జర్నల్ ఆఫ్ క్లినికల్ టాక్సికాలజీ
అందరికి ప్రవేశం

నైరూప్య

Tamoxifen for the Treatment of Batten Disease

Chiara Soldati, Sandro Montefusco, Valentina Bouché, Diego Luis Medina

Batten Diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration, and represent the most common forms of neurodegeneration in children. By phenotypic screening, we recently discovered a novel accumulation of Globotriaosylceramide (Gb3) in cellular and murine models of two subtypes of BD, namely CLN3 and CLN7 diseases, which together account for almost 60% of all BD patients. We used fluorescent-conjugated bacterial toxins to label Gb3 and developed a cell-based High Content Imaging (HCI) screening assay that resulted in the repurposing of the FDA-approved hit tamoxifen. Interestingly, tamoxifen showed in vitro and in vivo the activity to ameliorate BD phenotypes through a mechanism that, at least in part, involves the activation of the Transcription Factor EB (TFEB), a master gene of lysosomal function and autophagy. Together, these results might represent the first small molecule therapy to treat BDs and, if supported by accurate preclinical studies and clinical trials to determine dose and safety, tamoxifen might offer an unprecedented opportunity for BD-affected children.