Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA716857 | ENA |
REPOSITORIES: ENA
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Project description:Gene transfer into HSCs by gammaretroviral vectors (RV) is an effective treatment for inherited blood disorders, although potentially limited by the risk of insertional mutagenesis. We evaluated the genomic impact of RV integration in T-lymphocytes from adenosine deaminase (ADA)-Severe combined immunodeficiency (SCID) patients 10 to 30 months after infusion of autologous, genetically-corrected CD34+ cells. Expression profiling on ex vivo T-cell bulk population revealed no difference with respect to healthy controls. To assess the effect of vector integration on gene expression at the single cell level, primary T-cell clones were isolated from two patients. T-cell clones harboured either one or two vector copies per cell and displayed partial to full correction of ADA expression, purine metabolism and TCR-driven functions. Analysis of retroviral integration sites (RIS) indicated a high diversity in T-cell origin, consistent with the polyclonal TCR-Vbeta repertoire. Quantitative transcript analysis of 120 genes within a 200kb-window around RIS showed modest (2.8- to 5.2-fold) disregulation of 5.8% genes in 18.6% of the T-cell clones compared to controls. Nonetheless, affected clones maintained a stable phenotype and normal functions in vitro. These results confirm that RV-mediated gene transfer for ADA-SCID is safe, and provide crucial information for the development of future gene therapy protocols. Global gene expression profiling was performed on CD4+ and CD8+ T-cell subsets purified ex vivo from three ADA-SCID patients at different times after gene therapy. The microarray analysis showed a substantial overlap with the expression patterns of T-cells from controls, indicating the absence of gross abnormalities in the development and function of T-cells derived from genetically corrected hematopoietic stem/progenitor cells. Experiment Overall Design: Transcript profiling was carried out in CD4+ and CD8+ T-cells purified with immunomagnetic beads (Miltenyi Biotec, Germany) from the peripheral blood lymphocytes of ADA-SCID patients (Pt1, 3 and 4) 10-30 months after autologous transplantation with genetically corrected CD34+ cells. At the indicated time points, the percentage of vector-positive T-cells by qPCR was >75%. Transcript profiles were determined using the Affymetrix HG-U133A microarray and compared to those of age-matched healthy controls (n=4; C1, C2, C3, C4).
2009-08-09 | E-GEOD-17354 | biostudies-arrayexpress
Project description:Gene transfer into HSCs by gammaretroviral vectors (RV) is an effective treatment for inherited blood disorders, although potentially limited by the risk of insertional mutagenesis. We evaluated the genomic impact of RV integration in T-lymphocytes from adenosine deaminase (ADA)-Severe combined immunodeficiency (SCID) patients 10 to 30 months after infusion of autologous, genetically-corrected CD34+ cells. Expression profiling on ex vivo T-cell bulk population revealed no difference with respect to healthy controls. To assess the effect of vector integration on gene expression at the single cell level, primary T-cell clones were isolated from two patients. T-cell clones harboured either one or two vector copies per cell and displayed partial to full correction of ADA expression, purine metabolism and TCR-driven functions. Analysis of retroviral integration sites (RIS) indicated a high diversity in T-cell origin, consistent with the polyclonal TCR-Vbeta repertoire. Quantitative transcript analysis of 120 genes within a 200kb-window around RIS showed modest (2.8- to 5.2-fold) disregulation of 5.8% genes in 18.6% of the T-cell clones compared to controls. Nonetheless, affected clones maintained a stable phenotype and normal functions in vitro. These results confirm that RV-mediated gene transfer for ADA-SCID is safe, and provide crucial information for the development of future gene therapy protocols. Global gene expression profiling was performed on CD4+ and CD8+ T-cell subsets purified ex vivo from three ADA-SCID patients at different times after gene therapy. The microarray analysis showed a substantial overlap with the expression patterns of T-cells from controls, indicating the absence of gross abnormalities in the development and function of T-cells derived from genetically corrected hematopoietic stem/progenitor cells.
