Macrophage Models of Gaucher Disease for Evaluating Disease Pathogenesis and Candidate Drugs

Aflaki, Elma; Stubblefield, Barbara; Maniwang, Emerson; Lopez, Grisel; Moaven, Nima; Goldin, Ehud; Marugán, Juan; Patnaik, Samarjit; Dutra, Amalia; Southall, Noel; Zheng, Wei; Tayebi, Nahid; Sidransky, Ellen

doi:10.1126/scitranslmed.3008659

Cited by 103 publications

(118 citation statements)

References 37 publications

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“…While iPSCs have been used to model a number of human diseases (Yagi et al 2011;Choi et al 2013;Liang et al 2013;Miller et al 2013;Aflaki et al 2014;Pashos et al 2017;Cayo et al 2017), there is a limited amount of work demonstrating their ability to model regulatory phenotypes Alasoo et al 2017). iPSC-CMs recapitulate gene expression patterns observed in primary heart tissue obtained from the GTEx Consortium, and eQTLs identified in iPSC-CMs are also enriched among eQTLs identified in primary heart tissue (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Impact of regulatory variation across human iPSCs and differentiated cells

et al. 2017

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Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type-specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type-specific chromatin accessibility.

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Section: Discussionmentioning

confidence: 99%

Impact of regulatory variation across human iPSCs and differentiated cells

et al. 2017

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“…Some of these compounds increased both wild-type and mutant glucocerebrosidase activities, as well as increased the amounts of enzyme localized to the lysosomes in the fibroblasts obtained from Gaucher patients . A medicinal chemistry optimized analog derived from the pyrazolopyrimidine series (NCGC00188758) has recently been reported to increase glucocerebrosidase activity and reduce glycolipid storage in monocytederived and induced pluripotent stem cell-derived macrophages obtained from Gaucher disease patients who carry different mutations (Aflaki et al, 2014). Another series of salicylic acid derivatives has recently been demonstrated to increase glucocerebrosidase activity and promote lysosomal translocation (Rogers et al, 2012).…”

Section: Pharmacological Chaperone Therapy (Pct)mentioning

confidence: 97%

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Sardi¹,

Cheng²,

Shihabuddin³

2015

Progress in Neurobiology

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Gaucher disease, the most common lysosomal storage disease, is caused by a recessively inherited deficiency in glucocerebrosidase and subsequent accumulation of toxic lipid substrates. Heterozygous mutations in the lysosomal glucocerebrosidase gene (GBA1) have recently been recognized as the highest genetic risk factor for the development of α-synuclein aggregation disorders ("synucleinopathies"), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased glucocerebrosidase activity has been demonstrated to promote α-synuclein misprocessing. Furthermore, aberrant α-synuclein species have been reported to downregulate glucocerebrosidase activity, which further contributes to disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect glucocerebrosidase insufficiency with α-synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1-related synucleinopathies, and potentially, for non-GBA1-associated neurodegenerative diseases. In summary, the link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.

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“…Tangier disease (mutations in ABCA1 ), lysosomal storage diseases including neuronal ceroid lipofuscinoses (NCLs) 27 and Gaucher disease (GD, mutations in GBA ), 28, 29 chronic granulomatous disease (CGD, defective NADPH oxidase), 30 Blau syndrome (mutation in NOD2 ), 31 and chronic infantile neurologic cutaneous and articular syndrome (CINCA syndrome, mutation in NLRP3 ). 32 Some of these studies compared the phenotypes of IPSDM and HMDM derived from the same subjects 8, 29 to further validate the fidelity of IPSDM in assessing the functionality of genetic mutations. CRISPR/Cas9 gene editing technologies further expanded the potential by introducing disease mutation in iPSC lines derived from healthy subjects and to correct mutations in the iPSC lines of affected patients to demonstrate causality and the functional impact of the disease mutations on a specific isogenic background.…”

Section: Disease Modeling and Functional Genomic Analyses With Ipsdmmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

Zhang

Reilly

2017

ATVB

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Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human iPSC-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this Review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing and cell therapeutics in cardiovascular diseases.

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Macrophage Models of Gaucher Disease for Evaluating Disease Pathogenesis and Candidate Drugs

Cited by 103 publications

References 37 publications

Impact of regulatory variation across human iPSCs and differentiated cells

Impact of regulatory variation across human iPSCs and differentiated cells

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

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