“Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by a progressive degeneration of mainly lower motor neurons (LMNs) that leads to muscle atrophy and paralysis, with no effective therapy. Recently, upper motor neurons (UMNs) have been considered as possible therapeutic target to be protected at the level of the motor cortex, with a possible beneficial effect to the entire MN circuitry, as first motoneurons have been shown to be involved in the pathogenesis of the disease.
Here, we explore a therapeutic approach based on the cortical transplant of cerebral organoid-derived human neural stem cells (NSCs) in the central nervous system of the murine model of ALS, SOD1G93A, in early-symptomatic and symptomatic phase of the disease and leveraging both the molecular and replacement potential of NSCs. Behavioral and ex-vivo tests were conducted to evaluate treatment efficacy. Improved outcomes have been reported in early symptomatic cortex-treated animals compared to control mice. No beneficial effect was observed in symptomatic mice. To understand the mechanism responsible for the amelioration of the phenotype, bulk-sequencing was performed on total RNA extracted from cortical motor area sections of grafted and non-grafted animals. Data analysis prompted the selection of some genes that encode for human proteins possibly produced by engrafted NSCs and likely contributing to the therapeutic neuroprotective effect.”