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Correlation of antigen expression with epigenetic modifications after rAAV delivery of a hyperactive human Factor IX variant in mice and rhesus macaques (CnT NHP)

ABSTRACT: We investigated long-term human coagulation Factor IX expression of a novel variant when delivered into mice and rhesus macaques and compare transduction efficiencies using two different AAV capsids. In hemophilic mice injected with KP1-packaged rAAV expressing the hyperactive FIX variant specific activity plasma levels were 10-fold or 2-fold enhanced when compared to wild-type or Padua huFIX injected mice, respectively. In rhesus macaques AAV-LK03 capsid outperformed AAV-KP1 in terms of antigen expression and liver transduction. Two animals from each group showed sustained low-level huFIX expression at 3 months post-administration, while one animal from each group lost huFIX mRNA and protein expression over time despite comparable vector copies. We investigated if epigenetic differences in the vector episomes could explain this loss of transcription. Cut&Tag analysis revealed lower levels of activating histone marks in the two animals that lost expression. When comparing rAAV genome associated histone modifications in rhesus macaques to those in mice injected with the same vector, the activating histone marks were starkly reduced in macaque-derived episomes. Differential epigenetic marking of AAV genomes may explain different expression profiles in mice and rhesus macaques as well as the wide dose response variation observed in primates in both preclinical and human clinical trials.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE261044 | GEO | 2024/03/11

REPOSITORIES: GEO

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Correlation of antigen expression with epigenetic modifications after rAAV delivery of a hyperactive human Factor IX variant in mice and rhesus macaques (CnT mouse)

Project description:We investigated long-term human coagulation Factor IX expression of a novel variant when delivered into mice and rhesus macaques and compare transduction efficiencies using two different AAV capsids. In hemophilic mice injected with KP1-packaged rAAV expressing the hyperactive FIX variant specific activity plasma levels were 10-fold or 2-fold enhanced when compared to wild-type or Padua huFIX injected mice, respectively. In rhesus macaques AAV-LK03 capsid outperformed AAV-KP1 in terms of antigen expression and liver transduction. Two animals from each group showed sustained low-level huFIX expression at 3 months post-administration, while one animal from each group lost huFIX mRNA and protein expression over time despite comparable vector copies. We investigated if epigenetic differences in the vector episomes could explain this loss of transcription. Cut&Tag analysis revealed lower levels of activating histone marks in the two animals that lost expression. When comparing rAAV genome associated histone modifications in rhesus macaques to those in mice injected with the same vector, the activating histone marks were starkly reduced in macaque-derived episomes. Differential epigenetic marking of AAV genomes may explain different expression profiles in mice and rhesus macaques as well as the wide dose response variation observed in primates in both preclinical and human clinical trials.

2024-03-11 | GSE261043 | GEO

Correlation of antigen expression with epigenetic modifications after rAAV delivery of a hyperactive human Factor IX variant in mice and rhesus macaques (Tn5 NHP)

2024-03-11 | GSE261046 | GEO

Correlation of antigen expression with epigenetic modifications after rAAV delivery of a hyperactive human Factor IX variant in mice and rhesus macaques (Tn5 mouse)

2024-03-11 | GSE261045 | GEO

Expression data from injected mice overexpressing Tcfeb specifically in muscle

Project description:In order to identify the effects of Tcfeb overexpression on the muscle transcriptome, we performed Affymetrix Gene-Chip hybridization experiments for the mice injected with an AAV vector expressing Tcfeb as compared with mice injected with an AAV vector expressing GFP as control. Transcriptome analysis of the injected mice overexpressing Tcfeb specifically in muscle.

2016-12-23 | GSE62975 | GEO

Transcription profiling of mouse rds mutant eye infected with CNTF/rAAV vs. control untreated eye

