Splicing Modulators for Rare Disease Indications

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Several years ago we identified polyketides GEX1A (herboxidiene) and the pladienolides as potential lead compounds for two indications that are not addressed but current chemotherapeutic treatments. Niemann-Pick Type C is a rare, lethal genetic disease associated with aberrant cholesterol and sphingolipid storage within the lysosome with no current FDA-approved treatment and recent disappointing results of candidates in late-stage trials. During the most recent research period of our NIH R01 grant, we complemented this discovery with new results that show GEX1A has potent and selective activity against acute myeloid leukemia with mutations within the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3 mutations are the most common somatic mutations observed in acute myeloid leukemia (AML) and their presence may be a prognostic factor for poor outcome and remain a clinical challenge in need of new treatment options. 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 and other gene products through pre-RNA splicing modulation. Recent FDA- approved drugs and candidates in current clinic suggests that modulation of RNA-splicing and the spliceosome are biological targets with growing clinical relevance. In both indications we have demonstrated activity through in vitro cellular studies and in vivo mouse models. Thus, therapeutic dosages have been identified without potential toxicity and thus our continued effort is seen as both significant and innovative with respect to fundamental and translational research. The collaborative, multidisciplinary strategy utilizes bacterial fermentation, natural product degradation and semi-synthesis as a complement to total synthesis as means to provide access to compounds for biological studies and pharmacological optimization. We will determine the solution conformational preferences of GEX1A and pladienolides and apply this information to the design and synthesis of conformational analogues through total chemical synthesis. The combination of synthetic technologies will ensure an adequate supply of GEX1A and related analogues for a number of key biochemical experiments to help establish and correlate the mechanisms of action in both indications. Finally, we will continue our efforts to evaluate the translational potential of optimized congeners through exploration of their in vivo activity in mouse models of NPC disease. Two murine, whole animal models will be assessed. A greater understanding of the mode of action can help identify commonalities between Niemann-Pick Type C, other lysosomal disorders, and more common diseases. About 25M Americans are affected by a rare disease and rare disease research has the potential to increase our understanding of more common afflictions through their study.