These are the basic reasons for using iPSCs for drug discovery.
Patient-derived somatic cells (for example, fibroblasts) can be reprogrammed to generate iPSCs carrying a disease-specific genetic aberration. These cells can then be differentiated into the disease-affected cell type (for example, neurons in neurodegenerative diseases). After the establishment of a cellular disorder model with disease-specific phenotypes, three main strategies are commonly used: high-throughput screening (HTS) of drugs, the candidate drug approach or patient-specific therapy. In HTS, a very large number of compounds are tested on the differentiated cells, followed by phenotype re-evaluation. This method is extremely valuable for identifying novel therapies in vitro, by using large libraries of compounds. By contrast, both the candidate drug approach and the patient-specific therapy use a small number of potential drugs to attenuate the disease. These approaches are useful when the disease mechanism is known and potential therapies are available. Drugs found by both the HTS and candidate drug approaches usually require substantial safety assays before being prescribed to patients, whereas drugs already approved by regulatory agencies can be immediately prescribed for treatment.
Before using drugs on humans, their toxic effects must be properly evaluated for a safe administration of those drugs which is very costly. Only 10% of the drugs that enter clinical trials are able to reach market approval stage. The cost of developing a drug is increasing with the estimated cost of whole process being US $1.2–1.7 billion per drug compound. The development of 30% of the medicines was abandoned because of lack of efficacy and 30% due to concerns associated with safety (cardiotoxicity, hepatotoxicity).
iPSC-derived cells of various tissue types can be cultured in large grids and assayed for toxicity in a manner analogous to high-throughput screens for drug discovery. Using this approach, iPSC technology can be integrated into the current paradigm for drug development as part of safety testing in the early phases of clinical trials.
The benefits of using iPSCs in toxicity testing are:
Human neurons derived from iPSCs can be attractive models to study the neurotoxicity. The iPSC-derived neurons exhibit functionality and behavior of mature neurons and are available in large quantities. The neurotoxicity test models will allow for studying on one hand the adverse effect of drug candidates on neuronal cells and on the other hand the general neurotoxicity in assays that are well suited for screening of lead compounds and potentially important for reducing animal experimentation and the cost of preclinical development.
Currently, cell lines such as PC12 are typically used for the analysis of calcium signaling with the purpose of determining the complex cellular changes triggered by environmental and pharmacologic neurotoxicants.
Cardiotoxicity can lead to the formation of reactive oxygen species (ROS), apoptosis, altered contractibility, change in cardiac rhythm, and altered cardiac gene expression, which can be life threatening or may lead to long-term alterations of cardiovascular functions. Of the 40% of drug failures during the clinical trials[i],19% drug withdrawal has been observed due to cardiotoxicities.
In many cardiotoxicity cases, a direct interaction of drugs with specific ion channels expressed by the cardiomyocytes leads to alteration in ion conduction through these specific channels. Drug effects on potassium currents could lead to QT-prolongation, potentially fatal arrhythmias and sometimes cardiomuscular damage without affecting ion channels.
The ESC- and iPSC-derived cardiomyocytes are considered to be well suited to study the effects of compounds which do not interfere with the ion channel functions but still cause cardiotoxicity, an effect that cannot be revealed by using the conventional cell line and receptor overexpression-based approaches[ii].
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