58

Bioinformatics of the Brain

2.3.4

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is another neurodegenerative pathology

with severe defects in motor neurons and concomitantly fatal failures in multi-

organ systems. ALS is the most prevalent adult neuromotor disorder, with a

prevalence of 5.4 per 100,000 people in the population and an average sur-

vival time of 4 years [134, 135]. Genetic and other factors lead to devasta-

tion in upper and lower motor neurons in the motor cortex, brain stem, and

spinal cord. Loss of motor control, stagnation, and weakness in voluntary

muscle activity due to muscle atrophy, respiratory failure due to decay in res-

piratory muscles, paralysis, and difficulty in swallowing can be listed among

the catastrophic symptoms of ALS. Although pathogenic variants of approx-

imately 50 genes (involving SOD1, C9orf72, TARDBP, FUS, ATXN2, VCP,

OPTN, and UBQLN2, etc.) have been associated with ALS risk so far, the

non-genetic factors behind the pathological mechanisms that contribute to

ALS progression have not clearly been elucidated yet [135]. Genetic variations

in the alleles above correspond to the hereditary side of the disease, called

familial amyotrophic lateral sclerosis (fALS). Nonetheless, glutamate neuro-

toxicity, oxidative stress, disruptions in axonal transport, neuroinflammation,

impaired RNA metabolism, oligodendrocyte dysfunction, mitochondrial dys-

function, excitotoxicity, vesicular transport and secretion defects, and faults

in DNA repair are some of the common proposed cellular mechanisms [136].

Therefore, lack of knowledge is accompanied by the unavailability and inef-

fectiveness of the medication. Herein, stem cells again come to the forefront

as potential instruments for ALS modeling and cell replacement therapy.

2.3.4.1

Drug Screening in iPSC/ESC-based ALS Models

Ignorance of the molecular background has urged researchers to discover

ALS-related mechanisms and then find therapeutics targeting these path-

ways. Moreover, creating preclinical ALS models in vivo is challenging, and

attempted animal models remain inadequate to mimic the pathological fea-

tures of ALS. Hence, iPSCs have contributed to troubleshooting and have

overcome the obstacles in this context via reprogramming the cells derived

from the ALS patients themselves. Human motor neurons differentiated from

patient iPSCs have established an in vitro platform for ALS-specific drug test-

ing. Firstly, the anti-epileptic drug Ezogabine (Retigabine), a voltage-gated

potassium (K⁺) channel activator, was repurposed for the treatment of fALS-

dependent neuronal hyperexcitability [137]. Ezogabine then proceeded to a

phase II trial (NCT02450552) involving 65 fALS patients. Secondly, Ropini-

role was distinguished as a result of screening a panel including FDA-approved

drugs in an iPSC-derived sporadic ALS model. ALS-related phenotypes could

be relatively reversed in motor neurons from FUS/TARDBP-ALS iPSCs ex-

posed to Ropinirole [138]. This drug has been self-tolerated and safe for 29

enrolled participants in a phase 1/2a randomized trial [139]. Meanwhile, drug

screening assay in the iPSC-derived SOD1-fALS model suggested Bosutinib, a

src tyrosine kinase inhibitor, as a potent agent, rescuing motor neuron deteri-