Excel · study · 2026
Developing Midbrain-like Organoid of Gaucher Disease as A Platform for Drug Assessment
Listed in NCBI GEO
Gaucher disease (GD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glucosylsphingolipids, causing inflammation and neurodegeneration.
Description
We developed midbrain-like organoids (MLOs) from induced pluripotent stem cells (iPSCs) of nGD patients with GBA1L444P/P415R and GBA1L444P/RecNcil mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiencies, reduced enzyme activities, lipids accumulation, transcriptomic alterations, and impaired dopaminergic neuron differentiation, mirroring nGD pathology.
GBA1 correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipids levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy (SRT) with GZ452, a glucosylceramide synthase (GCS) inhibitor currently under clinical investigation.
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These treatments either restored GCase activity, and/or reduced lipid accumulation, improved lysosomal function, and partially corrected dysregulated neural development and lysosomal pathways identified by transcriptomic analysis. These findings highlight MLOs as a physiologically relevant platform for studying nGD mechanisms and testing novel therapies, offering insights into potential treatments for this devastating disorder.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE303nnn/GSE303993 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303993 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1298596 ncbi.nlm.nih.gov/bioproject/PRJNA1298596 ↗
project · from NCBI GEO
- PubMed 42334452 pubmed.ncbi.nlm.nih.gov/42334452 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Disease 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE303993 | 14 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |