Mutant CAG Repeats Effectively Targeted by RNA Interference in SCA7 Cells

Fiszer, Agnieszka; Wróblewska, Joanna; Nowak, Bartosz M.; Krzyżosiak, Włodzimierz J.

doi:10.3390/genes7120132

Cited by 15 publications

(17 citation statements)

References 30 publications

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“…The sd-siRNAs efficiently form base mismatch complex with their CAG repeat targets, which results in selective inhibition of mutant mRNA translation [182]. When tested in SCA7 patient fibroblasts, sd-siRNAs showed a high efficiency and allele selectivity for silencing the mATXN7 protein (by about 75%) with the simultaneous upregulation of wild type ATXN7 [184]. Although targeting the expansion carries a promising application potential, the (non)protein-coding transcriptional offtarget silencing should be carefully assessed in more advanced animal models.…”

Section: Silencing Gene Expressionmentioning

confidence: 99%

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

Niewiadomska-Cimicka

Trottier

2019

Neurotherapeutics

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Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in understanding the pathogenesis and in developing biomarkers and therapeutic strategies. ATXN7 is a bona fide subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons, two highly vulnerable neuronal cell types in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms. However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development for SCA7.

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Section: Silencing Gene Expressionmentioning

confidence: 99%

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

Niewiadomska-Cimicka

Trottier

2019

Neurotherapeutics

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“…Testing of these siRNAs in HD cell models led to the activation of the silencing mechanism preferentially for the mutant allele, due to the binding of multiple RISCs to an extended sequence of repeats [ 28 , 29 ]. Additionally, this strategy is also effective for other polyQ diseases [ 30 , 31 , 32 ].…”

Section: Disease-modifying Strategies For Hdmentioning

confidence: 99%

What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

Przybył

Woźna-Wysocka

Kozłowska

et al. 2021

IJMS

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Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

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“…Testowanie tych siRNA w modelach komórkowych HD prowadziło do aktywacji mechanizmu wyciszania preferencyjnie dla allelu zmutowanego, z racji związania wielu kompleksów RISC do wydłużonego ciągu powtórzeń. Dodatkowo ta strategia jest skuteczna także dla innych chorób poliQ [50][51][52].…”

Section: Technologia Rnaiunclassified

Strategie wyciszania ekspresji zmutowanego genu w terapii choroby Huntingtona

Fiszer

Nowak

2020

Postepy Biochem

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Choroba Huntingtona (HD) jest chorobą genetyczną spowodowaną przez zbyt dużą liczbę powtórzeń CAG w egzonie 1 genu HTT, kodującym huntingtynę. Od wystąpienia pierwszych symptomów choroby średnia długość życia wynosi 15-20 lat, kiedy to postępują objawy wynikające z neurodegeneracji. W związku z tym istnieje duże zapotrzebowanie na skuteczną metodę leczenia tego schorzenia. Opracowywane są strategie wykorzystujące mechanizmy wyciszenia ekspresji genów, w tym techniki edycji DNA. W tej pracy przedstawione są najważniejsze testowane obecnie podejścia, ze szczególnym uwzględnieniem strategii opierających się na wykorzystaniu oligonukleotydów antysensowych (ASO), technologii interferencji RNA (RNAi) i CRISPR-Cas9. Omówione są prowadzone obecnie próby kliniczne leczenia przyczynowego, inne najważniejsze próby terapii, a także obecnie stosowane środki farmakologiczne.

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Mutant CAG Repeats Effectively Targeted by RNA Interference in SCA7 Cells

Cited by 15 publications

References 30 publications

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

Strategie wyciszania ekspresji zmutowanego genu w terapii choroby Huntingtona

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