Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenous<i>CYBB</i>regulation and expression

Wong, Randall; Sackey, Sarah; Brown, Devin; Senadheera, Shantha; Masiuk, Katelyn E.; Quintos, Jason P.; Colindres, Nicole; Riggan, Luke; Morgan, Richard A.; Malech, Harry L.; Hollis, Roger P.; Kohn, Donald B.

doi:10.1182/blood.2022016074

Cited by 11 publications

(5 citation statements)

References 38 publications

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“…The primary immunodeficiency caused by mutations in the CYBB gene results in the inability of phagocytes to clear the infection ( Wong et al, 2023 ). Numerous studies have demonstrated the role of CYBB as an inflammatory factor in developing multiple diseases ( Chen et al, 2021 ; Hong et al, 2021 ; Wang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and prediction of Alzheimer’s disease and alcohol dependence based on Ferroptosis-related genes

Tian

Shen

et al. 2023

Front. Aging Neurosci.

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BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease whose origins have not been universally accepted. Numerous studies have demonstrated the relationship between AD and alcohol dependence; however, few studies have combined the origins of AD, alcohol dependence, and programmed cell death (PCD) to analyze the mechanistic relationship between the development of this pair of diseases. We demonstrated in previous studies the relationship between psychiatric disorders and PCD, and in the same concerning neurodegeneration-related AD, we found an interesting link with the Ferroptosis pathway. In the present study, we explored the bioinformatic interactions between AD, alcohol dependence, and Ferroptosis and tried to elucidate and predict the development of AD from this aspect.MethodsWe selected the Alzheimer’s disease dataset GSE118553 and alcohol dependence dataset GSE44456 from the Gene Expression Omnibus (GEO) database. Ferroptosis-related genes were gathered through Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and relevant literature, resulting in a total of 88 related genes. For the AD and alcohol dependence datasets, we conducted Limma analysis to identify differentially expressed genes (DEGs) and performed functional enrichment analysis on the intersection set. Furthermore, we used ferroptosis-related genes and the DEGs to perform machine learning crossover analysis, employing Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify candidate immune-related central genes. This analysis was also used to construct protein-protein interaction networks (PPI) and artificial neural networks (ANN), as well as to plot receiver operating characteristic (ROC) curves for diagnosing AD and alcohol dependence. We analyzed immune cell infiltration to explore the role of immune cell dysregulation in AD. Subsequently, we conducted consensus clustering analysis of AD using three relevant candidate gene models and examined the immune microenvironment and functional pathways between different subgroups. Finally, we generated a network of gene-gene interactions and miRNA-gene interactions using Networkanalyst.ResultsThe crossover of AD and alcohol dependence DEG contains 278 genes, and functional enrichment analysis showed that both AD and alcohol dependence were strongly correlated with Ferroptosis, and then crossed them with Ferroptosis-related genes to obtain seven genes. Three candidate genes were finally identified by machine learning to build a diagnostic prediction model. After validation by ANN and PPI analysis, ROC curves were plotted to assess the diagnostic value of AD and alcohol dependence. The results showed a high diagnostic value of the predictive model. In the immune infiltration analysis, functional metabolism and immune microenvironment of AD patients were significantly associated with Ferroptosis. Finally, analysis of target genes and miRNA-gene interaction networks showed that hsa-mir-34a-5p and has-mir-106b-5p could simultaneously regulate the expression of both CYBB and ACSL4.ConclusionWe obtained a diagnostic prediction model with good effect by comprehensive analysis, and validation of ROC in AD and alcohol dependence data sets showed good diagnostic, predictive value for both AD (AUC 0. 75, CI 0.91–0.60), and alcohol dependence (AUC 0.81, CI 0.95–0.68). In the consensus clustering grouping, we identified variability in the metabolic and immune microenvironment between subgroups as a likely cause of the different prognosis, which was all related to Ferroptosis function. Finally, we discovered that hsa-mir-34a-5p and has-mir-106b-5p could simultaneously regulate the expression of both CYBB and ACSL4.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and prediction of Alzheimer’s disease and alcohol dependence based on Ferroptosis-related genes

Tian

Shen

et al. 2023

Front. Aging Neurosci.

