Characterization of the ocular inflammatory response to AAV reveals divergence by sex and age
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1106775 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28860300.fastq.gz | Fastqsanger.gz | |||
| SRR28860400.fastq.gz | Fastqsanger.gz | |||
| SRR28860301.fastq.gz | Fastqsanger.gz | |||
| SRR28860401.fastq.gz | Fastqsanger.gz | |||
| SRR28860302.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 256 |
Similar Datasets
Project description:Recombinant adeno-associated virus (AAV) is the leading platform for gene therapy in ocular disease. Progress for gene therapy has been hindered by AAV-induced inflammation, which limits dose escalation and long-term efficacy. Characterisation of the ocular immune response to AAV in mice has been restricted to young animals and demonstrate activation of microglia, antigen presentation and a dominant T cell lymphocyte infiltration. The extent of the inflammatory response alters with age and sex and these factors have not been fully represented in the pre-clinical development of ocular AAV gene therapies. Here, we intravitreally inject a null AAV2 vector in young (3-month), middle aged (9-month) and old (18-month) Cx3cr1-creER:R26tdTomato+/- mice of both sexes. Applying clinical imaging, flow cytometric analyses and bulk-sequencing of sorted resident microglia we interrogate the impact of sex and age on the longitudinal response of both microglia and infiltrating cellular response to AAV. Young animals have a dynamic response, with a peak in inflammation at D10-12 and signs of clinical resolution by D28. Despite similar kinetics in the inflammatory response between young male and females, sex differences are observed in the magnitude of the transcriptional response by microglia and the adaptive component of the infiltrating response. With age, the inflammation increases and persists after AAV2 injection. Based on the microglia transcriptional response to AAV, males maintain similar signature across age, although enhanced with increasing age. Contrary, females have greater divergence in their inflammatory response across age. Of particular note, old females have enriched cellular stress and inflammatory microglia gene signatures, with corresponding retinal degeneration. These findings inform crucial sex and age differences for therapeutic application of ocular gene therapy. Our dataset highlight the need to further define these differences to appropriately tackle AAV immunogenicity for all populations.
2025-01-29 | GSE266332 | GEO
Project description:Progress for ocular adeno-associated virus (AAV) gene therapy has been hindered by AAV-induced inflammation, limiting dose escalation and long-term efficacy. Broadly, the extent of inflammatory responses alters with age and sex, yet these factors are poorly represented in pre-clinical development of ocular AAV gene therapies. Here, we combined clinical imaging, flow cytometry, and bulk sequencing of sorted microglia to interrogate the longitudinal inflammatory response following intravitreal delivery of AAV2 in young (3-month-old), middle aged (9-month-old), and old (18-month-old) Cx3cr1-creER:R26tdTomato+/- mice of both sexes. Young males and females exhibited a similar dynamic response, with peak inflammation evident at days 10-12 and signs of clinical resolution by day 28. However, the magnitude of the transcriptional response by microglia and adaptive T cell infiltrate differed between sexes. With age, increased and persistent inflammation were observed in both sexes, although old males maintained their microglia transcriptional AAV response signature. Contrarily, females demonstrated greater divergence in their inflammatory response across age, with enriched cellular stress and inflammatory gene expression in older mice and corresponding signs of retinal degeneration. These findings inform crucial sex and age differences for the therapeutic application of ocular gene therapy, highlighting the need to further understand these factors to overcome AAV immunogenicity.
| S-EPMC11897812 | biostudies-literature
Project description:Although not all sex-dependent gene expression is adaptive, it is likely an important genomic mechanism that allows each sex to independently adapt to environmental changes. Among Drosophila species, sex-biased genes display remarkably consistent evolutionary patterns; male-biased genes evolve faster than unbiased genes in both coding sequence and expression level, suggesting sex-differences in selection through time. However, comparatively little is known of the evolutionary process shaping sex-biased expression within species. Latitudinal clines offer an opportunity to examine how changes in key ecological parameters also influence sex-specific selection and the evolution of sex-biased gene expression. We assayed male and female gene expression in Drosophila serrata along a latitudinal gradient in eastern Australia spanning most of its endemic distribution. Analysis of 11,631 genes across eight populations revealed strong sex differences in the frequency, mode, and strength of divergence. Divergence was far stronger in males than females and while latitudinal clines were evident in both sexes, male divergence was often population-specific, suggesting responses to localized selection pressures that do not covary predictably with latitude. While divergence was enriched for male-biased genes, there was no overrepresentation of X-linked genes in males. By contrast, X-linked divergence was elevated in females, especially for female biased genes. Many genes that diverged in D. serrata have homologs also showing latitudinal divergence in D. simulans and D. melanogaster on other continents, likely indicating parallel adaptation in these distantly related species. Our results suggest that sex differences in selection play an important role in shaping the evolution of gene expression over macro- and micro-ecological spatial scales.
2017-01-04 | GSE90733 | GEO
Project description:Purpose: PDGF-D is a potent angiogenic and immune-related factor. It has been demonstrated that PDGF-D play roles in the pathological process of ocular angiogenesis and degenerative diseases. In our previous study, we established a retinal pigment epithelial (RPE) cell-specifc AAV-PDGF-D/GFP mouse model to study PDGF-D's role in age-related macular degeneration (AMD). In this study, we utilized the single-cell transcriptiome seqeuncing technique to explore the cell types of immune cells attracted by PDGF-D overepxression using the same animal models, with emphases on the impact of PDGF-D overexpression on individual cell's behaviour.
