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

ABSTRACT: Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human Factor IX variant in mice and rhesus macaques

PROVIDER: PRJNA1084871 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28248100_1.fastq.gz	Fastqsanger.gz
	SRR28248100_2.fastq.gz	Fastqsanger.gz
	SRR28248101_1.fastq.gz	Fastqsanger.gz
	SRR28248101_2.fastq.gz	Fastqsanger.gz
	SRR28248102_1.fastq.gz	Fastqsanger.gz

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

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.

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

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

2024-03-11 | GSE261044 | GEO

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

2024-03-11 | GSE261043 | GEO

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

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

| PRJNA1084872 | ENA

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

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

| PRJNA1084873 | ENA

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

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

| PRJNA1084874 | ENA

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

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

| PRJNA1084875 | ENA

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-11 | GSE261047 | GEO

Effects of Different Doses of rAAV 5-mCherry on Transcriptome of Hippocampal Pyramidal Neurons in Male Mouse

Project description:Purpose: Here, we evaluated the effects of three different doses of rAAV5 vectors, which are widely used for functional studies in the brain, on hippocampal pyramidal neurons transcription in male mice. Results: There was a strong correlation between rAAV dose and toxicity. As dose increased, rAAV5-DIO-mCherry upregulated genes related to the immune and inflammation response and neuron death and downregulated genes associated with the synapse and axon compartments, mitochondrial potein complex suggesting that higher dose rAAV 5-DIO-mCherry may induce pyramidal neuronal fragility and impair synaptic transmission and structure. Conclusions:the dose should be taken into consideration when rAAV vectors are used for gene transduction studies.

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