Small molecule experimental treatments of Niemann-Pick A/B disease in cell-based models

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The goal of this project is to develop small-molecules for a potential treatment and diagnosis of Niemann-Pick Disease of types A and B (NPD A/B). As a prerequisite, adequate cellular disease models will be established using CRISPR/Cas9 or so-called base modifiers. Previous evidence from our group and from others clearly suggests that in NPD A/B cases sufficient protein is produced. Moreover, some of the most prevalent ASM variants are active in catalysis, if the protein is overexpressed from Sf9 cells and purfied. Assaying of ASM in intact living cells, which are homo-allelic for the most common NPD mutations will be key for the identification of molecules that can reconstitute ASM activity in NPD and might ameliorate pathology. Towards the latter goal, we plan to adapt and optimize our FRET probe-based flow cytometry assay for maximum sensitivity. Promising compounds will be characterized by lipidomics with an option to later test them in patient-derived cells or in living mice.