Toxicity testing and drug screening using iPSC-derived hepatocytes, cardiomyocytes, and neural cells

2016 ◽  
Vol 94 (7) ◽  
pp. 687-694 ◽  
Author(s):  
Mária Csöbönyeiová ◽  
Štefan Polák ◽  
L’uboš Danišovič
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Animal Studies ◽  
Clinical Stage ◽  
Toxicity Testing ◽  
Security Evaluation ◽  
Neural Cells ◽  
Toxicity Screening ◽  
Drug Candidates ◽  
Induced Pluripotent

Unexpected toxicity in areas such as cardiotoxicity, hepatotoxicity, and neurotoxicity is a serious complication of clinical therapy and one of the key causes for failure of promising drug candidates in development. Animal studies have been widely used for toxicology research to provide preclinical security evaluation of various therapeutic agents under development. Species differences in drug penetration of the blood–brain barrier, drug metabolism, and related toxicity contribute to failure of drug trials from animal models to human. The existing system for drug discovery has relied on immortalized cell lines, animal models of human disease, and clinical trials in humans. Moreover, drug candidates that are passed as being safe in the preclinical stage often show toxic effects during the clinical stage. Only around 16% drugs are approved for human use. Research on induced pluripotent stem cells (iPSCs) promises to enhance drug discovery and development by providing simple, reproducible, and economically effective tools for drug toxicity screening under development and, on the other hand, for studying the disease mechanism and pathways. In this review, we provide an overview of basic information about iPSCs, and discuss efforts aimed at the use of iPSC-derived hepatocytes, cardiomyocytes, and neural cells in drug discovery and toxicity testing.

scholarly journals Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8196
Author(s):  
Dorit Trudler ◽  
Swagata Ghatak ◽  
Stuart A. Lipton
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Neural Function ◽  
Neural Cells ◽  
Human Samples ◽  
Healthy Donors ◽  
Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

scholarly journals Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

2016 ◽  
Vol 22 (6) ◽  
pp. 696-705 ◽  
Author(s):  
Tanut Kunkanjanawan ◽  
Richard Carter ◽  
Kwan-Sung Ahn ◽  
Jinjing Yang ◽  
Rangsun Parnpai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Drug Discovery ◽  
Trinucleotide Repeat ◽  
Yeast Cells ◽  
Neural Cells ◽  
Primate Model ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Induced Pluripotent

Huntington’s disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine [polyQ]) in the huntingtin ( HTT) gene, which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability, and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients, and induced pluripotent stem cells from patients. A transgenic nonhuman primate model of HD (HD monkey) shows neuropathological, behavioral, and molecular changes similar to an HD patient. In addition, neural progenitor cells (NPCs) derived from HD monkeys can be maintained in culture and differentiated to neural cells with distinct HD cellular phenotypes including the formation of mHTT aggregates, intranuclear inclusions, and increased susceptibility to oxidative stress. Here, we evaluated the potential application of HD monkey NPCs and neural cells as an in vitro model for HD drug discovery research.

scholarly journals hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery

2020 ◽  
Vol 21 (23) ◽  
pp. 8893
Author(s):  
Junjun Li ◽  
Ying Hua ◽  
Shigeru Miyagawa ◽  
Jingbo Zhang ◽  
Lingjun Li ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cardiac Tissue ◽  
Disease Modeling ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Toxicity Screening ◽  
The Difference ◽  
Induced Pluripotent ◽  
Novel Drug

Relevant, predictive normal, or disease model systems are of vital importance for drug development. The difference between nonhuman models and humans could contribute to clinical trial failures despite ideal nonhuman results. As a potential substitute for animal models, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) provide a powerful tool for drug toxicity screening, modeling cardiovascular diseases, and drug discovery. Here, we review recent hiPSC-CM disease models and discuss the features of hiPSC-CMs, including subtype and maturation and the tissue engineering technologies for drug assessment. Updates from the international multisite collaborators/administrations for development of novel drug discovery paradigms are also summarized.

scholarly journals Regulatory Forum Opinion Piece*: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey

2017 ◽  
Vol 45 (3) ◽  
pp. 372-380 ◽  
Author(s):  
Sherry J. Morgan ◽  
Jessica Couch ◽  
Peggy Guzzie-Peck ◽  
Douglas A. Keller ◽  
Ray Kemper ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Safety Assessment ◽  
Safety Issues ◽  
Drug Candidates ◽  
Animal Models Of Disease ◽  
Disease States ◽  
Good Laboratory ◽  
Biotechnology Companies ◽  
Models Of Disease

An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short-duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies. The survey determined that the majority of companies used AMDs during drug discovery primarily as a means for proactively assessing potential nonclinical safety issues prior to the conduct of toxicology studies, followed closely by the use of AMDs to better understand toxicities associated with exaggerated pharmacology in traditional toxicology models or to derisk issues when the target is only expressed in the disease state. In contrast, the survey results indicated that the use of AMDs in development is infrequent, being used primarily to investigate nonclinical safety issues associated with targets expressed only in disease states and/or in response to requests from global regulatory authorities.

scholarly journals Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)

2021 ◽  
Vol 9 ◽  
Author(s):  
Mridu Malik ◽  
Yang Yang ◽  
Parinaz Fathi ◽  
Gretchen J. Mahler ◽  
Mandy B. Esch
Keyword(s):  
Animal Models ◽  
Drug Toxicity ◽  
New Drugs ◽  
Drug Candidate ◽  
Preclinical Studies ◽  
Toxicity Screening ◽  
Drug Candidates ◽  
Microphysiological Systems

