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Dual AAV gene therapy in combination with rapamycin rescues muscle and liver impairment in a mouse model of GSDIII.

GSE232166 Mus musculus (mouse) RNA-seq (gene expression) 36 samples Submitted 2024/05/17 Platform GPL21626
At a glance

RNA-seq (gene expression) · mouse · 36 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
Mus musculus (mouse)
Samples
36 samples: 10 conditions, mostly with about 4 replicates eachGroups 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
Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liverJCI insight · 2024
Summary (written by the submitters)
Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation in liver, and in cardiac and skeletal muscles, responsible for impaired hepatic metabolism, heart function impairment, and muscle weakness. To date, there is no curative treatment for GSDIII.
Read the full summary ↓
The large 4.6 kb coding sequence of GDE represents a major limitation toward the development of clinically relevant AAV gene transfer strategy for GSDIII. We previously reported that liver and heart/muscle correction of the GSDIII phenotype can be achieved in a mouse model of GSDIII by using two distinct overlapping AAV vectors encoding GDE. Here, results of a long-term stability of an approach based on a dual AAV vector encoding for GDE under the control of a recently developed tandem liver-muscle promoter suggests that stable but partial correction of the muscle phenotype can be achieved at very long-term (12 months). In liver, the dual AAV had an only transient efficacy supporting the need for an optimization of the approach. We then assessed the efficacy of rapamycin, an autophagy inducer used in the clinic as an immunosuppressive drug that has shown efficacy in GSDIII. Combination of rapamycin with the dual vector expressing GDE resulted in better correction of glycogen accumulation and muscle strength impairment than AAV vector alone thus supporting a synergic effect of the two treatments. The combined treatment synergic effect was also demonstrated at the molecular level by transcriptomic analysis that indicated a better rescue of the lysosomal pathway in muscle, possibly due to the induction of autophagy by rapamycin and the clearance of glycogen achieved with the combination therapy. In GSDIII mice liver, rapamycin was also able to counteract an unexpected immune reaction to the AAV vector that seems specific of this model. In conclusion, these results indicate that correction of both liver and muscle can be achieved in symptomatic GSDIII mice by an overlapping vector expressing GDE with a tandem promoter when combined with rapamycin treatment. These data also indicate that the effect of rapamycin on AAV gene transfer although disease- and tissue-specific has a net positive impact on dual AAV gene therapy for GSDIII thus opening the way to the clinical translation of this combination approach.
Published in
Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver
Jauze L, Vie M, Miagoux Q et al. · JCI insight 2024 · PMID 38753465 · doi:10.1172/jci.insight.172614
This dataset
Open GSE232166 in finder → Find more mouse 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 GSE232166_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 PRJNA971156 and SRA study SRP436849. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38753465) ↗
Study design
10 conditions, mostly with about 4 replicates each
KO_CTL_Triceps ×4 KO_CTL_AAV_Triceps ×4 KO_RAPA_AAV_Triceps ×4 KO_CTL_Liver ×4 KO_CTL_AAV_Liver ×4 KO_RAPA_AAV_Liver ×4 WT_CTL_Triceps ×3 KO_RAPA_Triceps ×3 +2 more

Supports a between-group comparison across 36 samples.

How we read this: 10 replicated groups read from 36 sample titles; they account for 36 of them. 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
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