Abstract
Amyotrophic Lateral Sclerosis (ALS) is a motor neurodegenerative disorder whose cellular hallmarks are the progressive death of motor neurons (MNs) located in the anterior horn of the spinal cord, brainstem and motor cortex, and the formation of intracellular protein aggregates. Over the course of the disease, progressive paralysis takes place, leading to patient death within 3–5 years after the diagnosis. Despite decades of intensive research, only a few therapeutic options exist, with a limited benefit on the disease progression. Preclinical animal models have been very useful to decipher some aspects of the mechanisms underlying ALS. However, discoveries made using transgenic animal models have failed to translate into clinically meaningful therapeutic strategies. Thus, there is an urgent need to find solutions to discover drugs that could impact on the course of the disease, with the ultimate goal to extend the life of patients and improve their quality of life. Induced pluripotent stem cells (iPSCs), similarly to embryonic stem cells (ESCs), have the capacity to differentiate into all three embryonic germ layers, which offers the unprecedented opportunity to access patient-specific central nervous system cells in an inexhaustible manner. Human MNs generated from ALS patient iPSCs are an exciting tool for disease modelling and drug discovery projects, since they display ALS-specific phenotypes. Here, we attempted to review almost 2 decades of research in the field, first highlighting the steps required to efficiently generate MNs from human ESCs and iPSCs. Then, we address relevant ALS studies which employed human ESCs and iPSC-derived MNs that led to the identification of compounds currently being tested in clinical trials for ALS. Finally, we discuss the potential and caveats of using patient iPSC-derived MNs as a platform for drug screening, and anticipate ongoing and future challenges in ALS drug discovery.
Highlights
Neurodegenerative disorders (NDs) are a tremendous public health challenge worldwide
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is characterized by the progressive loss of motor neurons (MNs) that locate in the motor cortex, brainstem and anterior horn of the spinal cord (Figure 1) (Rowland and Shneider, 2001; Brown and Al-Chalabi, 2017)
Motor neurons are a type of specialized neurons of the central nervous system (CNS), which have their cell bodies located in the motor cortex, in the mid- and hind-brain nuclei and in columns throughout the ventral horns of the spinal cord (Figure 1) (Kanning et al, 2010)
Summary
Neurodegenerative disorders (NDs) are a tremendous public health challenge worldwide. Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is characterized by the progressive loss of motor neurons (MNs) that locate in the motor cortex, brainstem and anterior horn of the spinal cord (Figure 1) (Rowland and Shneider, 2001; Brown and Al-Chalabi, 2017). Motor neurons are a type of specialized neurons of the central nervous system (CNS), which have their cell bodies located in the motor cortex, in the mid- and hind-brain nuclei and in columns throughout the ventral horns of the spinal cord (Figure 1) (Kanning et al, 2010). We discuss the current challenges in the field, and novel avenues for drug discovery and drug repurposing using these models
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
