Using a disease-affected cell to synthesize its own drug

生物医学研究中的一个主要挑战是利用基因组测序的进展进入铅 治疗人类疾病的治疗方式。这种精准的医学方法很有希望 推进针对患者的治疗方法，并提供高选择性的功能化学探针进行研究 疾病生物学。在这份提案中，我们描述了一种创新的精准治疗方法 通过使用一种只在受疾病影响的细胞和组织中合成高选择性和有效的铅疗法 致病基因产物作为催化剂。也就是说，受疾病影响的细胞充当反应容器， 核糖核酸作为催化剂的致病核糖核酸，可用于自身治疗的合成与此形成对比的是 传统的精确医学方法，在这种方法中，健康和受疾病影响的细胞都暴露在 治疗性的，由于脱靶结合而可能导致毒性的。 我们的技术将被应用于开发化合物来治疗和研究影响 全世界有数百万人，而且还没有已知的治疗方法。微卫星疾病是由扩张型 位于编码区和非编码区的重复序列，其中RNA是关键致病因子 探员。我们以前已经证明，重复的转录本最有效地被多价靶向 化合物。然而，随着化合物价态的增加，它们的分子质量也会增加，它们的药物性质也会变得更相似 减少。因此，我们最近开发了一种创新的策略来合成多价 利用受疾病影响的细胞作为反应容器的纤维素中的化合物，来自它们的单价成分 以及一种有毒的、致病的RNA作为催化剂。我们将把这些令人兴奋的结果推向新的方向，并应用于 他们与其他衰弱的微卫星疾病有关，包括亨廷顿氏病，各种形式的肌肉 营养不良，导致脆性X综合征(唯一已知的导致自闭症的单基因)的遗传缺陷， 脆性X相关震颤共济失调综合征和一种导致肌萎缩侧索硬化的常见突变 硬化症和额叶颞叶痴呆(ALS/FTD)。因为大脑和神经系统的缺陷 在这些疾病中观察到的，设计方法将脑渗透化合物转化为高度有效的， 选择性的疾病抑制剂将是真正的变革性的。具体地说，我们将：(I)综合精确 受疾病影响的组织和微卫星病动物模型中的药物/化学探针；以及 在细胞和动物模型中为致病RNA的天然环境开发显像剂 疾病。

One major challenge in biomedical research is to leverage advances in genome sequencing into lead therapeutic modalities to treat human disease. This precision medicine approach holds great promise to advance patient-specific therapeutics and to provide highly selective chemical probes of function to study disease biology. In this proposal, we describe an innovative precision therapeutic approach to custom synthesize highly selective and potent lead therapeutics in only disease-affected cells and tissues by using a disease-causing gene product as a catalyst. That is, the disease-affected cell serves as a reaction vessel and a disease-causing RNA as a catalyst to allow for the synthesis of its own treatment. This is in contrast to traditional precision medicine approaches in which both healthy and disease-affected cells are exposed to the therapeutic, potentially causing toxicity due to binding off-targets. Our technology will be applied to develop compounds to treat and study microsatellite disorders that affect millions of people worldwide and have no known cure. Microsatellite disorders are caused by expanded repeating sequences located in both coding and non-coding regions, with the RNA being a key pathogenic agent. We have previously shown that repeating transcripts are most effectively targeted with multivalent compounds. However, as the compounds increase in valency, their molecular weights increase and their drug-likeness decreases. We therefore recently developed an innovative strategy to synthesize multivalent compounds, from their monovalent components, in cellulo using a disease-affected cell as a reaction vessel and a toxic, disease-causing RNA as a catalyst. We will take these exciting results in new directions and apply them to other debilitating microsatellite disorders including Huntington’s disease, various forms of muscular dystrophy, the genetic defect that causes fragile X syndrome (the only known single gene cause of autism), fragile X-associated tremor ataxia syndrome, and a common mutation that causes amyotrophic lateral sclerosis and frontal temporal dementia (ALS/FTD). Since defects in the brain and the nervous system are observed in these diseases, devising methods to transform brain-penetrant compounds into highly potent, selective inhibitors of disease would be truly transformative. Specifically, we will: (i) synthesize precise medicines/chemical probes in disease-affected tissues and animal models of microsatellite disease; and (ii) develop imaging agents for disease-causing RNAs in their native contexts in cellular and animal models of disease.