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AAV vectors trigger neurotoxic DNA damage responses and STING-dependent inflammation in human CNS cells.

ABSTRACT: AAV vectors trigger neurotoxic DNA damage responses and STING-dependent inflammation in human CNS cells.

PROVIDER: PRJNA1067328 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27673903_1.fastq.gz	Fastqsanger.gz
	SRR27673903_2.fastq.gz	Fastqsanger.gz
	SRR27673904_1.fastq.gz	Fastqsanger.gz
	SRR27673904_2.fastq.gz	Fastqsanger.gz
	SRR27673905_1.fastq.gz	Fastqsanger.gz

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AAV vectors trigger neurotoxic DNA damage responses and STING-dependent inflammation in human CNS cells [scRNAseq_dataset2]

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AAV vectors trigger neurotoxic DNA damage responses and STING-dependent inflammation in human CNS cells [scRNAseq_dataset1]

Project description:Adeno-associated viral (AAV) vector gene therapy is gaining ground as a treatment option for genetic neurodegenerative diseases tha currently have no cure. Nonetheless, significant toxicity and severe adverse events are emerging in recent clinical trials through mechanisms that remain unclear. We have modelled here AAV-mediated neurotoxicity in the context of the human brain taking advantage of human induced pluripotent stem cell-based technologies. We have used single-cell RNA sequencing technologies to interrogate vector-induced cell-intrinsic innate immune mechanisms that could contribute to neurotoxicity in mixed 2D neuron-glial cultures transduced with AAV vectors at different time-points and harvested at two different time-points.

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AAV vectors trigger neurotoxic DNA damage responses and STING-dependent inflammation in human CNS cells [scRNAseq_dataset2]

Project description:Adeno-associated viral (AAV) vector gene therapy is gaining ground as a treatment option for genetic neurodegenerative diseases tha currently have no cure. Nonetheless, significant toxicity and severe adverse events are emerging in recent clinical trials through mechanisms that remain unclear. We have modelled here AAV-mediated neurotoxicity in the context of the human brain taking advantage of human induced pluripotent stem cell-based technologies. We have used single-cell RNA sequencing technologies to interrogate vector-induced cell-intrinsic innate immune mechanisms that could contribute to neurotoxicity in 3D brain sphheroids transduced with AAV vectors at different time-points and harvested at two different time-points.

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AAV vectors trigger DNA damage responses and STING-dependent inflammation in human CNS cells

Project description:AAV vectors trigger DNA damage responses and STING-dependent inflammation in human CNS cells

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AAV vectors trigger DNA damage responses and STING-dependent inflammation in human CNS cells

Project description:Adeno-associated viral (AAV) vector-based gene therapy is gaining foothold as a treatment option for a variety of genetic neurodegenerative diseases. Nonetheless, dose-dependent toxicities and severe adverse events are emerging in recent clinical trials through mechanisms that remain unclear. We have modelled here AAV-mediated neurotoxicity in the context of the human brain taking advantage of human induced pluripotent stem cell-based technologies. Our work uncovers vector-induced cell-intrinsic innate immune mechanisms at the single-cell level that contribute to neurotoxicity in 2D and 3D models of the human central nervous system (CNS). The AAV genome triggered p53-dependent DNA damage responses across CNS cell types followed by induction of IL-1R- and STING-dependent inflammatory responses. In addition, transgene-expression led to MAVS-dependent RNA sensing and activation of type I interferon (IFN) signalling. Cell-intrinsic and paracrine neurotoxicity could be prevented by inhibiting p53 or acting downstream on STING- and IL-1R-mediated activation of inflammatory responses. Activation of DNA damage, type I IFN and CNS inflammation were confirmed in vivo. Together, our work sheds significant light on the cell-autonomous innate immune mechanisms of vector sensing that can contribute to AAV-associated neurotoxicity.

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