Project description:The retinal degeneration slow gene (rds/peripherin), is essential for normal photoreceptor (rods and cones) outer segment structure in the neurosensory retina. Our rds animal model, are stable transgenic mice that carry a null mutation (complete lost of function) in the rds gene. Those animals become blind, mimicking a human form of retinitis pigmentosa. In our experience we have observed dramatic levels of photoreceptor rescue after subretinal injection of those animals with a ciliary neurotrophic factor (CNTF) inserted into a recombinant Adeno-associate virus (rAAV) vector. However, this cell rescue is accompanied by changes in photoreceptor nuclear morphology, attenaution of the electroretinogram and evetually Apoptosis. By using Microarray analysis we hope to identify genes whose expression or lack thereof brings the cell to the brink of suicide. Identification of these genes will suggest therapeutic targets for the future. We will determine gene expression patterns in the retina of rds mice non-injected and injected with CNTF/rAAV virus after 60 days of injection. Our working hypothesis is that the injected CNTF/rAAV vector induces the expression of genes that somehow partially restores the photoreceptor morphology of rds mice. Paradoxically, it also has a negative effect on the phisiology of these cells (ERG). The up or down regulation of genes in different areas of the neurosensory retina collected by Laser Capture Microdissection will give us an insight on the relevance of candidate genes responsible for this phenomenon. We will use rds mice at age P25 and inject their rigth eye with CNTF/AVV virus (2.68x e13 particles/ml) and use the left eye as a control. Injection is performed via subretinal. Retinas will be collected at age P90 post injection. RNA will be extracted and processed accordingly for MIcroarray analysis.

2008-06-13 | E-GEOD-4756 | biostudies-arrayexpress

Production of rAAV by plasmid transfection induces antiviral and inflammatory responses in suspension HEK293

Project description:To understand the response of host cells to rAAV vector production via plasmid transfection, samples were collected throughout the course of three 50 L production batches and analyzed by bulk RNA sequencing of polyadenylated transcripts (RNA-seq). Gene ontology analysis determined that upregulated pathways included inflammatory and antiviral responses. Systematic analyses of the cellular transcriptional response to rAAV production indicates that these host cells are not passively supporting vector manufacture, and therefore may illuminate genes and pathways that influence rAAV production, thereby enabling the rational design of next-generation manufacturing platforms to support safe, effective, and affordable AAV-based gene therapies.

2023-02-06 | GSE224405 | GEO

AAV-mediated genome editing is influenced by the formation of R-loops.

Project description:Recombinant adeno-associated viral vectors (rAAV) hold a natural ability to stimulate homologous recombination (AAV-HR). Moreover, they are also reported to randomly integrate into numerous locations throughout the genome. Here, we describe DNA/RNA immune precipitation sequencing (DRIP-seq) studies in HEPA1-6 cells and whole murine liver to detect genomic r-loops. Through genetic and pharmacological manipulation of r-loops formation, we showed a significant enhancement of AAV-HR. Notably, we were able to detect different levels of r-loops along the Albumin locus. Both in vitro and in vivo experiments showed that the 3’ end of Albumin (high r-loops) is efficiently edited by AAV-HR, whereas the upstream region (low r-loops) did not result in any detectable vector integration. In addition, we were also able to find an interesting correlation between previously reported off-target rAAV integration and r-loop enriched genomic regions. Thus, we conclude that highly transcribed genes accumulate high levels of r-loops, and this could lead to rAAV vector genome integration. These findings may shed light on mechanisms for improving the safety and efficacy of genome editing and may enhance our ability to predict regions most susceptible to insertional mutagenesis with canonical rAAV vectors.

2024-05-05 | GSE261759 | GEO

transcriptional profiling of brain from WT, AAV9-Ids or Null-treated MPSII mice.

Project description:The experiment evaluates the therapeutic effect brain injected AAV9-IDS (Adeno-associated virus 9 encoding IDS enzyme) treatment in a mouse model of Mucopolysaccharidosis Type II (MPSII). Microarrays were performed in order to compare the transcriptional profiling after the treatment. Three groups were analyzed, wild type (WT) mice, MPSII mice treated with AAV-NULL (AAV vector alone) and MPSII mice treated with AAV-IDS (vector encoding IDS enzyme). Four months after vector administration (at 6 months of age), animals were sacrificed and tissues were harvested and processed. RNA isolated from the encephalon of three groups of mice was analysed using the Affimetrix® microarray platform

2019-05-20 | E-MTAB-4728 | biostudies-arrayexpress

Expression data from hepatocellular carcinoma and adjacent normal liver tissue

Project description:Assay of gene expression pattern differences between liver cancer tissue and normal liver tissue from the same mouse by microarray in 4 separate mice injected with recombinant adeno-associated viral (AAV) vector 4 Mice (M24, M48, M50, M60) were necropsied at 18 months post-injection of AAV-vector, and livers removed. Tumor tissue and adjacent normal tissue were identified and dissected for RNA extraction.

2010-11-14 | E-GEOD-23680 | biostudies-arrayexpress

ruiz-affy-mouse-243540

2006-05-02 | GSE4756 | GEO

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