Title:Human Embryonic and Induced Pluripotent Stem Cell Based Toxicity Testing Models: Future Applications in New Drug Discovery
Volume: 23
Issue: 30
Author(s): Vaibhav Shinde, Poornima Sureshkumar, Isaia Sotiriadou, Jurgen Hescheler and Agapios Sachinidis
Affiliation:
Keywords:
Pluripotent Stem Cells, Teratogenicity, Cardiotoxicity, Hepatotoxicity, Neurotoxicity, New Drug Discovery,
Alternative Testing Strategies.
Abstract: New drug discovery (NDD) is a fascinating discipline encompassing
different facets of medicine, pharmacology, biotechnology and
chemistry. NDD is very often restricted by efficacy or safety problems of
the new clinical candidate in human patients. Drug regulatory authorities
have provided various guidelines for advancement of safe new chemical entities
(NCEs) in clinical trials which must be strictly followed. In spite of
this, various drugs have failed in clinical trials or withdrawn from market
because of human safety issues related to cardiotoxicity, hepatotoxicity,
neurotoxicity and teratogenicity. The failure of safety prediction was
pointed to species specificity issues, lack of mechanistic toxicity data and
inadequate clinical trials. These drugs not only affect human health but also cause loss of
resources and time. The species specificity issues are partially addressed by use of primary
human cells but their availability is very limited. Human embryonic stem cells (hESCs) and
induced pluripotent stem cells (hiPSCs) offer sources for generation of an unlimited number
of human somatic cells. The emergence of mechanistic models for toxicity testing with transcriptomics,
proteomics along with toxicokinetics readouts based on hESCs and hiPSCs is
paving the way to design new human relevant testing strategies. Introduction of these models
at the timeframe of lead selection and optimization in parallel with in vitro pharmacokinetic
studies will significantly reduce compound attrition rate by selection of safer lead
molecules. We focused on upcoming hESCs and hiPSCs based toxicity testing models and
their future role to address safety gaps of present drug discovery and development.