Identification and approval of new drugs for use in patients requires extensive preclinical studies and clinical trials. Preclinical studies rely on in vitro experiments and animal models of human diseases. The transferability of drug toxicity and efficacy estimates to humans from animal models is being called into question. Subsequent clinical studies often reveal lower than expected efficacy and higher drug toxicity in humans than that seen in animal models. Microphysiological systems (MPS), sometimes called organ or human-on-chip models, present a potential alternative to animal-based models used for drug toxicity screening. This review discusses multi-organ MPS that can be used to model diseases and test the efficacy and safety of drug candidates. The translation of an in vivo environment to an in vitro system requires physiologically relevant organ scaling, vascular dimensions, and appropriate flow rates. Even small changes in those parameters can alter the outcome of experiments conducted with MPS. With many MPS devices being developed, we have outlined some established standards for designing MPS devices and described techniques to validate the devices. A physiologically realistic mimic of the human body can help determine the dose response and toxicity effects of a new drug candidate with higher predictive power.

scholarly journals High Throughput Cell-Based Assay of Hematopoietic Progenitor Differentiation

2001 ◽  
Vol 6 (6) ◽  
pp. 383-392 ◽  
Author(s):  
Dale E. Greenwalt ◽  
Janet Szabo ◽  
Ilana Manchel
Keyword(s):  
Drug Discovery ◽  
Toxicity Screening ◽  
Time Resolved ◽  
Hematopoietic Stem ◽  
Colony Assay ◽  
Drug Candidates ◽  
Hematopoietic Lineage ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

The in vitro efficacy of drug candidates relative to hematopoietic stem cell proliferation and differentiation is currently assayed through use of the clonogenic "colony assay." The extremely low throughput of this assay precludes its use in library screening and much drug discovery work. A rapid-throughput assay of progenitor cell differentiation based on the quantification of hematopoietic lineage-specific markers has been developed. The CELISA assay employs a single incubation with a lanthanide-conjugated primary antibody and subsequent time-resolved fluorescence spectroscopy. The rapid-throughput nature of this assay is enhanced by the use of cell culture-compatible filter plates to reduce the number of manipulations as compared to currently available cell-based assays. The culture and assay are done in 96-well plates, and the quantitation process requires approximately 1 hour. The myeloid, erythroid, and megakaryocytic lineages can be objectively quantified; data from the assay correlate extremely well with data generated through use of the traditional colony assay. This assay makes possible both rapid-throughput drug discovery and toxicity screening in the area of hematopoiesis.

scholarly journals Redesigning antidepressant drug discovery

2014 ◽  
Vol 16 (1) ◽  
pp. 5-7
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Psychiatric Disorders ◽  
Antidepressant Drug ◽  
Diagnostic Process ◽  
Pharmaceutical Companies ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Rapid Transfer ◽  
Efficacy Studies

Antidepressant drug discovery and development have been put on hold by many pharmaceutical companies. The main reason for this is the negative efficacy studies with novel specific drugs. Here I argue that the main obstacles are the absence of gene tests and biomarkers as an integral part of a diagnostic process. Further, too much emphasis has been put on validating drug candidates in animal models of psychiatric disorders. A more rapid transfer of drug candidates into human research is necessary to overcome current obstacles that prevent the discovery of next-generation antidepressants.

Human Embryonic and Induced Pluripotent Stem Cell Based Toxicity Testing Models: Future Applications in New Drug Discovery

2016 ◽  
Vol 23 (30) ◽  
pp. 3495-3509 ◽  
Author(s):  
Vaibhav Shinde ◽  
Poornima Sureshkumar ◽  
Isaia Sotiriadou ◽  
Jurgen Hescheler ◽  
Agapios Sachinidis
Keyword(s):  
Stem Cell ◽  
Drug Discovery ◽  
Pluripotent Stem Cell ◽  
Toxicity Testing ◽  
Induced Pluripotent Stem Cell ◽  
New Drug ◽  
Induced Pluripotent

scholarly journals Toward Better Reproducibility in Experimental Research on New Agents for Pulmonary Hypertension. An Analysis of Data from Four Hundred Animal Studies

2020 ◽  
Author(s):  
Magdalena Jasińska-Stroschein
Keyword(s):  
Pulmonary Hypertension ◽  
Animal Models ◽  
Animal Studies ◽  
Exercise Intolerance ◽  
Potential Drug ◽  
New Agents ◽  
Systematic Analysis ◽  
Drug Candidates ◽  
Animal Survival ◽  
Methodological Aspects

Abstract Purpose Pre-clinical data can provide a rationale for subsequent clinical trials and they are the first step in drug development; however, the therapeutic effect observed during animal studies does not necessarily translate to similar results in humans. Methods Taking the example of pulmonary hypertension, the present study explores whether the methodological aspects of preclinical experiments can determine the final result. Results The present paper describes a systematic analysis of 409 studies conducted on a variety of animal models to identify potential drug candidates for PH treatment; it explores the influence of various aspects of study design on the final outcome, e.g. type of animal model of PH, dosage schedules of tested agents, type of anesthesia, measurement of exercise intolerance or animal survival. Conclusions The animal models of PH used for pre-clinical studies are diverse and there are several methodological items within the established protocols that can determine the obtained result.

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