Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

Abstract

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by loss of striatal-projecting dopaminergic neurons of the ventral forebrain, resulting in motor and cognitive deficits. Despite extensive efforts in understanding PD pathogenesis, no disease-modifying drugs exist. Recent advances in cell reprogramming technologies have facilitated the generation of patient-derived models for sporadic or familial PD and the identification of early, potentially triggering, pathological phenotypes while they provide amenable systems for drug discovery. Emerging developments highlight the enhanced potential of using more sophisticated cellular systems, including neuronal and glial co-cultures as well as three-dimensional systems that better simulate the human pathophysiology. In combination with high-throughput high-content screening technologies, these approaches open new perspectives for the identification of disease-modifying compounds. In this review, we discuss current advances and the challenges ahead in the use of patient-derived induced pluripotent stem cells for drug discovery in PD. We address new concepts implicating non-neuronal cells in disease pathogenesis and highlight the necessity for functional assays, such as calcium imaging and multi-electrode array recordings, to predict drug efficacy. Finally, we argue that artificial intelligence technologies will be pivotal for analysis of the large and complex data sets obtained, becoming game-changers in the process of drug discovery.

Human Induced Pluripotent Stem Cell-Derived Exosomes as a New Therapeutic Strategy for Various Diseases

“…The mutated genes of diseased iPSCs can be repaired using the homologous recombination method and differentiated into therapeutic somatic cells and then sequentially transferred into diseased patients for cell therapy. In addition, iPSCs generated from healthy or diseased cells can also be used for the in vitro screening of drug candidates [ 3 , 4 , 5 , 6 , 7 , 8 ]. In consideration of the possibility of eliciting alloimmune responses towards allogeneic iPSCs, autologous iPSC-differentiated therapeutic cells are preferred for use in diseased patients.…”

An Alternative Cell Therapy for Cancers: Induced Pluripotent Stem Cell (iPSC)-Derived Natural Killer Cells

“…This process helps to create iPSC-based disease cell models, which could be beneficial for new drug screenings [60]. iPSC-based drug screening platforms are especially helpful for complicated or unintelligible diseases such as Parkinson's disease [61,62], Alzheimer's disease [63,64] and spinal cord injuries [65,66]. Figure 2 summarizes the generation of iPSCs and applications.…”

Electrophysiological Properties of Induced Pluripotent Stem Cell-Derived Midbrain Dopaminergic Neurons Correlate With Expression of Tyrosine Hydroxylase

“…The generation of induced pluripotent stem cells (iPSCs) from patient-derived blood cells or fibroblasts using cellular reprogramming techniques ( Takahashi et al, 2007 ) enabled the generation of patient-specific in vitro disease models, including PD-relevant DN cultures, suitable for analyzing disease mechanisms at cellular and molecular levels ( Shi et al, 2017 ) as well as drug screening ( Garcia-Leon et al, 2019 ; Kouroupi et al, 2020 ). Among the various established differentiation procedures ( Cooper et al, 2010 ; Kriks et al, 2011 ; Kirkeby et al, 2012 ; Sanchez-Danes et al, 2012 ), the “midbrain floor plate protocol” ( Kriks et al, 2011 ), which is based on early patterning of differentiating cells toward a floor plate stage, is considered one of the most effective protocols for generating human DNs from iPSCs ( Weykopf et al, 2019 ).…”