Splicing Modulators for Rare Disease Indications

用于罕见疾病适应症的剪接调节剂

• 批准号: 10501840
• 负责人: STEPHEN Laurence STURLEY
• 金额: $ 40.16万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10501840
• 关键词: Acute Myelocytic Leukemia; Affect; Alleles; Alternative Splicing; American; Animal Model; Animals; Autophagocytosis; Binding Sites; Biochemical; Biological; Biological Assay; Boron; Carbon; Carboxylic Acids; Catalysis; Cell Line; Cells; Chemicals; Chemistry; Chimeric Proteins; Cholesterol; Clinic; Clinical; Collaborations; Collection; Complement; Data; Disease; Ensure; Evaluation; FDA approved; FLT3 gene; Fermentation; Fibroblasts; Genes; Genetic Diseases; Grant; Growth; Heat-Shock Response; Homeostasis; Human; In Vitro; Individual; Intellectual Property; Interdisciplinary Study; Intervention; Laboratories; Lead; Lipids; Lysosomal Storage Diseases; Lysosomes; Mediating; Methodology; Missense Mutation; Modeling; Modification; Molecular Conformation; Mus; Mutate; Mutation; NPC1 gene; Natural Products; Nickel; Orthologous Gene; Outcome; Pathway interactions; Pharmacology; Prognostic Factor; Property; Proteins; RNA Splicing; Rare Diseases; Reaction; Reporter Genes; Research; Saccharomyces cerevisiae; Somatic Mutation; Source; Sphingolipids; Spliced Genes; Spliceosomes; Structure; Structure-Activity Relationship; Supraoptic Vertical Ophthalmoplegia; Technology; Testing; Therapeutic; Toxic effect; Translational Research; United States National Institutes of Health; Yeast Model System; Yeasts; acute myeloid leukemia cell; analog; anti-cancer; base; chemical synthesis; clinically relevant; collaborative approach; deletion library; design; dosage; drug candidate; drug discovery; efficacy evaluation; experimental study; fundamental research; gene product; herboxidiene; in vitro activity; in vivo; innovation; interdisciplinary approach; mRNA Precursor; mouse model; multidisciplinary; mutant; novel; preference; rare genetic disorder; restoration; specific biomarkers; translational potential; yeast genome

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.

几年前，我们发现聚酮化合物 GEX1A（herboxidiene）和 pladienolides 具有潜力 用于两种尚未解决但目前化疗治疗的适应症的先导化合物。 Niemann-Pick C 型是一种罕见的致命遗传病，与异常胆固醇和 鞘脂储存在溶酶体内，目前尚无 FDA 批准的治疗方法，并且最近有 候选人在后期试验中的结果令人失望。在我们 NIH 最近的研究期间 R01 资助，我们用新结果补充了这一发现，表明 GEX1A 具有有效和选择性 对 FMS 样酪氨酸激酶 3 (FLT3) 突变的急性髓系白血病具有活性 基因。 FLT3突变是急性髓系白血病中最常见的体细胞突变 （AML）及其存在可能是不良结果的预后因素，并且仍然是临床挑战 需要新的治疗方案。尽管最初研究了它们的抗癌潜力，但初步 这些聚酮化合物的结果表明与调节相关的和/或额外的活性 突变NPC1蛋白和其他基因产物通过RNA前体剪接调节。最近FDA- 当前临床中批准的药物和候选药物表明，RNA 剪接的调节和 剪接体是具有日益增长的临床相关性的生物靶标。在这两种迹象中我们都有 通过体外细胞研究和体内小鼠模型证明了其活性。因此，治疗 已确定剂量没有潜在毒性，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要和创新意义。协作、 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 药理优化。我们将确定 GEX1A 的解决方案构象偏好 pladienolides 并将这些信息应用于构象类似物的设计和合成 全化学合成。合成技术的结合将确保充足的供应 GEX1A 和相关类似物用于许多关键的生化实验，以帮助建立和 关联两种适应症的作用机制。最后，我们将继续努力评估 通过探索小鼠体内活性优化同系物的转化潜力 鼻咽癌疾病模型。将评估两种小鼠完整动物模型。更深入地了解 作用模式有助于识别 Niemann-Pick C 型与其他溶酶体之间的共性 疾病和更常见的疾病。大约 2500 万美国人患有罕见疾病和罕见疾病 疾病研究有可能通过以下方式增加我们对更常见疾病的了解 他们的学习。