GEO series

Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo

GSE255022 Homo sapiens (human) RNA-seq (gene expression) 14 samples Submitted 2024/11/15 Platform GPL30173

At a glance

RNA-seq (gene expression) · human · 14 samples

What it is: RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism: Homo sapiens (human)
Samples: 14 samples: 14 samples, each with a distinct title — no replicated groupsGroups are read from the sample names, not from the paper. Check the list below.
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper: Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivoNature communications · 2025

Summary (written by the submitters)

The most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a G4C2 repeat expansion in intron 1 of the C9orf72 gene. This repeat expansion undergoes bidirectional transcription to produce sense and antisense repeat RNA species. Both sense and antisense-derived repeat RNAs undergo repeat-associated non-AUG translation in all reading frames to generate five distinct dipeptide repeat proteins (DPRs).

Read the full summary ↓

Importantly, toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs. This suggests targeting both sense and antisense repeat RNA may provide the most effective therapeutic strategy. The RNA-targeting CRISPR-Cas13 systems offer a promising avenue for simultaneous targeting of multiple RNA transcripts, as they mature their own guide arrays, thus allowing targeting of more than one RNA species from a single construct. We show that CRISPR-Cas13d originating from Ruminococcus flavefaciens (CasRx) can successfully reduce C9orf72 sense and antisense repeat transcripts and DPRs to background levels in HEK cells overexpressing C9orf72 repeats. CRISPR-CasRx also markedly reduced the endogenous sense and antisense repeat RNAs and DPRs in three independent C9orf72 patient-derived iPSC-neuron lines, without detectable off-target effects. To determine whether CRISPR-CasRx is effective in vivo, we treated two distinct C9orf72 repeat mouse models using AAV delivery and observed a significant reduction in both sense and antisense repeat-containing transcripts. Taken together this work highlights the potential for RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.

Published in

Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo

Kempthorne L, Vaizoglu D, Cammack AJ et al. · Nature communications 2025 · PMID 39779704 · doi:10.1038/s41467-024-55550-x

This dataset

Open GSE255022 in finder → Find more human RNA-seq datasets →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE255022_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1073247 and SRA study SRP488058. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39779704) ↗

Study design

14 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 14 sample titles: 14 distinct titles with little repetition. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

GSM8062712 Guide 8 Induction 1, i3Neurons, DIV5 [i1_G8]
GSM8062713 Guide 8 Induction 2, i3Neurons, DIV5 [i2_G8]
GSM8062714 Guide 8 Induction 3, i3Neurons, DIV5 [i3_G8]
GSM8062715 Guide 10 Induction 1, i3Neurons, DIV5 [i1_G10]
GSM8062716 Guide 10 Induction 2, i3Neurons, DIV5 [i2_G10]
GSM8062717 Guide 10 Induction 3, i3Neurons, DIV5 [i3_G10]
GSM8062718 Guide 11 Induction 1, i3Neurons, DIV5 [i1_G11]
GSM8062719 Guide 11 Induction 2, i3Neurons, DIV5 [i2_G11]
GSM8062720 Guide 11 Induction 3, i3Neurons, DIV5 [i3_G11]
GSM8062721 Guide 17 Induction 1, i3Neurons, DIV5 [i1_G17]
GSM8062722 Guide 17 Induction 2, i3Neurons, DIV5 [i2_G17]
GSM8062723 Guide 17 Induction 3, i3Neurons, DIV5 [i3_G17]
GSM8062724 Guide NT Induction 1, i3Neurons, DIV5 [i1_GNT]
GSM8062725 Guide NT Induction 2, i3Neurons, DIV5 [i2_GNT]

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