Jutta Rohrbacher
Janssen Pharmaceutica
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Publication
Featured researches published by Jutta Rohrbacher.
Journal of Biomolecular Screening | 2005
Adrienne E. Dubin; Nadia Nasser; Jutta Rohrbacher; An N. Hermans; Roger Marrannes; Christopher James Grantham; Koen van Rossem; Miroslav Cik; Sandra R. Chaplan; David J. Gallacher; Jia Xu; António Guia; Nicholas G. Byrne; Chris Mathes
The authors used the PatchXpress® 7000A system to measure compound activity at the hERG channel using procedures that mimicked the “gold-standard” conventional whole-cell patch clamp. A set of 70 compounds, including hERG antagonists with potencies spanning 3 orders of magnitude, were tested on hERG302-HEK cells using protocols aimed at either identifying compound activity at a single concentration or obtaining compound potency from a cumulative concentration dependence paradigm. After exposure to compounds and subsequent washout of the wells to determine reversibility of the block, blockade by a reference compound served as a quality control. Electrical parameters and voltage dependence were similar to those obtained using a conventional whole-cell patch clamp. Rank order of compound potency was also comparable to that determined by conventional methods. One exception was flunarizine, a particularly lipophilic compound. The PatchXpress® accurately identified the activity of 29 moderately potent antagonists, which only weakly displace radiolabeled astemizole and are false negatives in the binding assay. Finally, no false hits were observed from a collection of relatively inactive compounds. High-quality data acquisition by PatchXpress® should help accelerate secondary screening for ion channel modulators and the drug discovery process
Scientific Reports | 2016
Jacobine Kuijlaars; Tutu Oyelami; Annick Diels; Jutta Rohrbacher; Sofie Versweyveld; Giulia Meneghello; Marianne Tuefferd; Peter Verstraelen; Jan R. Detrez; Marlies Verschuuren; Winnok H. De Vos; Theo F. Meert; Pieter J. Peeters; Miroslav Cik; Rony Nuydens; Bert Brône; An Verheyen
Impaired neuronal network function is a hallmark of neurodevelopmental and neurodegenerative disorders such as autism, schizophrenia, and Alzheimer’s disease and is typically studied using genetically modified cellular and animal models. Weak predictive capacity and poor translational value of these models urge for better human derived in vitro models. The implementation of human induced pluripotent stem cells (hiPSCs) allows studying pathologies in differentiated disease-relevant and patient-derived neuronal cells. However, the differentiation process and growth conditions of hiPSC-derived neurons are non-trivial. In order to study neuronal network formation and (mal)function in a fully humanized system, we have established an in vitro co-culture model of hiPSC-derived cortical neurons and human primary astrocytes that recapitulates neuronal network synchronization and connectivity within three to four weeks after final plating. Live cell calcium imaging, electrophysiology and high content image analyses revealed an increased maturation of network functionality and synchronicity over time for co-cultures compared to neuronal monocultures. The cells express GABAergic and glutamatergic markers and respond to inhibitors of both neurotransmitter pathways in a functional assay. The combination of this co-culture model with quantitative imaging of network morphofunction is amenable to high throughput screening for lead discovery and drug optimization for neurological diseases.
Frontiers in Physiology | 2017
Elisa Passini; Oliver J. Britton; Hua Rong Lu; Jutta Rohrbacher; An N. Hermans; David J. Gallacher; Robert J.H. Greig; Alfonso Bueno-Orovio; Blanca Rodriguez
Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na+ and Ca2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca2+-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.
Journal of Pharmacological and Toxicological Methods | 2012
Jutta Rohrbacher; Petra Bex; David J. Gallacher
Journal of Pharmacological and Toxicological Methods | 2018
Karel Van Ammel; Hua Rong Lu; Ivan Kopljar; Jutta Rohrbacher; Ard Teisman; David J. Gallacher
Journal of Pharmacological and Toxicological Methods | 2017
Jutta Rohrbacher; Brigitte Loenders; An N. Hermans; David J. Gallacher
Journal of Pharmacological and Toxicological Methods | 2016
An N. Hermans; Danny Geyskens; Jutta Rohrbacher; Hua Rong Lu; Lieve Lammens; David J. Gallacher
Journal of Pharmacological and Toxicological Methods | 2016
Elisa Passini; Oliver J. Britton; Hua Rong Lu; David J. Gallacher; Jutta Rohrbacher; Hermans An; Alfonso Bueno-Orovio; Blanca Rodriguez
Journal of Pharmacological and Toxicological Methods | 2016
Hua Rong Lu; An N. Hermans; Ivan Kopljar; Jutta Rohrbacher; Ard Teisman; David J. Gallacher
Journal of Pharmacological and Toxicological Methods | 2015
Michael K. Pugsley; Jutta Rohrbacher; David J. Gallacher; Ian Waldie; Nigel Gillard