Developing Novel Combinatorial Treatments for Tuberous Sclerosis Complex (TSC).

The aim of this project is to identify new drug treatments for tuberous sclerosis complex (TSC). TSC is an autosomal dominant genetic disorder effecting 1 in 6000 births, it is characterised by the formation of hamartomas (benign tumours) throughout the body causing disfigurement, learning difficulties and organ failure. The development of new treatments is important because the current treatment, rapamycin, is severely limited, only showing a cytostatic effect on hamartoma development. Several drug candidates have been identified as potential TSC treatments using a network of SS/L interactions between Drosophila and preapproved drugs (Housden et al., 2017; Valvezan et al., 2017). I assessed these candidates in Drosophila mutant cells to identify which would be most promising as the basis for a combinatorial treatment. Lithium chloride proved to be the most effective of the candidates tested, exhibiting a selective cytotoxic effect in Drosophila TSC cells. Lithium chloride was then screened against a library of one hundred and fifty-four FDA targets identified by Housden et al (2017) to identify possible synergistic combinations. Fifteen possible candidates were identified in this screen. Three of the genes identified were related to purine synthesis, which has been identified as a potential candidate for TSC treatment before. Of these genes ras (analogous to IMPDH) has two approved drugs, Ribavirin and Mycophenolic acid (MPA), and one experimental drug, mizoribine. These drugs were tested in combination with lithium chloride in murine and human cells in order to identify possible synergistic interactions. The preliminary results in both human and murine cells suggest that the synergy identified in the screen is conserved. However, preliminary results in human cells were inconclusive. Further testing is needed to properly validate these results and to develop new treatments for TSC.US Department of Defens