Splicing Modulators for Rare Disease Indications

University Of Notre Dame, Notre Dame IN

Investigators

Linked publications, trials & patents

Abstract

A recent investigation in the principal investigator's lab identified polyketides GEX1A (herboxidiene) and the pladienolides as potential new leads for Niemann-Pick Type C (NPC), a rare, lethal genetic disease associated with aberrant cholesterol and sphingolipid storage within the lysosome. Although originally investigated for their anti-cancer potential, preliminary results with these polyketides point to related and/or additional activity associated with modulation of mutant NPC1 protein potentially through RNA processing. Coupled with the fact that there exists no current FDA-approved treatment for NPC disease, this effort is seen as both significant and innovative. The collaborative, multidisciplinary strategy presented here represents a significant advance over previously reported synthetic efforts by exploiting diverse synthetic tools including: fermentation and biosynthetic manipulation, natural product degradation and semi-synthesis creating a foundation for a practical total synthesis of the natural products as well as their congeners. Structures prepared and isolated in the first objective will be harnessed as a valuable feedstock for the generation of novel analogues through the application of state-of-the-art nickel- and photo-catalyzed decarboxylative cross coupling reactions. A new route to the pladienolides based on macrocyclic carbonyl coupling reaction takes advantage of conformational pre-organization and overcomes an inability to access the producing organism. As the pladienolides are a scaffold used in clinical trials for some cancer indications, their use in non-cancer diseases such as NPC could expedite clinical evaluation. Towards evaluation of their therapeutic potential, compounds isolated via fermentation and prepared both synthetically and semi-synthetically will be evaluated for their ability to correct the NPC-phenotype in NPC mutant cell lines and optimize pharmacological properties such as PK, brain-plasma ratios, and general toxicity. GEX1A, pladienolide B and active congeners (activity being determined by reversal of lipid accumulation in cultured cells) will be utilized in more detailed biological studies to determine the mode of action and their activity in mouse models of this rare disease. Two murine, whole animal models will be assessed. The majority of studies will be accomplished in the NPC1nmf model comprising a missense mutation in the murine NPC1 gene. This model produces significant but reduced levels of partially functional NPC1 protein and is thus amenable to therapeutic correction by multiple mechanisms. By contrast, NP-C disease in NPC1nih animal arises from a true null allele of NPC1 and can thus only be corrected independently of NPC1 activity. We anticipate testing all compounds in the NPC1nmf model and then proceeding to the null model with only the most efficacious compounds as a means to determining mechanism of action.