Evolvable 'Resistance-Proof' Therapies

描述（由申请人提供）：我们最强大的抗菌剂正在迅速变得无保护性。从常见的葡萄球菌感染到结核病，抗药性微生物的迅速出现有可能使疾病控制的时钟倒退到日常感染致命的时代。我们目前的治疗方法的根本问题是病原体是动态的它们会变异和传播而我们的治疗方法是静态的，既不会变异也不会传播。这种不匹配必然会选择耐药逃逸变体，这些变体的出现速度远远快于当前平台识别和开发新抗菌药物的速度。面对动态的病原体，我提出了一个根本性的转变，在治疗策略工程动态，可进化的疗法。 对于病毒，这些动态疗法基于只能使用病毒的分子机制复制的工程分子寄生虫（即，它们“背驮”）。在HIV的情况下，这些分子寄生虫是削减的HIV载体，其中必需的蛋白质产物已经被消融，迫使载体在细胞内竞争病毒复制和包装资源，从而从HIV感染的细胞产生治疗性干扰颗粒（TIP）。通过使艾滋病毒自身缺乏必要的元素，TIPs起到了治疗作用，减少了患者体内的病毒载量。与传统疗法的根本区别在于，TIPs利用病原体的固有生物学，以与病原体相同的速度和相同的进化适应潜力进行复制。TIP处于强进化选择下以维持它们与病原体的寄生关系，并且自然选择推动分子寄生虫共同进化并与病原体保持同步（即，在治疗和病原体之间建立共同进化的“军备竞赛”）。 该提案将开发一套新的技术，以推动共同进化的抗病原体分子寄生虫的概念。研究进化论代表了一个全新的领域

DESCRIPTION (provided by applicant): Our most powerful antimicrobials are rapidly becoming non-protective. From common Staph infection to tuberculosis, the rapid emergence of drug-resistant microbes threatens to roll back the clock on disease control to an era when everyday infections were deadly. The fundamental problem with our current therapies is that pathogens are dynamic-they mutate and transmit-while our therapies are static, neither mutating nor transmitting. This mismatch necessarily selects for drug-resistant escape variants, which arise far quicker than current platforms can identify and develop new antimicrobials. Faced with dynamic pathogens, I propose a radical shift in treatment strategy toward engineering dynamic, evolvable therapies. For viruses, these dynamic therapies are based on engineered molecular parasites that can only replicate using the molecular machinery of the virus (i.e., they 'piggyback'). In the case of HIV, these molecular parasites are pared-down HIV vectors where the essential protein products have been ablated, forcing the vectors to intracellularly compete for viral replication and packaging resources, thereby generating Therapeutic Interfering Particles (TIPs) from HIV-infected cells. By starving HIV of its own essential elements, TIPs act as therapy, reducing viral loads in the patient. The fundamental departure from traditional therapies is that TIPs harness the inherent biology of the pathogen, replicating with equal speed and with the same evolutionary adaptive potential as the pathogen. TIPs are under strong evolutionary selection to maintain their parasitic relationship with the pathogen and natural selection pushes the molecular parasite to co-evolve and keep pace with the pathogen (i.e., establishing a co-evolutionary 'arms race' between therapy and pathogen). This proposal will develop a new set of technologies to propel the concept of co-evolving anti-pathogen molecular parasites. Studying evolution represents an entirely new dire