Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438481 | ENA |
REPOSITORIES: ENA
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Project description:Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 out of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear sub-compartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures, identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may impact the efficacy of LV-based cellular therapies.
2023-10-06 | GSE163082 | GEO
Project description:Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 out of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear sub-compartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures, identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may impact the efficacy of LV-based cellular therapies.
2023-10-06 | GSE163081 | GEO
Project description:Hypoxia-regulated endothelial-specific lentiviral vector that can be used for endothelial-targeted gene therapy.
2021-08-12 | GSE151832 | GEO
Project description:Improved understanding of mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. We revealed a novel regulatory axis that SIRT1-deficiency induced TET2 hyperacetylation promotes MDS HSPC functions, and provide an approach to target MDS HSPCs by activating SIRT1 deacetylase. Four Groups: Group1: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for SIRT1); Group2: MDS-L cells transduced with lentiviral vector containing interference squence targeting SIRT1 (SIRT shRNA); Group 3: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for TET2); Group 4: MDS-L cells transduced with lentiviral vector containing interference squence targeting TET2 (TET2 shRNA).
2018-08-13 | GSE117272 | GEO
Project description:Severe combined immunodeficiency (SCID) occurs in various species, including humans, at a frequency as high as one per 50,000 live births. Generally, SCID can be classified according to the cause of the immunodeficiency, and it includes impaired cytokine-mediated signalling, defective V(D)J recombination, impaired pre-T-cell receptor signalling, and metabolic enzyme deficiencies. Although mice with disrupted SCID-causing genes have provided important insights into the human disease, not all the SCID mice have phenotypes that resemble those in human SCID patients. In humans, most SCID patients are reported to have impaired cytokine-mediated signalling in immune cells. IL2RG is a key component of the immune system, which is associated with the development of X-linked SCID in humans. Despite some phenotypic characterisations and functional studies being performed in SCID animals, little is known about the molecular basis of the different phenotypes of SCID in mouse and pig. In the present experiment, we generated monoallelic IL2RG (mIL2RG+/Δ69-368) KO pigs and investigated patterns of gene expression during their immune development in order to further explore our understanding of immune responses in X-linked SCID.
2016-09-27 | GSE77581 | GEO
Project description:Severe combined immunodeficiency (SCID) occurs in various species, including humans, at a frequency as high as one per 50,000 live births. Generally, SCID can be classified according to the cause of the immunodeficiency, and it includes impaired cytokine-mediated signalling, defective V(D)J recombination, impaired pre-T-cell receptor signalling, and metabolic enzyme deficiencies. Although mice with disrupted SCID-causing genes have provided important insights into the human disease, not all the SCID mice have phenotypes that resemble those in human SCID patients. In humans, most SCID patients are reported to have impaired cytokine-mediated signalling in immune cells. IL2RG is a key component of the immune system, which is associated with the development of X-linked SCID in humans. Despite some phenotypic characterisations and functional studies being performed in SCID animals, little is known about the molecular basis of the different phenotypes of SCID in mouse and pig. In the present experiment, we generated monoallelic IL2RG (mIL2RG+/Δ69-368) KO pigs and investigated patterns of gene expression during their immune development in order to further explore our understanding of immune responses in X-linked SCID.
2016-09-27 | GSE77580 | GEO
Project description:Severe combined immunodeficiency (SCID) occurs in various species, including humans, at a frequency as high as one per 50,000 live births. Generally, SCID can be classified according to the cause of the immunodeficiency, and it includes impaired cytokine-mediated signalling, defective V(D)J recombination, impaired pre-T-cell receptor signalling, and metabolic enzyme deficiencies. Although mice with disrupted SCID-causing genes have provided important insights into the human disease, not all the SCID mice have phenotypes that resemble those in human SCID patients. In humans, most SCID patients are reported to have impaired cytokine-mediated signalling in immune cells. IL2RG is a key component of the immune system, which is associated with the development of X-linked SCID in humans. Despite some phenotypic characterisations and functional studies being performed in SCID animals, little is known about the molecular basis of the different phenotypes of SCID in mouse and pig. In the present experiment, we generated monoallelic IL2RG (mIL2RG+/Δ69-368) KO pigs and investigated patterns of gene expression during their immune development in order to further explore our understanding of immune responses in X-linked SCID.
2016-09-27 | GSE77579 | GEO