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Authors & Affiliations
Hanna Trebesova, Francesca Bacchetti, Matilde Balbi, Tiziana Bonifacino, Massimo Grilli, Marco Milanese
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death, leading to motor paralysis and cognitive and behavioural disorders. In clinical trials, ALS patients are stratified by disease stage, whereas in preclinical studies, animals are recruited based solely on age, neglecting individual disease progression. Additionally, both ALS onset and progression are influenced by sex, a factor often mirrored in animal models. This mismatch might contribute to the frequent failures of translating preclinical data to clinical success, suggesting the importance of selecting animals based on the severity of symptoms to personalize the treatment strategy.This study aimed at identifying a new stratification paradigm for precise recruitment in preclinical studies to produce more robust results and overcome most preclinical trial pitfalls.To achieve this goal, we characterized the motor and behavioral progression of the SOD1G93A ALS mouse model using a comprehensive battery of in-vivo tests (Open field, Rotarod, Been Balance, Grip test) throughout their lifespan. Male and female mice were assessed from weaning until their humane endpoint.We identified an early disease stage around 70 days of age. Principal Component Analysis of motor and behavioral variables revealed early sex- and disease-specific characteristics. Notably, stress-related behaviors, measured by the number and duration of freezing events, distinguished SOD1G93A mice from controls, very early and sex-dependently.These data suggest that the same disease stage has been reached in different time windows in the two sexes, thus paving the way to a combined motor and behavioural approach for personalized ALS therapy.