Abstract
A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients’ CNS and serve as a platform for therapeutic development and personalized precision medicine.
Highlights
Central neural system (CNS) diseases are perplexed with variable genetic, epigenetic and environmental factors [1]
A constant high attrition rate of neurotherapeutics and low efficacy of clinical translation are derived from mismatch outcomes between disease modeling and human pathophysiology
An induced pluripotent stem cell (iPSC)-based disease modeling is favored in drug discovery due to their scalability for large-scaled, fast, high-throughput screening (HTS), pluripotency to generate multiple independent disease-relevant cell types, patient-specific genetic backgrounds to develop personalized therapy, and flexibility to integrate with multi-disciplinary technologies for extension of the iPSC application
Summary
Central neural system (CNS) diseases are perplexed with variable genetic, epigenetic and environmental factors [1]. Pharmaceutical development of CNS disease therapies is thwarted with a high rate of clinical trial attritions, and an estimate of 8.1 years is needed for the Phase II and III development of CNS drugs, which is 2 years longer than that for non-CNS drugs. We will review promising opportunities of human iPSC disease models over primary cell culture and animal models in pre-clinical drug development. We will introduce up-to-dated 3D iPSC models integrated with multi-disciplinary techniques to dissect complex pathophysiological features of CNS diseases, their ground-breaking success in uncovering and recapitulating disease pathologies and a potential for further improvement. We will illustrate how diverse and cutting-edged iPSC-based disease modeling can help improve our understanding of CNS diseases and pioneer therapeutic development in the context of prevalent and rare neurological disorders. We will cover application of iPSC-based models on facilitating high-throughput drug toxicity screening, and discuss current limitations of iPSCs and their technological extension for drug discovery in the foreseeable future
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