I am working on drug discovery for atypical lysosomal storage disease, Niemann-Pick type C disease (NPC) and NPC-related diseases. Very significantly, we have recently found that the NPC pathway is inhibited as a secondary consequence of the primary metabolic defect in multiple rare metabolic diseases and by a major human microbial pathogen, Mycobacterium tuberculosis. Importantly, the treatments we have developed for NPC disease are unexpectedly proving to be effective in treating NPC-related diseases.
We are now looking to develop a new class of NPC therapeutics to treat this wider family of NPC-related disorders, building upon our extensive drug discovery/development history (miglustat). We will exploit the broad range of cellular and animal models of these diseases established within our laboratory for screening and efficacy studies.
- Identify analogues of curcumin with a virtual screen using shape and electrostatics and predicted bioavailability.
- Develop and validate a high-content cellular screen for endolysosomal trafficking defects using a cell model of NPC.
- Determine the activity of known drugs (marketed and abandoned) in the high-content cellular screen.
- Determine the activity of the top-ranking compounds from the virtual screen in the high-content cellular screen.
- Determine the activity of compounds positive in the cellular screen in a proof-of-concept study in NPC mice.