Using a disease-affected cell to synthesize its own drug

 描述（由申请人提供）：生物医学研究的一个主要挑战是利用基因组测序的进展来治疗人类疾病。这种精准医学方法在推进患者特异性治疗和提供高选择性化学功能探针以研究疾病生物学方面具有很大的前景。在这项提案中，我们描述了一种创新的精确治疗方法，通过使用致病基因产物作为催化剂，仅在受疾病影响的细胞和组织中定制合成高选择性和有效的先导疗法。也就是说，受疾病影响的细胞充当反应容器，而致病RNA充当催化剂，以允许合成其自身的治疗。这与传统的精确医学方法相反，在传统的精确医学方法中，健康和受疾病影响的细胞都暴露于治疗药物，可能会由于结合脱靶而导致毒性。 我们的技术将被应用于开发化合物，以治疗和研究影响全球数百万人的微卫星疾病，并且没有已知的治愈方法。微卫星疾病是由位于编码区和非编码区的扩增重复序列引起的，其中RNA是关键致病因子。我们以前已经表明，重复的成绩单是最有效的多价化合物的目标。然而，随着化合物的化合价增加，它们的分子量增加并且它们的药物相似性降低。因此，我们最近开发了一种创新策略，使用受疾病影响的细胞作为反应容器，使用有毒的致病RNA作为催化剂，在细胞中从其单价组分合成多价化合物。我们将把这些令人兴奋的结果用于新的方向，并将其应用于其他使人衰弱的微卫星疾病，包括亨廷顿病，各种形式的肌肉萎缩症，导致脆性X综合征的遗传缺陷（孤独症的唯一已知单基因原因），

 DESCRIPTION (provided by applicant): 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 auti