SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

Lee, Peiyee; Martin, Nathan; Nakamura, Kotoka; Azghadi, Soheila; Amiri, Mojgan; Ben‐David, Uri; Perlman, Susan; Gatti, Richard A.; Hu, Hailiang; Lowry, William E.

doi:10.1038/ncomms2824

Cited by 37 publications

(28 citation statements)

References 46 publications

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“…We were not able to detect any consistently up or downregulated genes or pathways in pluripotent state between A-T iPSCs and iPSCs generated from healthy donor fibroblasts (WT iPSCs). These data show that ATM deficiency does not affect global gene expression in the pluripotent state, similar to previous reports [21][22][23][24].…”

Section: Ipscs With Deficiencies In Atmsupporting

confidence: 92%

“…Mutations in ATM result in defective cell cycle checkpoint activation and a reduced capacity for repair of DNA double-strand breaks (DSBs). iPSCs from A-T patients have been generated by multiple laboratories, but the issue of genomic variation has not been comprehensively investigated [20][21][22][23][24]. We analyze the CNVs of iPSCs derived from A-T patient using high-resolution single-nucleotide polymorphism (SNP) array and discovered differential genome-wide distribution relative to replication timing organization and the effects of integrating versus nonintegrating reprogramming methods.…”

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confidence: 99%

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Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Baccei

et al. 2016

Stem Cells and Development

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Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM-deficient iPSCs relative to wild-type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral (RV) reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DDR reveals unique vulnerability of early replicating open chromatin to RV vectors.

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Section: Ipscs With Deficiencies In Atmsupporting

confidence: 92%

mentioning

confidence: 99%

Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Baccei

et al. 2016

Stem Cells and Development

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“…Another study found that a chemical screen could identify a compound reversing the effects of the rare disease, ataxia-telangiectasia, in neural cells derived from patient iPSCs [61]. An additional benefit of modeling rare diseases with iPSCs is that the identification of the mechanisms of action in these disorders may facilitate the development of new therapeutics and the elucidation of fundamental processes such as survival and proliferation, which may be applied to other neurodegenerative diseases.…”

Section: Modeling Rare Cns Diseases With Ipscsmentioning

confidence: 99%

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

Hunsberger

Efthymiou

Malik

et al. 2015

Stem Cells and Development

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There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts.Disease Modeling D iseases of the central nervous system (CNS) affect a large number of people, but therapeutic intervention is hampered by the lack of useful models for many of these diseases. Current research on human subjects, particularly for drug discovery for CNS diseases, is severely (and appropriately) limited by ethical guidelines. Therefore, surrogate models are needed that share important anatomical, physiological, and genetic features to advance new treatments and therapies for CNS diseases [1].Developing rapid and effective therapies for CNS diseases requires the availability of in vitro models that accurately recapitulate disease phenotypes and predict patient treatment response. A proper model must be both sensitive and predictive while reflecting both normal and disease processes. Equally important, these models should enable the investigation of genetic and environmental risk factors contributing to diseases in a rapid and economical way. Currently used models often do not reflect a typical human response [2-4], despite efforts underway to better characterize these models and increase their preclinical value in predicting safety and efficacy in the clinic [5,6]. Therefore, there is a great need to develop disease-and patient-specific models from cells directly affected in CNS disorders. These cellbased models, we envision, could either replace or supplement current animal models and enable the efficient translation of basic research into the clinical setting. Limitations with current CNS modelsCurrently, drug discovery relies on the use of animalbased or cell-based models, ...

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“…This was, to the best of our knowledge and at the time of writing the first exemplification of an iPS cell derived neuronal model of A-T. However this has recently changed [196,212].…”

Section: Discussionmentioning

confidence: 83%

“…It is becoming harder to ignore the accumulating evidence implicating mitochondria in a myriad of different neurological syndromes and ataxias [176,178]. A handful of papers provide evidence that ATM may be involved in regulating mitochondrial homeostasis [113,[194][195][196], however none propose a mechanism that may explain the involvement of mitochondria with the neurodegeneration in A-T. In addition to the role of mitochondria in providing energy for cellular respiration and balance of ROS, the mitochondria are also the second largest source of calcium buffering within the cell [197].…”

Section: Discussionmentioning

confidence: 99%

Induced pluripotent stem cells from patients with ataxia-telangiectasia

Nayler¹

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A-T (Ataxia-Telangiectasia) is a multi-systemic, rare genetic disorder hallmarked by predisposition to cancer, immune deficiency and most notably progressive neurodegeneration [1]. A-T results from mutation of the ATM gene (11q22.3). ATM is a protein kinase belonging to the phosphatidylinositol 3-kinase-like family [2]. ATM exerts control over genomic integrity by recognizing and responding to DNA damage, through phosphorylation of substrates involved in cell cycle control and DNA damage repair [1]. The ATM protein is involved with numerous cellular processes and as such, A-T represents a paradigm for neurodegenerative disorders, as well as cancer.Experimental models of ATM function have been restricted to systems of limited context to understanding ATM biology and its potential role in development and tissue formation.Animal models have failed to faithfully recapitulate the full spectrum of A-T symptoms including the neurodegenerative aspect, which remains poorly understood. To date, studies on A-T have failed to answer the fundamental question of why certain cell types are seemingly more affected than others. As access to pluripotent stem cells becomes mainstream, it becomes possible, to a degree, to recreate and study in vitro processes giving rise to various cell types, including neurons, using directed differentiation protocols.We hypothesized that ATM deficient cells may be difficult or impossible to reprogram without intervention or assistance, and that this difficulty may be at least in part due excessive levels of reprogramming-induced or existing DNA damage, to the poor growth characteristics of A-T cells or the inability to participate in certain pathways necessary for reprogramming. We show that it was indeed possible to generate iPSCs from A-T patients albeit at reduced efficiency. This thesis describes the first generation and characterization of bona fide iPS cells from patients with A-T. Additionally we use this model system to explore the role and functionality of ATM in an embryonic setting, showing that ATM signaling is vitally required for the maintenance of cell cycle control and DNA fidelity after DNA damage. We have defined the transcriptional landscape of pluripotent stem cells from patients with A-T and point to novel findings regarding oxidative phosphorylation pathways. Further to this, we have used this model system to explore the role of ATM in neurogenesis and neuronal activity. We provide evidence that fosters support for the theory that A-T involves aspects of mitochondrial dysfunction and explore whether calcium trafficking is defective in neurons generated from patient iPSCs. Importantly we have illustrated the proof of concept that genetic manipulation of neuronal cells is possible by delivery of full length ATM, which also restored a functional DNA damage response.Finally, we utilized a neuronal differentiation protocol to generate neural progenitors characteristic of the developing cerebellum, and describe the transcriptome of these cells in the absence of ATM. These ...

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SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

Cited by 37 publications

References 46 publications

Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

Induced pluripotent stem cells from patients with ataxia-telangiectasia

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