Evolvable 'Resistance-Proof' Therapies

描述(申请人提供)：我们最有效的抗菌剂正在迅速变得无保护性。从常见的金黄色葡萄球菌感染到结核病，耐药微生物的迅速出现可能会使疾病控制的时钟倒退到一个日常感染是致命的时代。我们目前疗法的根本问题是，病原体是动态的--它们会突变和传播--而我们的疗法是静态的，既不会突变，也不会传播。这种错配必然会选择耐药逃逸变体，这种变体出现的速度远远快于目前的平台识别和开发新的抗菌剂。面对动态的病原体，我建议从根本上改变治疗策略，转向工程化的动态、可进化的治疗方法。对于病毒，这些动态疗法是基于改造的分子寄生虫，这些寄生虫只能利用病毒的分子机制(即，它们‘搭载’)进行复制。在HIV的情况下，这些分子寄生虫是精简的HIV载体，其中基本蛋白质产物已经被去除，迫使载体在细胞内竞争病毒复制和包装资源，从而从HIV感染的细胞中产生治疗性干扰粒子(TIPS)。通过使艾滋病毒缺乏其自身的基本元素，TIPS起到了治疗的作用，减少了患者的病毒载量。与传统疗法的根本不同之处在于，TIPS利用病原体的固有生物学，以与病原体相同的速度和进化适应潜力进行复制。TIPS处于强大的进化选择之下，以维持它们与病原体的寄生关系，而自然选择推动分子寄生虫与病原体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一场共同进化的“军备竞赛”)。这项提议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。研究进化论代表着一种全新的可怕

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