Splicing Modulators for Rare Disease Indications

几年前，我们发现聚酮化合物GEX 1A（草环氧二烯）和普拉二烯内酯是潜在的 先导化合物的两个适应症，没有解决，但目前的化疗治疗。 C型尼曼匹克是一种罕见的，致命的遗传性疾病与异常胆固醇和 鞘脂储存在溶酶体内，目前没有FDA批准的治疗， 候选人在后期试验中的结果令人失望。在我们国家卫生研究院最近的研究期间， R 01授予，我们补充了这一发现与新的结果表明，GEX 1A具有强大的和选择性 对FMS样酪氨酸激酶3（FLT 3）内突变的急性髓性白血病的活性 基因FLT 3突变是在急性髓细胞白血病中观察到的最常见的体细胞突变 (AML)它们的存在可能是预后不良的预后因素， 需要新的治疗方案。虽然最初是为了研究它们的抗癌潜力， 这些聚酮化合物的结果表明与调节 突变NPC 1蛋白和其它基因产物通过前体RNA剪接调节。最近FDA- 目前临床上批准的药物和候选药物表明，调节RNA剪接和 剪接体是具有日益增长的临床相关性的生物学靶标。在这两种迹象中， 通过体外细胞研究和体内小鼠模型证实了活性。因此，治疗 剂量已经确定没有潜在的毒性，因此我们的持续努力被视为 在基础研究和转化研究方面具有重大意义和创新性。合作， 多学科策略利用细菌发酵、天然产物降解和半合成 作为全合成的补充，作为提供用于生物学研究的化合物的手段， 药理学优化我们将确定GEX 1A的溶液构象偏好， pladienolides和应用此信息的构象类似物的设计和合成，通过 全化学合成合成技术的结合将确保充足的 GEX 1A和相关类似物用于一些关键的生化实验，以帮助建立和 将两种适应症的作用机制联系起来。最后，我们将继续努力， 通过在小鼠中探索其体内活性的优化同源物的翻译潜力 NPC疾病模型。将评估两种鼠整体动物模型。更好地了解 作用方式可以帮助鉴定C型尼曼-匹克、其它溶酶体 疾病和更常见的疾病。大约2500万美国人受到罕见疾病的影响， 疾病研究有可能通过以下方式增加我们对更常见疾病的理解 他们的研究。

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.