MSD is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene which encodes an enzyme that post-translationally activates all cellular sulfatases in the Endoplasmic Reticulum (ER). In our current funding from the MSD Action Foundation, we are developing and characterising 2 zebrafish models of MSD, one with a null mutation in SUMF1 and one with a hypomorph mutation. By the end of October 2018, we will have determined which of these is most suitable for compound screening, the optimal time window for drug treatment and the most informative disease measures.
In this proposal to the MRCG/HRB Joint Funding Scheme, our overall aim is to identify novel compounds that show disease rescue in vivo and which can be developed as potential treatments for the disease. Our first aim is to screen a diverse chemical library to identify compounds that show efficacy in the zebrafish disease model. Our second aim is to validate hits arising from the primary screen and perform structure-activity relationship assays to identify whether any FDA-approved drugs share structural similarity to our hits and therefore could be developed rapidly into treatments for the disease. We will screen a library with broad chemical diversity to identify novel structures with rescuing activity. Our aim is to perform a non-hypothesis based screen, i.e. not biased towards screening for one particular mechanism but that will identify any compound with in vivo efficacy and with potential to identify novel rescuing mechanisms. We will also test ‘hit’ compounds from cell-based screens funded by the MSD Action Foundation.
The expected outcome of this project is to identify ‘hit’ compounds that show efficacy in vivo. We will also identify any FDA-approved drugs with structural similarity to ‘hit compounds’ and test these for efficacy in the zebrafish MSD model.