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  1. Article ; Online: High-Throughput Screening Assay for Detecting Drug-Induced Changes in Synchronized Neuronal Oscillations and Potential Seizure Risk Based on Ca 2+ Fluorescence Measurements in Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neuronal 2D and 3D Cultures

    Hua-Rong Lu / Manabu Seo / Mohamed Kreir / Tetsuya Tanaka / Rie Yamoto / Cristina Altrocchi / Karel van Ammel / Fetene Tekle / Ly Pham / Xiang Yao / Ard Teisman / David J. Gallacher

    Cells, Vol 12, Iss 958, p

    2023  Volume 958

    Abstract: Drug-induced seizure liability is a significant safety issue and the basis for attrition in drug development. Occurrence in late development results in increased costs, human risk, and delayed market availability of novel therapeutics. Therefore, there ... ...

    Abstract Drug-induced seizure liability is a significant safety issue and the basis for attrition in drug development. Occurrence in late development results in increased costs, human risk, and delayed market availability of novel therapeutics. Therefore, there is an urgent need for biologically relevant, in vitro high-throughput screening assays (HTS) to predict potential risks for drug-induced seizure early in drug discovery. We investigated drug-induced changes in neural Ca 2+ oscillations, using fluorescent dyes as a potential indicator of seizure risk, in hiPSC-derived neurons co-cultured with human primary astrocytes in both 2D and 3D forms. The dynamics of synchronized neuronal calcium oscillations were measured with an FDSS kinetics reader. Drug responses in synchronized Ca 2+ oscillations were recorded in both 2D and 3D hiPSC-derived neuron/primary astrocyte co-cultures using positive controls (4-aminopyridine and kainic acid) and negative control (acetaminophen). Subsequently, blinded tests were carried out for 25 drugs with known clinical seizure incidence. Positive predictive value (accuracy) based on significant changes in the peak number of Ca 2+ oscillations among 25 reference drugs was 91% in 2D vs. 45% in 3D hiPSC-neuron/primary astrocyte co-cultures. These data suggest that drugs that alter neuronal activity and may have potential risk for seizures can be identified with high accuracy using an HTS approach using the measurements of Ca 2+ oscillations in hiPSC-derived neurons co-cultured with primary astrocytes in 2D.
    Keywords hiPSC neurons ; 2D ; 3D ; high throughput screening HTS ; Ca 2+ neuronal oscillations ; neuronal active drugs ; Biology (General) ; QH301-705.5
    Subject code 333
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking

    Ivan Kopljar / Hua Rong Lu / Karel Van Ammel / Martin Otava / Fetene Tekle / Ard Teisman / David J. Gallacher

    Stem Cell Reports, Vol 11, Iss 6, Pp 1365-

    2018  Volume 1377

    Abstract: Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the ... ...

    Abstract Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the challenge remains to implement hiPSC-CMs into cardiac de-risking of new chemical entities (NCEs) during preclinical drug development. Here, we used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities. Tolerance interval calculations and evaluation of different classes of cardio-active drugs enabled us to develop a weighted scoring matrix. This approach allowed the translation of various pharmacological effects in hiPSC-CMs into a single hazard label (no, low, high, or very high hazard). Evaluation of 587 internal NCEs and good translation to ex vivo and in vivo models for a subset of these NCEs highlight the value of the cardiac hazard scoring in facilitating the selection of compounds during early drug safety screening. : Kopljar and colleagues developed a scoring system to evaluate the potential cardiac hazard of drugs using a hiPSC-CM-based screening assay. This approach allows translation of various pharmacological responses in hiPSC-CMs into a single hazard label. Early evaluation of thousands of new chemical entities within drug discovery and development should enhance the development of new drugs with a favorable cardio-safety profile. Keywords: cardiomyocytes, stem cells, drug discovery and development, drug screening, cardiac safety, cardiac hazard, pharmacology, arrhythmia, torsade de pointes, hERG
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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