silencing strategy, which reduced expression of both the disease-associated and the healthy alleles of MYH7, showed great improvements in contractility between treated and untreated cells. Our

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Oligonucleotide therapeutics in neurodegenerative diseases

Cited by 48 publications

References 75 publications

Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases

Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

Dissociation of disease phenotype and allele silencing in hypertrophic cardiomyopathy

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