I020 The steroid sulfatase inhibitor ONESTX-1, as a novel pharmacological approach to treat of Huntington Disease (HD)

<h3>Background</h3> ONESTX-1/STX64/irosustat is a small molecule that inhibits steroid sulfatase (STS), increasing the ratio of sulfated/free steroids in animals and humans. In addition, ONESTX-1 showed a good safety and tolerability profile studied in several Phase I and II clinical trials for oncology indications. ONESTX-1 increased the life-span of C. elegans, and improved symptoms in Alzheimer disease (AD) mice models (Pérez-Jiménez, 2021). ONESTX-1 seems to improve others hallmarks of aging, that appear exacerbated in neurodegenerative disease, such as adult neurogenesis decreases, and neuroinflammation, suggesting a multilevel action of sulfated steroid. <h3>Aims</h3> To study the effect of oral treatment with ONESTX-1 on the age-dependent progression of motor and cognitive behaviours shown in the R6/1 mouse model of HD. Method: R6/1 HD mice model undergoing chronic oral treatment with ONESTX-1 on the progression of age-dependent motor and cognitive symptoms of HD. C. elegans was also used to study the molecular pathways involve in HD reversion by ONESTX-1 treatment. <h3>Results</h3> Twelve weeks-old R6/1 mice were oral treated with ONESTX-1 until their death. During the treatment time, HD progression was evaluated by rotarod and object recognition memory. ONESTX-1 treatment showed cognitive recovery, and an improvement in motor coordination. Furthermore, in a C. elegans HD model, STS inhibition decreased the number of protein aggregates related with HD pathology, indicating that the beneficial is conserved in very evolutionary distant animal models. <h3>Conclusion</h3> According to the preclinical data, ONESTX-1 treatment may be a novel strategy to revert or improve several main symptoms of HD patients.