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Proteolysis resistant huntingtin isoform induced by antisense oligonucleotide maintains normal huntingtin function in mouse

ABSTRACT: Proteolysis resistant huntingtin isoform induced by antisense oligonucleotide maintains normal huntingtin function in mouse

PROVIDER: PRJNA862886 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20669901_1.fastq.gz	Fastqsanger.gz
	SRR20669901_2.fastq.gz	Fastqsanger.gz
	SRR20669903_1.fastq.gz	Fastqsanger.gz
	SRR20669903_2.fastq.gz	Fastqsanger.gz
	SRR20669804_1.fastq.gz	Fastqsanger.gz

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Proteolysis resistant huntingtin isoform induced by antisense oligonucleotide maintains normal huntingtin function in mouse

Project description:Huntington’s disease (HD) is a late onset neurological disorder for which no neuroprotective therapies efficiently delay onset or progression. A key pathological mechanism in disease involves the proteolysis of polyglutamine (polyQ)-expanded mutant huntingtin (mHTT) generating polyQ-containing N-terminal fragments that are crucial contributors to HD pathogenesis since inhibition of the cleavage at the putative caspase-6 site reduces pathology in a HD mouse model. Interestingly, a naturally occurring alternative spliced form of HTT lacking exon12 (HTTΔ12) leads to a protein with an internal deletion of the caspase-6 N-terminal cleavage site. Here, we have taken a multidisciplinary approach to characterize the therapeutic potential of targeting exon12 of HTT. We show that HTTΔ12 is fully resistant to caspase-6 cleavage in both cell-free and tissue lysate assays, while maintaining overall biochemical and structural properties similar to wild-type (wt)-HTT. We generated mouse deleted for exon12 and found that exon12 is dispensable for HTT main physiological functions including embryonic development and intracellular trafficking such as BDNF transport. Finally, we pharmacologically induced HTTΔ12 using an antisense oligonucleotide (ASO). QRX-704 ASO efficiently distributes in the whole brain, is stable several months, and reduces pathogenic proteolysis. Thus, ASO-induced exon12 deletion of HT We performed gene expression profiling analysis using data obtained from RNA-seq of brain tissue (cortex and striatum) samples originating from mouse littermates from HttΔ12 (Δ12;KI) and HttKO (KO) lines at 3 month of age.

2022-07-29 | GSE209893 | GEO

A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function.

Project description:Huntington's disease (HD) is a late-onset neurological disorder for which therapeutics are not available. Its key pathological mechanism involves the proteolysis of polyglutamine-expanded (polyQ-expanded) mutant huntingtin (mHTT), which generates N-terminal fragments containing polyQ, a key contributor to HD pathogenesis. Interestingly, a naturally occurring spliced form of HTT mRNA with truncated exon 12 encodes an HTT (HTTΔ12) with a deletion near the caspase-6 cleavage site. In this study, we used a multidisciplinary approach to characterize the therapeutic potential of targeting HTT exon 12. We show that HTTΔ12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTTΔ12 retained overall biochemical and structural properties similar to those of wt-HTT. We generated mice in which HTT exon 12 was truncated and found that the canonical exon 12 was dispensable for the main physiological functions of HTT, including embryonic development and intracellular trafficking. Finally, we pharmacologically induced HTTΔ12 using the antisense oligonucleotide (ASO) QRX-704. QRX-704 showed predictable pharmacology and efficient biodistribution. In addition, it was stable for several months and inhibited pathogenic proteolysis. Furthermore, QRX-704 treatments resulted in a reduction of HTT aggregation and an increase in dendritic spine count. Thus, ASO-induced HTT exon 12 splice switching from HTT may provide an alternative therapeutic strategy for HD.

| S-EPMC9536263 | biostudies-literature

Antisense oligonucleotide therapy for calmodulinopathy

Project description:Antisense oligonucleotide therapy for calmodulinopathy

| PRJNA1030420 | ENA

Liver proteome upon in vivo N-acetylgalactosamine-conjugated antisense oligonucleotide silencing of ceramide synthase 2

Project description:Mouse liver proteome was investigated upon in vivo mouse treatment with a N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. The data is a part of a study on the involvement of ceramide enzymatic machinery in cardiovasular disorders and its potential as a target for the disease treatment.

2023-05-10 | PXD025957 | Pride

Expression data from dosing an antisense oligonucleotide in mice I

Project description:We used microarrays to globally profile the gene expression changes observed in liver after 3 days when dosing an antisense oligonucleotide in mice

2018-04-30 | GSE100697 | GEO

Expression data from dosing an antisense oligonucleotide in mice

Project description:Expression data from dosing an antisense oligonucleotide in mice

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Expression data from transfection of an antisense oligonucleotide in 518A2 cells

Project description:We used microarrays to globally profile the gene expression changes observed after 3 days when transfecting an antisense oligonucleotide in 518A2 cells

2017-04-21 | GSE93185 | GEO

LINE-1 antisense oligonucleotide ameliorate HGPA and WRN aging phenotype.

Project description:LINE-1 antisense oligonucleotide ameliorate HGPA and WRN aging phenotype.

| PRJNA816443 | ENA

DMS-MapSeq Analysis of Antisense Oligonucleotide Binding to lncRNA PANDA

Project description:DMS-MapSeq Analysis of Antisense Oligonucleotide Binding to lncRNA PANDA

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Antisense oligonucleotide activity in tumour cells is influenced by intracellular LBPA distribution and 6 extracellular vesicles recycling

Project description:Next generation modified antisense oligonucleotides (ASOs) are commercially approved new therapeutic modalities, yet poor productive uptake and endosomal entrapment in tumour cells limit their broad application. We compared intracellular traffic of anti KRAS antisense oligonucleotide (AZD4785) in good and poor productive uptake tumour cells, PC9 and LK2 respectively. We found that the majority of AZD4785 is rapidly delivered to CD63+ late endosomes (LE) in both cell lines. Importantly, lysobisphosphatidic acid (LBPA) that triggers ASO LE escape is presented in CD63+ LE in PC9 but not in LK2 cells. Moreover, both cells recycle AZD4785 in the extracellular vesicles (EVs) however AZD4785 quantification by advanced mass spectrometry and proteomic analysis revealed that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhanced AZD4785 activity in LK2 but not in PC9 cells thus offering novel strategy to possibly enhance ASO potency in poor productive uptake tumour cells.

2021-11-10 | PXD027804 | Pride

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