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Tweaking lentiviral vector design balances efficacy and safety in liver-directed gene therapy for familial hypercholesterolemia

GSE315905 Mus musculus (mouse) RNA-seq (gene expression) 21 samples Submitted 2026/04/15 Platform GPL24247
At a glance

RNA-seq (gene expression) · mouse · 21 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
21 samples: 5 conditions, mostly with about 5 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
Tweaking lentiviral vector design balances efficacy and safety in liver-directed gene therapy for familial hypercholesterolemiaMolecular therapy : the journal of the American Society of Gene Therapy · 2026
Summary (written by the submitters)
Elevated low-density lipoprotein (LDL) cholesterol is the hallmark of familial hypercholesterolemia (FH), an inherited disease mostly due to mutations in the LDL receptor (LDLR)-encoding gene. Here we enforced overexpression of LDLR in hepatocytes by in vivo lentiviral vector (LV) gene therapy and normalized circulating LDL cholesterol in a mouse model of FH.
Read the full summary ↓
One year after gene therapy we detected a high incidence of hepatic tumors in treated mice. Analysis of LV genomic integration sites in the liver tumors revealed expanded clones bearing LV insertions within the Fyn-related kinase (Frk) gene, a known hepatic oncogene, inducing the formation of aberrant LDLR-FRK transcripts. When we purposely overexpressed LDLR-FRK by LV gene transfer, we observed hepatocellular hyperplasia and hypertrophy, supporting a role of this chimeric protein in oncogenesis. Since high expression of this chimeric oncogene and the LDLR likely cooperated to cause liver toxicity, we reduced the strength of LDLR expression within LV. We achieved normalization of circulating LDL cholesterol in two FH mouse models and prevention of atherosclerosis, even under high-fat diet challenge, without any long-term liver tumorigenicity. Overall, our in-depth assessment of the efficacy and safety of in vivo gene therapy for FH provides new insights into mechanisms of action and potential vulnerabilities, with implications for future developments of lipid-lowering gene therapies.
Published in
Tweaking lentiviral vector design balances efficacy and safety in liver-directed gene therapy for familial hypercholesterolemia
Canepari C, Milani M, Degl'Innocenti S et al. · Molecular therapy : the journal of the American Society of Gene Therapy 2026 · PMID 41449803 · doi:10.1016/j.ymthe.2025.12.036
This dataset
Open GSE315905 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 GSE315905_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 PRJNA1399906 and SRA study SRP660627. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41449803) ↗
Study design
5 conditions, mostly with about 5 replicates each
Ldlr-_UT ×5 WT_UT ×5 Ldlr-_ET-mLDL ×4 Ldlr-_ET-co.mLDLR_mass ×3 Ldlr-_ET-hLDLR_mass ×3 Ldlr-_ET-co.mLDL ×1

Supports a between-group comparison across 20 samples.

How we read this: 5 replicated groups read from 21 sample titles; they account for 20 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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