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Transcriptional profiling of striatum from a zQ175 KI mouse model of Huntington's disease treated with HTT-10150 siRNA targeting full-length Htt

ABSTRACT: In this study we conducted a comprehensive transcriptional profiling of the striatum utilizing a zQ175 knock-in (KI) mouse model of Huntington's disease, which was treated with HTT-10150 siRNA specifically designed to target the full-length huntingtin (Htt) mRNA. Our investigation aimed to assess the impact of this intervention across different time points.

ORGANISM(S): Mus musculus

PROVIDER: GSE284497 | GEO | 2026/05/05

REPOSITORIES: GEO

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Transcriptional profiling of hippocampus from a zQ175 KI mouse model of Huntington's disease treated with either HTT-10150 siRNA targeting full-length HTT or combination of HTT-634 and HTT-486 siRNAs targeting HTT1a

Project description:In this study, we conducted a comprehensive transcriptional profiling of the hippocampus utilizing a zQ175 knock-in (KI) mouse model of Huntington's disease, which was treated with either HTT-10150 siRNA specifically designed to target the full-length huntingtin (Htt) mRNA or combination of HTT-634 and HTT-486 siRNAs targeting HTT1a. Our investigation aimed to assess the impact of this intervention across different time points.

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Project description:Huntington's disease (HD) is a debilitating progressive neurodegenerative disorder that has profound effects on an individual's cognitive, motor, and behavioral functions. HD is caused by mutation in the huntingtin (HTT) gene that results in CAG repeat expansion and production of an aggregation-prone polyglutamine-containing protein (mHTT). The expression of mHTT causes selective degeneration, mainly in the striatum and cortex brain regions. Yet, the molecular signatures that underlie their selective sensitization remain incompletely characterized. In HD mouse models, we systematically employed immunopurification-mass spectrometry using HTT antibodies targeting non-overlapping epitopes to capture distinct sub-cellular pools of HTT complexes and postulate domain-specific interactions. We also identified mHTT- and tissue-dependent interactions at different disease stages, which were validated using targeted mass spectrometry and computational analysis of HD genetic modifiers. Among the polyQ-dependent, striatum-enriched interactions, we identified interaction with the mediator complex that results in its altered nuclear-cytoplasmic distribution. Integrating IP-MS data with thermal profiling of the mediator complex in HTT deficient cells supports an interaction interface with the mediator tail domain. Broadly, striatum-enriched HTT interactions highlight calcium homeostasis and ion transport at the synapse as sensitizing molecular signatures.

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Project description:Huntington's disease (HD) is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (HTT) gene. Recent advances in gene editing technologies, such as CRISPR/CasRx, have opened new avenues for therapeutic interventions. In this study, we explored the efficacy of CRISPR/CasRx, which can specifically and accurately digest single-stranded RNA and down-regulate the expression of related genes, in targeting the HTT mRNA and its potential as a treatment strategy for HD. Our results showed that CRISPR/CasRx could significantly down-regulate HTT mRNA in different models, including human embryonic kidney (HEK) 293T cells, HD140Q-knockin (HD 140Q-KI) mice at various disease stages, and Huntingtin knockin (HD-KI) pigs, and lead to a subsequent decrease in the expression of mutant Huntingtin (mHTT) protein. Moreover, this intervention could significantly ameliorate the neurological symptoms in HD 140Q-KI mice and HD-KI pigs. These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.

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