Towards Advanced iPSC-based Drug Development for Neurodegenerative Disease

No curative treatment is currently available for neurodegenerative diseases (NDDs), and most clinical trials fail owing to the limited translational potential of preclinical disease models, phenotypic heterogeneity between patients, and the lack of disease biomarkers. Human iPSC technology will help to reduce the gap between preclinical and clinical studies, aid in capturing patient heterogeneity, facilitate patient stratification, and promote the development of new drug candidates. Application of patient-derived iPSC-generated cell types in platforms that support a 3D growth environment and disease-relevant cell–cell interactions, such as brain organoids and microfluidic chips, will further increase the physiological relevance and translational potential of in vitro NDD models. Neurodegenerative diseases (NDDs) are a heterogeneous group of diseases that are characterized by the progressive loss of neurons leading to motor, sensory, and/or cognitive defects. Currently, NDDs are not curable and treatment focuses on alleviating symptoms and halting disease progression. Phenotypic heterogeneity between individual NDD patients, lack of robust biomarkers, the limited translational potential of experimental models, and other factors have hampered drug development for the treatment of NDDs. This review summarizes and discusses the use of induced pluripotent stem cell (iPSC) approaches for improving drug discovery and testing. It highlights challenges associated with iPSC modeling and also discusses innovative approaches such as brain organoids and microfluidic-based technology which will improve drug development for NDDs. Neurodegenerative diseases (NDDs) are a heterogeneous group of diseases that are characterized by the progressive loss of neurons leading to motor, sensory, and/or cognitive defects. Currently, NDDs are not curable and treatment focuses on alleviating symptoms and halting disease progression. Phenotypic heterogeneity between individual NDD patients, lack of robust biomarkers, the limited translational potential of experimental models, and other factors have hampered drug development for the treatment of NDDs. This review summarizes and discusses the use of induced pluripotent stem cell (iPSC) approaches for improving drug discovery and testing. It highlights challenges associated with iPSC modeling and also discusses innovative approaches such as brain organoids and microfluidic-based technology which will improve drug development for NDDs. the main constituent of the neuritic plaques observed in the brain of Alzheimer's disease (AD) patients. Aβ is generated by sequential proteolytic cleavage (by α- and γ-secretases) of the amyloid precursor protein (APP). Cleavage results in Aβ peptides of various lengths (Aβ38, Aβ40, or Aβ42) of which Aβ42 aggregates most efficiently. Aβ42 is the major component of neuritic amyloid plaques. an endothelial structure that prevents molecules in the blood circulation from non-selectively crossing into the extracellular fluid of the CNS. The BBB is formed by BMECs, brain pericytes, and astrocytes. human endothelial cells that comprise the major component of the BBB and limit passage of molecules from the blood circulation into the brain. BMECs have specific features that distinguish them from other endothelial cells, for example specialized tight junctions, efflux transporter activity, and reduced non-specific transcytosis capacity. self-assembled 3D structures derived from pluripotent stem cells with cell types and a cytoarchitecture that resembles in vivo brain tissue. Different types of neurons and glial cells (e.g., astrocytes and microglia) can be present in brain organoid models. a drug discovery process that allows automated testing of large numbers of chemical and/or biological compounds for a specific biological target or process. cells that have been reprogrammed from somatic cells (e.g., skin or blood) into an embryonic-like pluripotent state and that can form cells from all three germ layers. a set of microchannels etched or molded into a material and connected together in which cells or tissues can be cultured in a compartmentalized manner. central and peripheral nervous system diseases characterized by the progressive loss and/or dysfunction of neurons leading to various motor, sensory, and/or cognitive deficits. a synapse between the axon of motor neurons in the brainstem or spinal cord and a muscle fiber. It allows signal transduction from motor neurons to muscle, leading to muscle contraction. is encoded by the SNCA gene and is genetically and pathologically linked to Parkinson's disease (PD). α-Synuclein is an aggregation-prone presynaptic protein that accumulates in neurons in PD, thereby disturbing cellular homeostasis. an electrical parameter to assess barrier integrity of in vitro cellular barriers such as the BBB.