A CAG repeat-targeting artificial miRNA lowers the mutant huntingtin level in the YAC128 model of Huntington's disease

Kotowska-Zimmer, Anna; Przybył, L; Pewińska, Marianna; Suszyńska-Zajczyk, Joanna; Wronka, Dorota; Figiel, Maciej; Olejniczak, Marta

doi:10.1016/j.omtn.2022.04.031

Cited by 14 publications

(11 citation statements)

References 53 publications

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“…We found that mHTT lowering initiated in the CNS of YAC128 mice early (at 8 months) and later (at 12 months) during mHTT inclusion formation led to a signi cant reduction in mHTT inclusion load in the cortex and correlated strongly with levels of soluble mHTT from paired cortical samples. Other groups have previously reported sustained reduction of mHTT aggregate load in YAC128 mice following treatment with virally-encoded RNAi modalities targeting HTT (111)(112)(113). However, to our knowledge, this is the rst report to demonstrate that transient mHTT lowering in CNS using an ASO leads to a reduction of mHTT aggregates in the brain.…”

Section: Discussionmentioning

confidence: 68%

Plasma and CSF neurofilament light chain are stabilized in response to mutant huntingtin lowering in the brain of Huntington disease mice

Caron,

Byrne,

Lemarié

et al. 2024

Preprint

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Background Therapeutic approaches aimed at lowering levels of toxic mutant huntingtin (mHTT) in the brain can reverse disease phenotypes in animal models of Huntington disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with HD progression. However, it remains unknown whether NfL in biofluids may be useful as a response biomarker for assessing the efficacy of disease-modifying therapies for HD. Methods Longitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild type littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide targeting the mutant HTT transgene (HTT ASO) at ages either before or after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology. Results Plasma and CSF NfL concentrations were significantly elevated in YAC128 compared to wild type littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high dose HTT ASO treatment up 6 months. Lowering of mHTT in the brain with HTT ASO initiated prior to the onset of regional brain atrophy and HD-like motor deficits in YAC128 mice had minimal effect on plasma NfL at either dose but resulted in a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF. Conclusions Our data provides evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may represent a promising exploratory response biomarker for HD.

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Section: Discussionmentioning

confidence: 68%

Plasma and CSF neurofilament light chain are stabilized in response to mutant huntingtin lowering in the brain of Huntington disease mice

Caron,

Byrne,

Lemarié

et al. 2024

Preprint

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“…Kotowska-Zimmer et al have shown that artificial miRNAs targeting the CAG repeat specifically reduced mHTT in YAC128 mice. 122 …”

Section: Therapeutic Strategies To Reduce N-terminal Htt and Htt-ex1mentioning

confidence: 99%

“…Many studies have tested ASOs or RNAi agents to target the CAG repeat. [109][110][111][112][113][114][115][116][117][118][119][120][121][122] In general, CAG-targeting confers preference towards the expanded allele, as this allows for binding of multiple molecules per mRNA. 111 Only a few studies included in vivo efficacy.…”

Section: Antisense Oligonucleotides and Rnai Agentsmentioning

confidence: 99%

“…Kotowska-Zimmer et al have shown that artificial miRNAs targeting the CAG repeat specifically reduced mHTT in YAC128 mice. 122 A number of strategies that target other regions of HTT-ex1 have been described as well. [123][124][125][126][127][128][129][130][131][132][133][134][135][136][137] This approach would be expected to lower both wtHTT and mHTT.…”

Section: Antisense Oligonucleotides and Rnai Agentsmentioning

confidence: 99%

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Emerging Therapies for Huntington’s Disease – Focus on N-Terminal Huntingtin and Huntingtin Exon 1

Bent¹,

Evers²,

Vallès³

2022

BTT

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Huntington’s disease is a devastating heritable neurodegenerative disorder that is caused by the presence of a trinucleotide CAG repeat expansion in the Huntingtin gene, leading to a polyglutamine tract in the protein. Various mechanisms lead to the production of N-terminal Huntingtin protein fragments, which are reportedly more toxic than the full-length protein. In this review, we summarize the current knowledge on the production and toxicity of N-terminal Huntingtin protein fragments. Further, we expand on various therapeutic strategies targeting N-terminal Huntingtin on the protein, RNA and DNA level. Finally, we compare the therapeutic approaches that are clinically most advanced, including those that do not target N-terminal Huntingtin, discussing differences in mode of action and translational applicability.

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“…For several repeat expansion diseases, it has already been shown in preclinical studies that a repeat-targeting approach can result in improved behavioral and motor phenotypes. A variety of repeat-targeting oligonucleotide-based tools were used in these studies in mouse models, e.g., blocking ASOs in fragile X-associated tremor/ataxia syndrome (FXTAS; CGG repeat expansion), 3 artificial miRNAs (amiRNAs) in Huntington’s disease (HD; CAG repeat expansion), 4 and morpholino oligomers in DM1. 5 An important advantage of such strategies is a preferential targeting of mutant alleles, which seems to be even easier to achieve in DM1 due to large expansions.…”

mentioning

confidence: 99%

All roads lead to cure: Diversity of oligonucleotides in DM1 therapy

Fiszer

2023

Molecular Therapy - Nucleic Acids

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A CAG repeat-targeting artificial miRNA lowers the mutant huntingtin level in the YAC128 model of Huntington's disease

Cited by 14 publications

References 53 publications

Plasma and CSF neurofilament light chain are stabilized in response to mutant huntingtin lowering in the brain of Huntington disease mice

Plasma and CSF neurofilament light chain are stabilized in response to mutant huntingtin lowering in the brain of Huntington disease mice

Emerging Therapies for Huntington’s Disease – Focus on N-Terminal Huntingtin and Huntingtin Exon 1

All roads lead to cure: Diversity of oligonucleotides in DM1 therapy

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