2009-07-29 | GSE17354 | GEO
Project description:<p>Individuals with a past diagnosis of severe combined immune deficiency (including many cases of "leaky SCID", Omenn syndrome, and reticular dysgenesis) who have undergone blood and marrow transplant, gene therapy, or enzyme replacement in the past may be eligible for 6902. The purpose of 6902 is very similar to 6901, except 6902 is looking backwards at what has already been done in the past (compared to 6901 which is looking into the future). Over 800 patients with SCID are expected to be enrolled on 6902. This makes 6902 the largest study ever to describe outcomes for patients with SCID treated at many different hospitals around North America. </p> <p>One of the most important components of the 6902 study is the "cross sectional" study. Patients who have received their treatments (BMT, gene therapy, enzyme replacement) many years ago are asked to come back to the hospital where they were treated. During this visit, additional research blood work is drawn and information is gathered regarding long-term transplant outcomes such as infections, graft-versus-host disease, autoimmune diseases, and quality of life. This will allow PIDTC researchers to better understand long-term outcomes from procedures that occurred many years ago (sometimes over 30 years ago) - something that is not possible at the present time with 6901. This will help researchers to best design new treatments and clinical trials in the future for children with SCID.</p>
| phs001326 | dbGaP
Project description:<p>Individuals, including infants who were identified by newborn screening, with a recent/new diagnosis of severe combined immune deficiency (SCID) may be eligible to be enrolled in the PIDTC research study: A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children with SCID Disorders. To determine eligibility for this study, potential participants (or, in the case of children, their parents/guardians) should consult with their doctors. The study follows participants with SCID prospectively. That is, the study enrolls participants who already have a plan to receive a blood and marrow transplant (BMT), enzyme therapy, or gene therapy in the future. After the procedure, participants are followed according to a study schedule. The participants' study visits will coincide with the follow-up visits with their doctors as part of their regular ongoing medical care. Participants with “leaky SCID”, reticular dysgenesis, and Omenn syndrome may also be eligible to participate in this study. As the PIDTC recognizes that there are many complex factors that go into the decision of which therapy (BMT, enzyme therapy, or gene therapy), the study does NOT dictate how the doctors should treat their patients. The decisions regarding therapy are made by the participants and their doctors. The study simply follows the participants' progress over time. This study does not involve experimental therapies.</p> <p>A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children with SCID Disorders has been open since August 2010 and continues to be open and enrolling patients to the present day. The study plans to enroll approximately 540 patients with SCID. By studying new patients undergoing treatment for SCID, the goal is to learn more about: (1) outcomes from the treatment of SCID in the modern era of medicine, (2) what factors lead to the best long-term outcomes, such as best donor, conditioning regimen, timing of transplant, etc. and (3) what impact newborn screening and the early diagnosis of SCID has had on the long-term outcomes following BMT or gene therapy. A significant amount of information is also being gathered on how and when the immune system recovers after BMT, quality of life for long-term survivors, and about whether children develop normally after treatment. </p> <p>A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children with SCID Disorders is the largest coordinated prospective study of patients with SCID ever performed. Information that we will learn, both now and in the future, will help doctors and other health professionals to better treat children with SCID. All hospitals within the PIDTC are enrolling patients with SCID for A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children with SCID Disorders study, ensuring that the outcomes are reflective of what happens in the “real world” as opposed to at just one or two large centers. </p>
| phs001392 | dbGaP
Project description:Cellular circular RNAs (circRNAs) are generated by head-to-tail splicing and are present in all multicellular organisms studied so far. Recently, circRNAs have emerged as large class of RNA which can function as post-transcriptional regulators. It has also been shown that many circRNAs are tissue- and stage specifically expressed. Moreover, the unusual stability and expression specificity make circRNAs important candidates for clinical biomarker research. Here, we present a circRNA expression resource of twenty human tissues highly relevant to disease-related research: vascular smooth muscle cells (VSMCs), human umbilical vein (HUVECs), artery endothelial cells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples from mesenchymal stem cell differentiation. In eight different samples from a single donor, we found highly tissue-specific circRNA expression. Circular-to-linear RNA ratios revealed that many circRNAs were higher expressed than their linear host transcripts. Among the 65 validated circRNAs, we noticed potential biomarkers. In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID) patients and in Wiskott-Aldrich-Syndrome (WAS) patients’ samples, we found evidence for differential circRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes. Our findings underscore the need to assess circRNAs in mechanisms of human disease.
