Imaging · study · 2026
Single-cell and spatial transcriptomic analyses of gene therapy-associated retinal inflammation in non-human primates
Listed in NCBI GEO
Adeno-associated viral (AAV) vectors are rapidly advancing as gene therapies for inherited and common retinal disorders, but gene therapy-associated uveitis (GTAU) limits their broader application.
Description
To investigate the primate ocular immune response, we administered subretinal AAV gene therapy to two non-human primates (NHPs): NHP1 received AAV2-CAG-hRPE65 (voretigene neparvovec) bilaterally at clinical dose; NHP2 received AAV8-GRK1-hRPGRco alongside an analogous mScarlet reporter vector in separate blebs.
Longitudinal assessments over three months included multimodal imaging, electroretinography and cytokine profiling, followed by immunohistological, single-cell and spatial transcriptomic analyses of retinal punches. Both therapies were well-tolerated, with preserved retinal structure and function. Single-cell RNA-sequencing revealed that the AAV8 vector transduced 80% of cones/rods in treated areas, while AAV2 targeted 30% of retinal pigment epithelium (RPE)/rods.
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Transgene expression did not correlate with apoptotic markers. Persistent immune infiltration (dominated by myeloid and T cells) suggested a type 1 cell-mediated response. Adjunctive intravitreal anti-TNFα (adalimumab) did not appear to mitigate this anti-viral response.
Spatial analysis highlighted microglia migration to the subretinal space, consistent with upregulated cytokines (MCP-1/CCL2, IP-10/CXCL10, IL-8/CXCL8, IL-6), which implicate monocytic phagocytes in driving local inflammation. These findings elucidate the mechanism of GTAU and identify potential therapeutic targets to prevent immune-mediated complications in retinal gene therapy.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304504 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304504 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1301394 ncbi.nlm.nih.gov/bioproject/PRJNA1301394 ↗
project · from NCBI GEO
- PubMed 42137601 pubmed.ncbi.nlm.nih.gov/42137601 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Macaca mulatta · Other
- From keywords
- Life Sciences
- Inferred from text
- Imaging 75% · Longitudinal study 65%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE304504 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:other | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[method].local:method:longitudinal-study | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[modality].local:modality:imaging | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:9544 | 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 |