Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons

Hauser, Stefan; Helm, Jacob; Kraft, Melanie; Korneck, Milena; Hübener‐Schmid, Jeannette; Schöls, Lüdger

doi:10.1016/j.omtn.2021.11.015

Cited by 23 publications

(15 citation statements)

References 42 publications

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“…Toxic gain-of-function of mutant Atx3 can be directly targeted by lowering the protein levels using antisense oligonucleotides. The positive effects of lowering the expression of polyQ-expanded Atx3 in cell models and transgenic rodents were demonstrated by several authors [17][18][19], thus providing evidence in support of the ongoing pharmacokinetic and safety studies of antisense oligonucleotides in MJD (ClinicalTrials.gov Identifier: NCT05160558). Ideally, the safe and effective inhibition of Atx3 aggregation should abolish the formation of NNI known as major neuropathological hallmarks of MJD without compromising the still incompletely disclosed cellular functions of Atx3.…”

Section: Introductionmentioning

confidence: 67%

Drug repurposing of dopaminergic drugs to inhibit Ataxin-3 aggregation

Figueiredo

Sárkány

Silva

et al. 2022

Preprint

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The accumulation of mutant ataxin-3 (Atx3) in neuronal nuclear inclusions is a pathological hallmark of Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia Type 3. Decreasing the protein aggregation burden is a possible disease-modifying strategy to tackle MJD and other neurodegenerative disorders for which only symptomatic treatments are currently available. We performed a drug repurposing screening to identify inhibitors of Atx3 aggregation with known toxicological and pharmacokinetic profiles. Interestingly, dopamine hydrochloride and other catecholamines are among the most potent inhibitors of Atx3 aggregation in vitro. Our results indicate that low micromolar concentrations of dopamine markedly delay the formation of mature amyloid fibrils of mutant Atx3 through the inhibition of the earlier oligomerization steps. Although dopamine itself does not pass the blood-brain barrier, dopamine levels in the brain can be increased by low doses of dopamine precursors and dopamine agonists commonly used to treat Parkinsonian symptoms. These findings disclose a possible application of dopaminergic drugs to halt or reduce Atx3 accumulation in the brains of MJD patients.

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Section: Introductionmentioning

confidence: 67%

Drug repurposing of dopaminergic drugs to inhibit Ataxin-3 aggregation

Figueiredo

Sárkány

Silva

et al. 2022

Preprint

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“…Recently, it has been shown that the protein tau has increased levels in CSF of SCA2 patients [ 37 ], and the protein neurofilament light (NfL) chain is suitable to indicate axonal degeneration in many neurodegenerative diseases, including SCA2 [ 34 , 65 ]. Therapeutic strategies that reduce specifically polyQ-expanded protein levels are currently being applied to slow or stop disease progression in polyQ diseases like SCA1 [ 66 , 67 ], SCA2 [ 68 ], HD [ 69 , 70 ], and SCA3 [ 71 – 74 ]. Therefore, the disease proteins itself could serve as an excellent and primary potential therapeutic biomarker to monitor disease protein lowering by, e.g., antisense oligonucleotides.…”

Section: Discussionmentioning

confidence: 99%

TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2

et al. 2023

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease, which belongs to the trinucleotide repeat disease group with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to early death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein-lowering therapeutic intervention strategies. The aim of this study was to establish a sensitive technique to measure the amount of soluble polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/or therapeutic biomarker in SCA2. Time-resolved fluorescence energy transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions to evaluate the best assay conditions. We established a TR-FRET-based immunoassay for soluble polyQ-expanded ataxin-2 and validated measurements in human cell lines including iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. We successfully established the first sensitive ataxin-2 immunoassay to measure specifically soluble polyQ-expanded ataxin-2 in human biomaterials.

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“…Etwa 70 % aller SCA3-Patienten haben einen spezifischen SNP am 3´-Ende des CAG-Repeats. Behandlung humaner SCA3-Zellen mit einem gegen diesen SNP gerichteten ASO führte zu einer selektiven Verminderung des abnormen Proteins, während die Konzentration des normalen Proteins unverändert blieb [26].…”

Section: Polyglutamin-scasunclassified

Gentherapie für Ataxien

Klockgether

2023

Fortschr Neurol Psychiatr

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ZusammenfassungAtaxien sind progredient verlaufende Krankheiten, die meist Folge einer Degeneration des Kleinhirns sind. Ataxien werden in genetische, sporadisch degenerative und erworbene (sekundäre) Formen unterteilt. Während es bei den erworbene (sekundäre) Ataxien etablierte Therapien gibt, sind genetische und sporadische degenerative Ataxien derzeit nicht medizinisch behandelbar. Für diese Ataxien ist die Entwicklung somatischer Gentherapien ein vielversprechender Weg. Ziele der Gentherapien bei genetischen Ataxien sind die Inaktivierung schädlicher Gene durch Gen-Silencing oder der Ersatz oder die Korrektur eines nicht funktionsfähigen Gens. Eine weitere Option, die auch für sporadisch degenerative Ataxien in Betracht kommt, sind Therapien, bei denen neue oder modifizierte Gene transferiert werden. Bei den häufigeren Ataxien, wie Friedreich-Ataxie, bestimmten spinozerebellären Ataxien und Multisystematrophie werden aktiv Gentherapien entwickelt, und erste Phase I-Studien werden bereits durchgeführt.

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Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons

Cited by 23 publications

References 42 publications

Drug repurposing of dopaminergic drugs to inhibit Ataxin-3 aggregation

Drug repurposing of dopaminergic drugs to inhibit Ataxin-3 aggregation

TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2

Gentherapie für Ataxien

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