2023-12-30 | GSE193002 | GEO
Project description:AAV gene therapy has recently been approved for clinical use and shown to be efficacious and safe in a growing number of clinical trials. However, the safety of AAV as a gene therapy has been challenged by a few studies that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. The association between AAV and HCC has been difficult to reconcile and is the subject of intense debate because numerous AAV studies have not reported toxicity. Here, we report a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the Rian locus and the over-expression of a proximal gene, Rtl1, were associated with HCC. In addition, we identify a number of genes with differential expression that maybe useful in the study, diagnosis and treatment of HCC. We demonstrate that AAV vector dose, enhancer-promoter selection, and the timing of gene delivery are the defining factors in AAV-mediated insertional mutagenesis. Our results help explain the AAV-mediated genotoxicity previously observed and have important implications for the design of both safer AAV vectors and gene therapy studies. To investigate the possibility that insertional mutagenesis by AAV contributed to the development of HCC, we collected normal and tumor tissues from adult mouse livers that received AAV injection at a neonatal stage.
2015-01-01 | E-GEOD-57597 | biostudies-arrayexpress
Project description:AAV gene therapy has recently been approved for clinical use and shown to be efficacious and safe in a growing number of clinical trials. However, the safety of AAV as a gene therapy has been challenged by a few studies that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. The association between AAV and HCC has been difficult to reconcile and is the subject of intense debate because numerous AAV studies have not reported toxicity. Here, we report a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the Rian locus and the over-expression of a proximal gene, Rtl1, were associated with HCC. In addition, we identify a number of genes with differential expression that maybe useful in the study, diagnosis and treatment of HCC. We demonstrate that AAV vector dose, enhancer-promoter selection, and the timing of gene delivery are the defining factors in AAV-mediated insertional mutagenesis. Our results help explain the AAV-mediated genotoxicity previously observed and have important implications for the design of both safer AAV vectors and gene therapy studies. To investigate the possibility that insertional mutagenesis by AAV contributed to the development of HCC, we collected normal and tumor tissues from adult mouse livers that received AAV injection at a neonatal stage.
2015-09-01 | E-GEOD-61632 | biostudies-arrayexpress
Project description:Early embryogenesis is a unique developmental stage where genetic control of development is handed off from mother to zygote. Yet the contribution of this transition to the evolution of gene expression is poorly understood. Here we study two aspects of gene expression specific to early embryogenesis in Drosophila: sex-biased gene expression prior to the onset of canonical X chromosomal dosage compensation, and the contribution of maternally supplied mRNAs. We sequenced mRNAs from individual unfertilized eggs, precisely staged and sexed blastoderm embryos and compared levels between D. melanogaster, D. yakuba, D. pseudoobscura and D. virilis. First, we find that mRNA content is highly conserved for a given stage and that studies relying on pooled embryos may systematically overstate the degree of gene expression divergence. Unlike studies done on larvae and adults, where most species show a larger proportion of genes with male-biased expression, we find that transcripts in Drosophila embryos are largely female-biased in all species, likely due to incomplete dosage compensation prior to the activation of the canonical dosage compensation mechanism. The divergence of sex-biased gene expression across species is observed to be often due to a decrease of expression, the most drastic example of which is the overall reduction of male expression from the neo-X chromosome in D. pseudoobscura, leading to a pervasive female-bias on this chromosome. We see no evidence for a faster evolution of expression on the X chromosome in embryos (no “faster X” effect), unlike in adults and contrary to a previous study on pooled non-sexed embryos. Finally, we find that most genes are conserved in regard to their maternal or zygotic origin of transcription, and present evidence that differences in maternal contribution to the blastoderm transcript pool may be due to species-specific divergence of transcript degradation rates We sequenced mRNA from D. melanogaser, D. yakuba, D. pseudoobscura and D. virilis single unfertilized eggs (1 to 2 per species) and from both single female and male embryos (3 per sex per species).
2015-04-21 | E-GEOD-68062 | biostudies-arrayexpress
Project description:Sex-limited experimental evolution drives transcriptomic divergence in a hermaphrodite
| PRJNA1012714 | ENA
Project description:Early embryogenesis is a unique developmental stage where genetic control of development is handed off from mother to zygote. Yet the contribution of this transition to the evolution of gene expression is poorly understood. Here we study two aspects of gene expression specific to early embryogenesis in Drosophila: sex-biased gene expression prior to the onset of canonical X chromosomal dosage compensation, and the contribution of maternally supplied mRNAs. We sequenced mRNAs from individual unfertilized eggs, precisely staged and sexed blastoderm embryos and compared levels between D. melanogaster, D. yakuba, D. pseudoobscura and D. virilis. First, we find that mRNA content is highly conserved for a given stage and that studies relying on pooled embryos may systematically overstate the degree of gene expression divergence. Unlike studies done on larvae and adults, where most species show a larger proportion of genes with male-biased expression, we find that transcripts in Drosophila embryos are largely female-biased in all species, likely due to incomplete dosage compensation prior to the activation of the canonical dosage compensation mechanism. The divergence of sex-biased gene expression across species is observed to be often due to a decrease of expression, the most drastic example of which is the overall reduction of male expression from the neo-X chromosome in D. pseudoobscura, leading to a pervasive female-bias on this chromosome. We see no evidence for a faster evolution of expression on the X chromosome in embryos (no “faster X” effect), unlike in adults and contrary to a previous study on pooled non-sexed embryos. Finally, we find that most genes are conserved in regard to their maternal or zygotic origin of transcription, and present evidence that differences in maternal contribution to the blastoderm transcript pool may be due to species-specific divergence of transcript degradation rates
2015-04-21 | GSE68062 | GEO
Project description:The aim of this project is to assess the impact that age and sex have as parameters for biomarker discovery in radiation research using high-throughput proteomics.
2022-05-10 | PXD015859 | Pride