Niemann-Pick type C is a rare and fatal disease that results in the accumulation of cholesterol within lysosomes. A monogenic disorder that shows recessive inheritance, there is currently no FDA approved treatment for this terrible disease. Research efforts have implicated the role of the NPC1 and NPC2 proteins in cholesterol trafficking within lysosomes. Histone deacetylase inhibitors, such as trichostatin A and vorinostat, have recently been shown to restore cholesterol homeostasis in Niemann-Pick type C mutant cell lines. This has been attributed to their ability to upregulate the expression of the NPC1 protein.In 1997, type I polyketide natural product GEX1A was shown to regulate cholesterol in a manner comparable to that of trichostatin A. Unlike trichostatin A, GEX1A does not impact histone acetylation. Rather, GEX1A modulates alternative pre-mRNA splicing by targeting the SF3b subunit of the spliceosome. Our laboratory determined that the novel cholesterol activity of GEX1A merited further investigation within the context of Niemann-Pick Type C.Through isolation of natural GEX1A from its producing organism, our laboratory has demonstrated that GEX1A represents a novel therapeutic candidate for Niemann-Pick type C. Specifically, GEX1A restores cholesterol homeostasis in NPC1 mutant cell lines and cells induced with the disease associated phenotype. To expand on these initial studies, our laboratory targeted novel structural analogues of GEX1A through a synthetic and semi-synthetic approach, in an effort to discern the pharmacophore responsible for this unique cholesterol regulatory ability.A synthetic strategy was devised that produced two novel analogues, as well as an additional compound that had previously been disclosed in the literature. Semi-synthesis of the natural product also generated a number of analogues, with a particular focus on the manipulation of the C18 hydroxyl moiety of GEX1A. The efficacy of these compounds with respect to restoring cholesterol homeostasis in Niemann-Pick type C mutant cell lines was examined, and the data has provided valuable insights regarding the structure and activity of GEX1A.Ultimately, the results of these studies have demonstrated that GEX1A represents a therapeutic candidate for the treatment of Niemann-Pick type C disease. This advocates that other natural products that modulate alternative splicing warrant further investigation as targets for the treatment of Niemann-Pick type C.