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

Abstract

Background 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.

Aims 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.

Results 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.

Conclusion According to the preclinical data, ONESTX-1 treatment may be a novel strategy to revert or improve several main symptoms of HD patients.