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Publication

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.

Cell reports. Medicine | 2023

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.

Pubmed ID: 36706754 RIS Download

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R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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ClinicalTrials.gov (tool)

RRID:SCR_002309

Registry and results database of federally and privately supported clinical trials conducted in United States and around world. Provides information about purpose of trial, who may participate, locations, and phone numbers for more details. This information should be used in conjunction with advice from health care professionals.Offers information for locating federally and privately supported clinical trials for wide range of diseases and conditions. Research study in human volunteers to answer specific health questions. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large groups of people or populations in natural settings. ClinicalTrials.gov contains trials sponsored by National Institutes of Health, other federal agencies, and private industry. Studies listed in database are conducted in all 50 States and in 178 countries.

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GraphPad Prism (tool)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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RRID:SCR_003199

Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.

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RRID:SCR_004129

Repository for all research outputs from across all fields of science in any file format as well as both positive and negative results. They assign all publicly available uploads a Digital Object Identifier (DOI) to make the upload easily and uniquely citeable. They further support harvesting of all content via the OAI-PMH protocol. They promote peer-reviewed openly accessible research, and curate uploads. ZENODO allows users to create their own collection and accept or reject all uploads to it. They allow for uploading under a multitude of different licenses and access levels.

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Genethon DNA and Cell Bank (tool)

RRID:SCR_004639

Since its creation in 1990, the mission of the Genethon''s DNA and Cell Bank is to promote advances in genetic research by providing the scientific community with a high quality cell and human tissue products resource. Europe''s leading bank for genetic diseases, it serves the whole of the medical and scientific community. Each year, Genethon''s DNA and Cell Bank: * Produces approximately 2,000 lymphoblastoid cell lines * Performs approximately 3,000 DNA extractions * Prepares primary myoblast and fibroblast cultures from approximately 100 biopsies Genethon has developed a computer database for ensuring sample management and traceability, which has been submitted to and approved by the CNIL. The Genethon DNA and Cell Bank has been AFNOR certified, according to French biological research center standard NF S 96-900. The activities of the DNA and Cell Bank are as follows: * Collecting blood or DNA from patients affected with genetic diseases and their families with the minimum identification data necessary for the monitoring and follow-up of samples. * Processing the samples in order to make them available to the scientific community and perpetuating DNA preservation (serum isolation and DNA extraction), isolating lymphocytes and establishing lymphoblastoid B lines and primary cultures (mainly myoblasts and fibroblasts). * Storing samples for future research and preserving the genetic heritage by ensuring the long-term physical security of the preserved samples. * Distributing samples as necessary for ongoing research while complying with the principles and laws of bioethics and using the best available technologies at minimum cost.All these activities are carried out following Standard Operating Procedures (SOP) validated by the Quality Assurance department at Genethon. The Bank is open to researchers in France or abroad wishing to store samples or use the services provided (extraction, establishment of cell lines etc.). Each sample received at Genethon is coded in order to guarantee confidentiality, in accordance with the rules established by the CNIL (French Data Protection Authority). All requests for collaboration with the DNA and Cell Bank should be made in writing to Dr Safaa SAKER-DELYE.

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PRISM (tool)

RRID:SCR_005375

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.

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FlowJo (tool)

RRID:SCR_008520

Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

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Miltenyi Biotec (tool)

RRID:SCR_008984

An Organization portal, Antibody supplier, Service resource,

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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