2017-09-01 | GSE100242 | GEO
Project description:Follicular helper T cells (Tfh) is indispensable for T-cell dependent antibody responses. Understanding the underlying mechanisms of their differentiation and function is critical for vaccine development. Using unique gene array analysis, we identified adenosine deaminase-1 (ADA-1), as a novel key molecule that drives Tfh helper program in proliferating germinal centers Tfh and circulatory Tfh cells following their interactions with B cells. ADA-1 expression and enzymatic activity is significantly higher in Tfh cells when compared to non-Tfh cells. Exogenous ADA-1 enhances the ability of less efficient cTfh and pro-follicular Tfh cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impeded Tfh function and blunted antibody response. Importantly, in vivo use of recombinant ADA-1 as an adjuvant in a DNA-based HIV vaccine enhanced Tfh differentiation and improved the quantity and the quality of HIV-specific antibody response. Thus, ADA-1 represents a good target for the design of new vaccine strategy.
2019-02-25 | GSE99781 | GEO
Project description:Follicular helper T cells (Tfh) is indispensable for T-cell dependent antibody responses. Understanding the underlying mechanisms of their differentiation and function is critical for vaccine development. Using unique gene array analysis, we identified adenosine deaminase-1 (ADA-1), as a novel key molecule that drives Tfh helper program in proliferating germinal centers Tfh and circulatory Tfh cells following their interactions with B cells. ADA-1 expression and enzymatic activity is significantly higher in Tfh cells when compared to non-Tfh cells. Exogenous ADA-1 enhances the ability of less efficient cTfh and pro-follicular Tfh cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impeded Tfh function and blunted antibody response. Importantly, in vivo use of recombinant ADA-1 as an adjuvant in a DNA-based HIV vaccine enhanced Tfh differentiation and improved the quantity and the quality of HIV-specific antibody response. Thus, ADA-1 represents a good target for the design of new vaccine strategy.
2019-02-25 | GSE99713 | GEO
Project description:Epstein-Barr Virus (EBV) immortalizes resting B-lymphocytes through a highly orchestrated process involving extensive reprogramming of host transcription and metabolism. Here, we use multiple omics-based approaches concurrently across the time course of B-cell infection to investigate the underlying mechanisms that control EBV-induced B-cell immortalization. ATAC-seq revealed that over a third of accessible chromatin is altered with the most perturbed sites overlapping Ets-family, including PU.1 and RUNX1 transcription factors. EBV nuclear antigens (EBNAs) clustered with different gene categories and RNA-seq identified the transcriptional response of these gene. Focusing on EBNA1 revealed a selection of gene targets involved in nucleotide metabolism. Metabolomics indicated that adenosine and purine metabolism are significantly altered by EBV immortalization, and we validated that adenosine deaminase (ADA) is a direct and critical target of EBNA1 and the EBV-directed immortalization process. These findings reveal that purine metabolism and ADA inhibitors may be a useful therapeutic for EBV-driven lymphoid cancers
2021-01-15 | GSE155345 | GEO
Project description:Adenosine DeAminase-1 (ADA-1) improves Follicular helper T cell function and vaccine response
| PRJNA389585 | ENA
Project description:Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. Additionally, ADA-OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA-OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. We then show ADA-OE improves tumor infiltration and clearance by α-HER2 CD4 and CD8 CAR-T with an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.
2023-05-18 | GSE225185 | GEO