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The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVivo]

ABSTRACT: The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVivo]

PROVIDER: PRJNA939199 | ENA |

REPOSITORIES: ENA

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The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner

Project description:The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner

| PRJNA939495 | ENA

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVitro]

Project description:The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVitro]

| PRJNA939193 | ENA

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVitro]

Project description:The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVitro]

| PRJNA939443 | ENA

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVivo]

Project description:The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVivo]

| PRJNA939192 | ENA

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVivo]

Project description:Recombinant adeno-associated viral vectors (rAAVs) are among the most commonly used vehicles for in vivo based gene therapies. However, it is hard to predict which AAV capsid will provide the most robust expression in human subjects due to the observed discordance in vector-mediated transduction between species. We used a primate specific capsid, AAV-LK03, and demonstrated that the limitation of this capsid towards transduction of mouse cells was unrelated to cell entry and nuclear transport but rather due to depleted histone H3 chemical modifications related to active transcription, namely H3K4me3 and H3K27ac, on the vector DNA itself. A single-amino acid insertion into the AAV-LK03 capsid enabled efficient transduction and the accumulation of active-related epigenetic marks on the vector chromatin in mouse without compromising transduction efficiency in human cells. Our study suggests that the capsid protein itself is involved in driving the epigenetic status of the vector genome, most likely during the process of uncoating. Programming viral chromatin states by capsid design may enable facile DNA transduction between vector and host species and ultimately led to rationale selection of AAV capsids for use in humans.

2023-02-28 | GSE226167 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVivo]

2023-02-28 | GSE226165 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVitro]

2023-02-28 | GSE226164 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVitro]

2023-02-28 | GSE226264 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner

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

2023-02-28 | GSE226268 | GEO

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.

2024-03-11 | GSE261046 | GEO

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