Use case: target ID for phenotypic screen for remyelination

[andrewsu]

This is a potential proof-of-concept for a target ID use case based on this paper: https://www.nature.com/articles/s41586-018-0360-3

In short, the authors did a phenotypic screen of 3000 compounds looking for enhancers of oligodendrocyte progenitor cells (OPCs) (a cell type that promotes remyelination for potential use in treating multiple sclerosis). Top hits are shown in Supp Table 1. Several hits had known roles as regulators of cholesterol biosynthesis. (Accumulation of 8,9-unsaturated sterols, a key intermediate in cholesterol biosynthesis, is known to promote formation of oligodendrocytes.) The authors then tested and confirmed several of the other hits for activity against CYP51, TM7SF2, or EBP, three genes that are key players in the cholesterol synthesis pathway (see Extended Data Figure 1). Although each of these compounds had other "primary targets" associated with their known indications, their activity in the OPC assay is presumed to be due to their effect on cholesterol biosynthesis.

From a BTE perspective, I think there are two possible things to test:

1. can we find the reasoning path that links these repurposing candidates to oligodendrocyte formation? e.g., something like benztropine - inhibits - EBP - part of - cholesterol biosynthesis pathway - produces - cholesterol intermediates/metabolites - promotes - oligodendrocyte formation
2. based on the hit list, could we have identified cholesterol biosynthesis as a highly-ranked process (based on enrichment, for example)

This use case is based on a conversation with Luke Lairson and @mmayers12