Engineering Triggered Nanomechanical Therapeutics

描述（由申请人提供）：该研究项目的目标是开发基于合成核酸装置触发纳米机械转导的新治疗范例的分子基础。传统药物可被视为一种“结构性疗法”，它与既作为疾病标志又作为治疗疾病手段的目标分子特异性结合。如果靶点对病变细胞不是特异性的（例如癌症化疗的毒副作用），或者如果靶点不能促进有效的治疗，这种双重作用是不可取的。在这里，我们建议开发“机械”疗法，其中治疗结构域的活性在独立诊断结构域的机械控制下：当且仅当诊断结构域与其靶标结合（选择其作为疾病标志物的特异性）时，最初不活跃的治疗结构域切换为激活构象，能够与第二个不相关的靶标结合（选择其有效激活治疗途径）。使用不同的诊断和治疗领域允许特异性和效力的独立优化；在这些结构域之间引入触发的机械转导提供了药物活性的主动抑制，直到在分子水平上获得阳性诊断（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，允许基于多种疾病标记物的诊断后触发激活。这种动态功能将被编码在治疗性RNA分子序列中，这些RNA分子相互作用并改变构象，以实现两种概念上强大的治疗策略：如果检测到基因A，通过触发RNA干扰沉默基因B。如果检测到基因A，通过触发的免疫反应杀死细胞。在这两种情况下，关键是药物的活性（即基因沉默或细胞死亡）是由检测到不相关的疾病标记物触发的。触发纳米机械转导的概念为治疗多种疾病提供了潜在的变革性治疗策略，包括癌症、自身免疫性疾病（如多发性硬化症）和蚊媒病毒感染（如登革热）。我们目前的目标是通过在哺乳动物细胞中强有力地触发基因沉默和细胞死亡来证明纳米机械转导的前景，为进一步探索这一新的治疗概念提供原理证明。

DESCRIPTION (provided by applicant): 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 binds 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 suppression 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 strategies 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. PUBLIC HEALTH RELEVANCE: The goal of this program of research is to develop drugs that diagnose and treat disease one cell at a time, activating treatment within a cell only after a positive diagnosis is achieved at the molecular level. This concept suggests potentially transformative therapeutic strategies for treating broad classes of disease, including cancers, autoimmune diseases such as multiple sclerosis, and mosquite-borne viral infections such as dengue fever.