Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis

Abstract

Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.

Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling

“…On the other hand, iPSC-derived motor neurons with A4V or D90A mutations in SOD1 exhibited neither protein aggregation nor mitochondrial abnormalities, implicating the less importance of these pathologies in human ALS compared with animal models. However, neurofilament aggregation is documented to be an early mechanism involved in ALS which leads to axonal pathology and neurite swelling and is a possible therapeutic target for ALS ( 28 , 29 , 71 , 72 ). Also, SOD1A4V mutation has proved to cause a reduction in the activity of delayed-rectifier potassium currents in motor neurons and subsequently, causes hyperexcitability.…”

Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

“…Thus, the outstanding capacity to generate relevant human neural cell types from pluripotent stem cellsboth ESCs and iPSCs, has opened unprecedented paths towards the understanding of ALS and other MN disorders (Han et al, 2011;Bellin et al, 2012;Haston and Finkbeiner, 2016). Regarding therapeutic development, it is also anticipated that by studying human cells and performing drug tests directly on them, the time of translation of interesting pre-clinical research findings towards clinical applicable strategies could be considerably shortened (Figure 3) (Ebert and Svendsen, 2010;Engle and Puppala, 2013;Engle and Vincent, 2014;Haston and Finkbeiner, 2016;Lee et al, 2018).…”

“…Hence, hiPSCs allow the generation in vitro of infinite quantities of different neuronal cell types that are patientspecific, enabling the study of early cellular dysfunction and other neurodegenerative processes (Figure 2), otherwise difficult to observe in post-mortem tissues. Finally, these patient cell-based innovative in vitro ALS models have the prospect to help unravel novel pathogenic mechanisms, and to evaluate the utility of new therapies, opening promising avenues towards the discovery of efficacious pharmacological agents to halt the progression or even cure ALS (Figure 3) (Sances et al, 2016;Lee et al, 2018;Hawrot et al, 2020;Okano et al, 2020;Vasques et al, 2020).…”

“…The usage of patient-specific ALS hiPSC-derived MNs has led to innovative in vitro disease models and also to drug screening campaigns, some of which involve drug repurposing (Haston and Finkbeiner, 2016;Lee et al, 2018;Hawrot et al, 2020). In the last decade, hiPSC-derived MNs have allowed the identification of several promising compounds to tackle ALS (Wainger et al, 2014;McNeish et al, 2015;Imamura et al, 2017;Fujimori et al, 2018;Lee et al, 2018;Okano et al, 2020). Among the candidate compounds identified, a few have already been translated into drug testing involving ALS patients, in well-designed clinical trials (Table 1).…”

From Multi-Omics Approaches to Precision Medicine in Amyotrophic Lateral Sclerosis

“…essential elements in the pathophysiology of ALS that cannot be otherwise obtained through other approaches used in living patients, these studies reveal end-stage pathogenic mechanisms and do not clarify whether transcriptional differences that separate patient subtypes are a cause or a consequence of the disease process. In that context, the use of iPSC derived from patients suffering from ALS has provided important insights into disease pathophysiology, enabling researchers to explore molecular heterogeneity of ALS and follow the course of degeneration in the dish (Coatti et al, 2015;Bohl et al, 2016;Hedges et al, 2016;Myszczynska and Ferraiuolo, 2016;Sances et al, 2016;Csobonyeiova et al, 2017;Selvaraj et al, 2017;Centeno et al, 2018;Fujimori et al, 2018;Ghaffari et al, 2018;Lee et al, 2018;Halpern et al, 2019;Ziff and Patani, 2019;Chang et al, 2020;Hawrot et al, 2020). In addition, transcriptome studies on whole tissue (i.e., motor cortex and spinal cord) fail to capture dynamic changes and the complex heterogeneity of the nervous system, making it difficult to determine how gene expression changes disrupt functional interaction between motor neurons and non-neuronal cells (e.g., microglia, oligodendroglia, and astroglia) implicated in ALS pathology.…”