Najah Abi-Gerges

Najah Abi-Gerges
AstraZeneca | AZ · Translational Safety

PhD

About

101
Publications
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2,565
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Publications

Publications (101)
Article
Full-text available
There is need for a reliable in vitro system that can accurately replicate the cardiac physiological environment for drug testing. The limited availability of human heart tissue culture systems has led to inaccurate interpretations of cardiac-related drug effects. Here, we developed a cardiac tissue culture model (CTCM) that can electro-mechanicall...
Article
Full-text available
Subtype-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising tools, e.g., to assess the potential of drugs to cause chronotropic effects (nodal hiPSC-CMs), atrial fibrillation (atrial hiPSC-CMs), or ventricular arrhythmias (ventricular hiPSC-CMs). We used single-cell patch-clamp reverse transcriptase-quantit...
Preprint
Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities. Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction sta...
Article
Full-text available
Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues f...
Preprint
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary human cardiomyocytes are used for in vitro cardiac safety testing. hiPSC-CMs have been associated with a vast heterogeneity regarding single-cell morphology, beating behavior and action potential duration, prompting a systematic analysis of single-cell characteristic...
Article
Full-text available
Substantial efforts have been recently committed to develop COVID-19 medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. While these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluate...
Article
Full-text available
Background and purpose: The lack of selective sodium-calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1. inhibitor. Experimental approach: A flavan series-based pharmacophore model was constructed. Virtu...
Article
Full-text available
Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the cu...
Article
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Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action. However, the pro-arrhythmic mechanisms in PCs are not entirely understood, particularly in humans, as most investigations are conducted in animals. The aims of this study are to present a novel human PCs electrophysiology biophy...
Article
In preclinical drug development, accurate prediction of drug effects on the human heart is critically important, whether in the context of cardiovascular safety or for the purpose of modulating cardiac function to treat heart disease. Current strategies have significant limitations, whereby cardiotoxic drugs can escape detection or, potential life-...
Article
Full-text available
Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white pap...
Article
Full-text available
To assess drug-induced pro-arrhythmic risk, especially Torsades de Pointe (TdP), new models have been proposed, such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs). Previously we evaluated the electrophysiological profile of 15 reference drugs in hESC-CMs and hiPSC-CMs for their effects on i...
Article
Full-text available
Cardiac safety remains the leading cause of drug development discontinuation. We developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk. Methods: Adult human primary cardiomyocytes from ethically consented organ dono...
Article
Full-text available
Background:In silico modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we direc...
Article
Introduction: The Comprehensive in vitro Proarrhythmic Assay (CiPA) aims to update current cardiac safety testing to better evaluate arrhythmic risk. A central theme of CiPA is the use of in silico approaches to risk prediction incorporating models of drug binding to hERG. To parameterize these models, accurate in vitro measurement of potency and...
Article
Cardiovascular toxicity is a prominent reason for failures in drug development, resulting in the demand for assays that can predict this liability in early drug discovery. We investigated whether iCell® cardiomyocytes have utility as an early QT/TdP screen. Thirty clinical drugs with known QT/TdP outcomes were evaluated blind using label-free micro...
Article
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-...
Article
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-...
Article
Risk stratification in the context of sudden cardiac death has been acknowledged as one of the major challenges facing cardiology for the past four decades. In recent years, the advent of high performance computing has facilitated organ-level simulation of the heart, meaning we can now examine the causes, mechanisms and impact of cardiac dysfunctio...
Chapter
This chapter highlights various non-automated classical in vitro techniques used today to evaluate drug effects on cardiac electrophysiology. It then outlines a three-pronged preclinical initiative called the Comprehensive In Vitro Proarrhythmia Assay (CiPA), which consists of understanding the effects of new molecular entities on multiple ion chan...
Article
Full-text available
Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analys...
Article
For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm...
Article
We sought to investigate whether drug-induced changes in contractility were affected by pacing rates that represent the range of heart rates encountered in vivo. Using the cell geometry measurement system (IonOptix™), we paced dog cardiomyocytes at different cycle lengths (CLs) of 2000, 1000, 500 and 333.3ms, before and after exposure to 13 inotrop...
Article
We aimed to characterise the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded potassium channel (Kv11.1). Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T o...
Article
Functional changes to cardiomyocytes are a common cause of attrition in preclinical and clinical drug development. Current approaches to assess cardiomyocyte contractility in vitro are limited to low throughput methods not amenable to early drug discovery. Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) were used to assess the...
Article
Cardiovascular toxicity, a prominent reason for late-stage failures in drug development, has resulted in a demand for in vitro assays that can predict this liability in early drug discovery. Current in vitro cardiovascular safety testing primarily focuses on ion channel modulation and low throughput cardiomyocyte (CM) contractility measurements. We...
Article
Full-text available
Introduction: Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and ther...
Article
Full-text available
BACKGROUND: RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β-adrenergic (β-AR) responsiveness is unknown. In this study, we examine whether β-AR response and signaling differ in right (RV) versus left (LV) ventricles. METHODS AND RESULTS: Sarcome...
Article
Cardiomyocytes represent one of the most useful models to conduct cardiac research. A single adult heart yields millions of cardiomyocytes, but these cells do not survive for long after isolation. We aimed to determine whether inhibition of myosin II ATPase that is essential for muscle contraction may preserve fully differentiated adult cardiomyocy...
Article
Since the discovery of the link that exists between drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new drugs inhibiting this channel. hERG inhibition is routinely screened for in new drugs and, typically, IC50 values are compared to projected plasma concentrations to define a safety margin. We a...
Article
Full-text available
Introduction Unwanted drug interactions with ionic currents in the heart can lead to an increased proarrhythmic risk to patients in the clinic. It is therefore a priority for safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using ce...
Article
Full-text available
Morphological damage to cardiomyocytes and/or loss of viability (structural cardiotoxicity) is a common cause of attrition in preclinical and clinical drug development. Currently, no predictive in vitro approaches are available to detect this liability early in drug discovery and knowledge of the mechanisms involved is limited. Human embryonic stem...
Article
Rationale: Spontaneous Ca(2+) release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased...
Article
Full-text available
The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions in order to improve the quantitative prediction. The blockade of the human hERG channel is a major concern for QT prolongat...
Article
Pharmaceutical companies are under pressure to produce potentially safe drugs (i.e., no effect on cardiac action potential (AP) and QT interval). Early testing strategies to reduce this risk rely on concentration–effect (C–E) curve data obtained from a panel of heterologously-expressed key ion channels (ICs) using standard IonWorks™ voltage protoco...
Article
Measurement of cardiac contractility is a logical part of pre-clinical safety assessment in a drug discovery project, particularly if a risk has been identified or is suspected based on the primary- or non-target pharmacology. However, there are limited validated assays available that can be used to screen several compounds in order to identify and...
Article
Full-text available
Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concent...
Article
Proarrhythmic side effects are a major limitation during the drug development process for cardiac and non-cardiac compounds. Because changes in cardiac action potential (AP) are undesirable, the evaluation of the effects of test compounds on the AP is essential before advancing new compounds to clinical testing. However, an increase in repolarizati...