Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

Keywords: Alzheimer’s disease; neurodegeneration.

Figure 1

hiPSC-derived brain models in drug discovery. Diagram illustrating the use of hiPSCs to generate various brain cells (neurons, astrocytes, microglia) and 3D cerebral organoids, which can be used to model different neurological disorders. Myelin-forming oligodendrocytes can also be modeled with hiPSC differentiation protocols but are not shown here. These hiPSCs can be used for drug discovery using various methods, e.g., high-throughput screening, CRISPR screening, and Connectivity Map score for transcriptome correction.