Compound library screening in a zebrafish model of MSD to identify novel therapeutic compounds

Multiple Sulfatase Deficiency (MSD) is currently an untreatable disease and while we know some of the processes inside cells that cause or influence the disease, there is still much to be understood. While progress has been made from studying simple cell culture systems, this does not tell us about how different disease changes may occur in different tissues (e.g. nerves compared to muscles) and whether defects in one tissue can have consequences for other parts of the body. Hence, we need to study animal models that share the same features of the disease as we see in patients. As we do not know the targets in cells (e.g. proteins, enzymes, pathways) which may affect MSD, it is hard to follow a path of conventional drug design. However, compound screens in MSD animal models are a promising strategy to detect new compounds that can be developed into drugs. This proposal will follow on from our existing funding from the MSD Action Foundation where we will generate and characterise two zebrafish models for MSD (null and hypomorph mutation) and identify which is most suitable for compound screening. We are aware of other cell-based MSD screening projects that will use FDA-approved drug libraries therefore we have selected a complimentary approach of screening a diverse chemical library. Our aim is to perform a non-hypothesis-based screen; we believe it is important to screen a library with broad chemical diversity to identify novel structures with rescuing activity. During our current funding, we will select the best zebrafish model for the compound screen, identify the optimal window for drug treatments and the most informative disease measures. In this proposal, we request funding to perform a compound screen on a diverse chemical library and to perform secondary validation assays on hits arising from the screen.

Award Date
28 June 2018
Award Value
Principal Investigator
Professor David Rubinsztein
Host Institution
University of Cambridge
MRCG-HRB Joint Funding Scheme