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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [TCR]

ABSTRACT: Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [TCR]

PROVIDER: PRJNA936120 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23509275_1.fastq.gz	Fastqsanger.gz
	SRR23509275_2.fastq.gz	Fastqsanger.gz
	SRR23509276_1.fastq.gz	Fastqsanger.gz
	SRR23509276_2.fastq.gz	Fastqsanger.gz
	SRR23509277_1.fastq.gz	Fastqsanger.gz

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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [TCR]

Project description:Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene, which result in impaired processing of cytotoxic vesicles and hence compromised T and NK cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show 30-40% mortality. As a first step to meet this medical need, we developed and tested a curative genome editing strategy in the FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site (cSD) in Unc13d intron 26 and develop the clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV). Here, we employed CRISPR-Cas technology to delete the disease-underlying mutation in HSCs, and transplanted the Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Genotyping, phenotyping and CAST-Seq based off-target analyses of cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wildtype cells were comparable. LCMV challenge of the transplanted mice resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, while Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH. In sum, our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T cell response in the absence of genotoxicity-associated clonal outgrowth or leukemogenesis.

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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

Project description:Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

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Project description:Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

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Project description:Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [Amplicon]

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Murine Model of Familial Hemophagocytic Lymphohistiocytosis Hepatitis is Mediated by IFN-γ in a Predominantly Hepatic-Intrinsic Manner

Project description:Interferon gamma (IFN-γ) is the main cytokine driving Familial Hemophagocytic Lymphohistiocytosis (FHL) organ dysfunction. Hepatocytes are known to have IFN-γ receptor (IFN-γ-R). Blockade of IFN-γ pathway ameliorates FHL hepatitis, in animal models and in humans. However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. We report that IFN-γ-mediated hepatic injury in the murine model of FHL is caused by direct effect on the liver and has a necessary role in recruitment of the inflammatory mediators of injury in FHL: inflammatory monocytes and CD8+ effector memory T lymphocytes (CD8+ CD44hi CD62Llo) (Tem).

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