I025 HX127 reverses behavioral and pathological phenotype of Huntington disease mice by restoring axonal transport of BDNF and mitochondria homeostasis

<h3></h3> There are currently no neuroprotective drugs to delay or prevent appearance and progression of the HD symptoms and pathology. The disease involves complex pathogenic mechanisms but one of the earliest and most fundamental changes in the HD brain involves defects in vesicular trafficking that hinder the transport of Brain-Derived Neurotrophic Factor (BDNF) in the corticostriatal network, which is the most profoundly affected in HD. By combining selective proteomic analysis of vesicles transported within corticostriatal projecting neurons and in silico screening we identified palmitoylation as a pathway that could restore defective HTT-dependent trafficking within HD neurons. We showed that HX127, a specific inhibitor of the palmitate-removing enzyme APT1, restores axonal transport of BDNF and synapse homeostasis in HD neurons within a microfluidic network-on-a-chip, and in human HD iPSC-derived cortical neurons. We recently found that HX127 is also efficient at restoring mitochondrial activity that is impaired in HD neurons. HX127 is a brain-permeable small molecule which restored abnormally low levels of neuronal protein palmitoylation and rescued locomotor deficits and anxio-depressive behaviors in HD mice model. Further de-risking of HX127 revealed a good safety profile and demonstrated the absence of any long-term toxicity during 6-months treatment in vivo. We propose HX127 as a therapeutic compound of interest for HD since in contrast to current silencing approaches that are costly and invasive and have not yet proved to be beneficial to HD patients. HX127 is the first neuroprotective compound that acts on mutant HTT itself and restores its normal function.