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Engineering Triggered Nanomechanical Therapeutics

工程引发的纳米机械治疗

基本信息

批准号：
8464655
负责人：
NILES A PIERCE
金额：
$ 30.35万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2015-05-31
项目状态：
已结题

项目摘要

Project Summary: Engineering Triggered Nanomechanical Therapeutics The goal of this program of research is to develop the molecular foundations for a new therapeutic paradigm based on triggered nanomechanical transduction using synthetic nucleic acid devices. Traditional drugs may be viewed as 'structural therapeutics' that bind specifically to a target molecule that serves as both the marker for the disease and the means of treating the disease. This dual role is undesirable if the target is not specific to diseased cells (exemplified by toxicity side effects with cancer chemotherapies), or limiting if the target does not facilitate potent treatment. Here, we propose to develop 'mechanical' therapeutics in which the activity of the treatment domain is under the mechanical control of an independent diagnosis domain: if and only if the diagnosis domain binds to its target (selected for its specificity as a disease marker), the initially inactive treatment domain switches to an activated conformation capable of binding to a second unrelated target (selected for its potent activation of a therapeutic pathway). The use of distinct diagnosis and treatment domains allows independent optimization of specificity and potency; the introduction of triggered mechanical transduction between these domains provides active suppres- sion of the drug's activity until a positive diagnosis is achieved at the molecular level (minimizing side effects). Mechanical transduction also provides the flexibility to implement elementary molecular logic, permitting triggered activation following diagnosis based on multiple disease markers. This dynamic functionality will be encoded in the sequences of therapeutic RNA molecules that interact and change conformation to implement two conceptually powerful therapeutic strategies: If gene A is detected, silence gene B via triggered RNA interference. If gene A is detected, kill the cell via triggered immune response. In both cases, the key point is that the activity of the drug (i.e., gene silencing or cell death) is triggered by the detection of an unrelated disease marker. The concept of triggered nanomechanical transduction suggests potentially transformative therapeutic strate- gies for treating broad classes of disease, including cancers, autoimmune diseases such as multiple sclerosis, and mosquite-borne viral infections such as dengue fever. Our current objective is to demonstrate the promise of nanomechanical transduction by robustly triggering gene silencing and cell death in mammalian cells, providing a proof-of-principle to motivate further exploration of this new therapeutic concept. 1

项目概要：工程触发纳米机械治疗该研究项目的目标是为新的治疗模式开发分子基础基于使用合成核酸装置的触发纳米机械转导。传统药物可能被认为是特异性结合靶分子的“结构治疗剂”，所述靶分子既作为疾病和治疗疾病的方法如果目标不是特定于病变细胞（以癌症化疗的毒性副作用为例），或者如果靶点不促进有效治疗。在这里，我们建议开发“机械”疗法，其中治疗域的活性在独立诊断域的机械控制：当且仅当诊断域与其靶标结合（由于其作为疾病标志物的特异性而被选择），最初不活跃的治疗结构域切换到激活的治疗结构域。构象能够结合第二个不相关的靶标（因其有效激活治疗剂而选择途径）。不同诊断和治疗领域的使用允许特异性和特异性的独立优化。效力;在这些结构域之间引入触发的机械转导提供了活性抑制，在分子水平上实现阳性诊断之前，药物活性的锡永（最小化副作用）。机械转导还提供了实现基本分子逻辑的灵活性，允许触发基于多种疾病标志物的诊断后激活。这种动态功能性将编码在治疗性RNA分子的序列中，所述治疗性RNA分子相互作用，改变构象，以实现两个概念上强大的治疗策略：如果检测到基因A，则通过触发的RNA干扰使基因B沉默。如果检测到基因A，通过触发免疫反应杀死细胞。在这两种情况下，关键点是药物的活性（即，基因沉默或细胞死亡）是由检测不相关的疾病标志物。触发纳米机械转导的概念表明了潜在的变革性治疗策略- 用于治疗多种疾病的药物，包括癌症，自身免疫性疾病如多发性硬化症，以及蚊子传播的病毒感染如登革热。我们目前的目标是展示通过在哺乳动物细胞中稳健地触发基因沉默和细胞死亡的纳米机械转导，这是一个原理证明，以激励进一步探索这一新的治疗概念。 1