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“…Wong et al took a bioinformatics-guided approach to design a lentiviral vector (LV) that can closely mimic the physiological regulation and expression of the endogenous CYBB gene. 130 This approach was rooted in identifying the enhancers that regulate the CYBB gene. An analysis of a 600-kilobase TAD surrounding the CYBB gene revealed 16 potential enhancer elements, including one in intron 3, which significantly increased expression.…”

Section: Bioinformatics-driven Design Of Lentiviral Gene Therapy For ...mentioning

confidence: 99%

“…Wong et al. took a bioinformatics‐guided approach to design a lentiviral vector (LV) that can closely mimic the physiological regulation and expression of the endogenous CYBB gene 130 . This approach was rooted in identifying the enhancers that regulate the CYBB gene.…”

Section: Precision In Practice: Highlighting Gene Therapy Innovations...mentioning

confidence: 99%

Gene regulation in inborn errors of immunity: Implications for gene therapy design and efficacy

Ghanim,

Porteus

2024

Immunological Reviews

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SummaryInborn errors of immunity (IEI) present a unique paradigm in the realm of gene therapy, emphasizing the need for precision in therapeutic design. As gene therapy transitions from broad‐spectrum gene addition to careful modification of specific genes, the enduring safety and effectiveness of these therapies in clinical settings have become crucial. This review discusses the significance of IEIs as foundational models for pioneering and refining precision medicine. We explore the capabilities of gene addition and gene correction platforms in modifying the DNA sequence of primary cells tailored for IEIs. The review uses four specific IEIs to highlight key issues in gene therapy strategies: X‐linked agammaglobulinemia (XLA), X‐linked chronic granulomatous disease (X‐CGD), X‐linked hyper IgM syndrome (XHIGM), and immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX). We detail the regulatory intricacies and therapeutic innovations for each disorder, incorporating insights from relevant clinical trials. For most IEIs, regulated expression is a vital aspect of the underlying biology, and we discuss the importance of endogenous regulation in developing gene therapy strategies.

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“…All genetic forms of CGD respond to transplantation, and the best outcomes are expected at a young age, before permanent organ damage has occurred [59]. For a few patients where HSCT may not be an option, e.g., because of severe pre-morbid conditions, clinical trials on gene therapy are currently underway [60,61]. However, current methods of introducing the corrected gene generally result in an increased but still sub-optimal oxidase activity, which may be sufficient to protect from infection but not the inflammatory complications previously described.…”

Section: Treatmentmentioning

confidence: 99%

Inflammatory Complications in Chronic Granulomatous Disease

Grammatikos,

Gennery

2024

JCM

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Chronic granulomatous disease (CGD) is a rare inborn error of immunity that typically manifests with infectious complications. As the name suggest though, inflammatory complications are also common, often affecting the gastrointestinal, respiratory, urinary tracts and other tissues. These can be seen in all various types of CGD, from X-linked and autosomal recessive to X-linked carriers. The pathogenetic mechanisms underlying these complications are not well understood, but are likely multi-factorial and reflect the body’s attempt to control infections. The different levels of neutrophil residual oxidase activity are thought to contribute to the large phenotypic variations. Immunosuppressive agents have traditionally been used to treat these complications, but their use is hindered by the fact that CGD patients are predisposed to infection. Novel therapeutic agents, like anti-TNFa monoclonal antibodies, anakinra, ustekinumab, and vedolizumab offer promise for the future, while hematopoietic stem cell transplantation should also be considered in these patients.

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Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenousCYBBregulation and expression

Cited by 11 publications

References 38 publications

Bioinformatics analysis and prediction of Alzheimer’s disease and alcohol dependence based on Ferroptosis-related genes

Bioinformatics analysis and prediction of Alzheimer’s disease and alcohol dependence based on Ferroptosis-related genes

Gene regulation in inborn errors of immunity: Implications for gene therapy design and efficacy

Inflammatory Complications in Chronic Granulomatous Disease

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