Engineering Triggered Nanomechanical Therapeutics

描述（由申请人提供）：该研究计划的目标是开发基于使用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。传统药物可以被视为“结构治疗剂”，其特异性结合靶分子，该靶分子既作为疾病的标志物又作为治疗疾病的手段。如果靶标对患病细胞不是特异性的（例如癌症化疗的毒性副作用），则这种双重作用是不期望的，或者如果靶标不促进有效治疗则是限制性的。在这里，我们建议开发“机械”疗法，其中治疗域的活动处于独立诊断域的机械控制下：当且仅当诊断结构域与其靶标结合时（因其作为疾病标志物的特异性而被选择），最初无活性的治疗结构域转变为能够结合第二个无关靶标的活化构象（因其有效激活治疗途径而被选择）。使用不同的诊断和治疗域允许特异性和效力的独立优化;在这些域之间引入触发的机械转导提供了对药物活性的主动抑制，直到在分子水平上实现阳性诊断（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，允许在基于多种疾病标志物的诊断之后触发激活。这种动态功能将被编码在治疗性RNA分子的序列中，这些RNA分子相互作用并改变构象以实施两种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）是由检测到不相关的疾病标志物而触发的。触发纳米机械转导的概念表明了治疗广泛类型疾病的潜在变革性治疗策略，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，提供原理证明以激励进一步探索这种新的治疗概念。 公共卫生相关性：该研究计划的目标是开发一次诊断和治疗一个细胞疾病的药物，只有在分子水平上获得阳性诊断后才能在细胞内激活治疗。这一概念提出了潜在的变革性治疗策略，用于治疗广泛类别的疾病，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）。

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.