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Small molecule activation of a pseudoexon triggers huntingtin-lowering (AmpliSeq)

ABSTRACT: Small molecule activation of a pseudoexon triggers huntingtin-lowering (AmpliSeq)

PROVIDER: PRJNA683141 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13209900.fastq.gz	Fastqsanger.gz
	SRR13209901.fastq.gz	Fastqsanger.gz
	SRR13209896.fastq.gz	Fastqsanger.gz
	SRR13209897.fastq.gz	Fastqsanger.gz
	SRR13209898.fastq.gz	Fastqsanger.gz

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Small molecule activation of a pseudoexon triggers huntingtin-lowering

Project description:Small molecule activation of a pseudoexon triggers huntingtin-lowering

| PRJNA683073 | ENA

Small molecule activation of a pseudoexon triggers huntingtin-lowering (AmpliSeq)

Project description:Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by abnormal expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The resultant mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin protein (HTT) levels alleviates HD-associated motor and neuropathological abnormalities, confirming the importance of huntingtin-lowering as a therapeutic approach. Several therapies in development repress HTT transcription or translation, including antisense oligonucleotides, virally-delivered microRNAs, and zinc finger protein transcription factors. However, they all require invasive procedures to reach the central nervous system (CNS) and do not distribute evenly to target areas in the brain. Systemically distributed therapeutics are needed to address the CNS and peripheral dysfunctions associated with HD. Here we report the discovery of small molecule splicing modifiers that lower HTT expression by selective modulation of pre-mRNA splicing. These compounds promote the inclusion of a pseudoexon containing a premature termination codon triggering HTT mRNA degradation and a reduction of HTT protein levels in vitro and in vivo. These orally bioavailable small molecules represent a non-invasive treatment option for HD and our findings support their continued development for the treatment of HD.

2021-07-01 | GSE162812 | GEO

Small molecule activation of a pseudoexon triggers huntingtin-lowering (RNA-Seq)

Project description:Small molecule activation of a pseudoexon triggers huntingtin-lowering (RNA-Seq)

| PRJNA683140 | ENA

Small molecule activation of a pseudoexon triggers huntingtin-lowering (RNA-Seq)

2021-07-01 | GSE162813 | GEO

Small molecule activation of a pseudoexon triggers huntingtin-lowering

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-01 | GSE162814 | GEO

Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

Project description:Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

| PRJNA872520 | ENA

Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

Project description:We used cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and experimentally evaluated the consequences of neuronal and astrocytic mHTT lowering on HD pathophysiology using cell-type specific RNA-seq

2022-12-15 | GSE211891 | GEO

Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

Project description:Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

| PRJNA513983 | ENA

AmpliSeq transcriptome profiling of human adipose tissue senescent progenitor cells

Project description:Transcriptomic profile of human adipose tissue progenitor cells was performed as follows. For AmpliSeq transcriptome sequencing library construction, AmpliSeq™ Library PLUS, AmpliSeq Transcriptome Human Gene Expression Panel and AmpliSeq CD indexes SetA kits were purchased from Illumina and sequencing libraries were constructed as described in AmpliSeq for Illumina Transcriptome Human Gene Expression Panel reference guide (Illumina). Equimolar concentrations of libraries were pooled at 4 nM and denatured and diluted as described in Denature and Dilute Libraries Guide (Illumina) and adjusted to final concentration of 1.4 pM. Resulting library was sequenced on NextSeq 500 using NextSeq 500/550 High Output v2 kit with 2 X 151 bp cycle. Generated raw files were converted to FASTQ files and used for data analysis. AmpliSeq transcriptome FASTQ files were analyzed on Array studio V10.0 (Omicsoft, Qiagen). Following raw read QC, first and last 10 bases were trimmed and mapped to reference genome Human.B38. The read count data was generated using GeneModel RefGene20170606. Resulting data was normalized by DESeq package, transformed to log2 value and used for ANOVA analyses.

2023-01-12 | GSE222749 | GEO

Huntingtin Lowering Strategies.

Project description:Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington's disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.

| S-EPMC7139361 | biostudies-literature

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