Delivery Strategies for Microbe Therapeutics

摘要 微生物治疗剂（MT）是一类新兴的FDA监管药物，包括微生物群移植， 基于孢子的治疗剂、活微生物（例如益生菌）和基因工程细菌， 治疗学MT目前正在广泛的临床试验中进行研究，以治疗炎症， 病原体感染和遗传疾病。MT用于胃肠道（GI）、皮肤， 和粘膜屏障（例如口腔）上。控制MT功效的作用机制可以从 微生物组调节、生物屏障强化、代谢物或生物分泌。这些 这些机制基本上是不同的，并且每个机制都与不同的MT相关联。因此，我们假设 每种MT根据其作用机制、靶部位/器官和 每个MT的特定属性。为此，一个关键的和未解决的挑战是确定理想的 MT的交付参数，以便可以开发和采用改进MT交付的方法。到 迄今为止，所有临床评价的MT都是通过最初设计和优化的技术提供的， 小分子和最近MT临床试验的失败归因于剂量不一致。为其他 药物，剂量已经得到解决和改善，通过采用配方方法，从 制药科学和药物输送方法从工程。我未来五年的目标是 目的：（i）理解成功MT交付的关键要求，（ii）介绍制药科学， 基于工程的药物递送方法，以配制并随后改善MT的递送，以及 (iii)突出了MT递送系统在使MT治疗影响不同的疾病/病症中的效用， 组织感染，如皮肤感染或胃肠道感染。我的计划将集中在定义 并随后应对具体的中期战略制定和交付挑战。我们将解决以下方面的差距： 限制合理开发与基本问题有关的具体的MT运载系统的知识 例如在正确的时间和正确的剂量将MT递送到正确的地点有多重要。我的程序 我将是第一个尝试系统地询问和回答这些关键问题的人， 中期战略的制定和实施。

ABSTRACT Microbe therapeutics (MTs) are an emerging class of FDA-regulated drugs that include microbiota transplants, spore-based therapeutics, living microbes (e.g. probiotics), and genetically engineered bacteria that secrete therapeutics. MTs are currently being investigated in a wide-range of clinical trials to treat inflammation, pathogenic infections, and genetic disorders. MTs are being used in the gastrointestinal (GI) tract, on the skin, and on mucosal barriers (e.g. oral cavity). The mechanism of action that governs MT efficacy can range from microbiome modulation, to biological barrier reinforcement, to metabolite or biologic secretion. These mechanisms are fundamentally distinct and each one is tied to a different MT. As such, we hypothesize that each MT has distinct delivery requirements based on their mechanism of action, the target site/organ, and the specific properties of each individual MT. To this end, a key and unaddressed challenge is identifying the ideal delivery parameters for MTs so that approaches to improve MT delivery can be developed and employed. To date, all clinically evaluated MTs are delivered via technologies that were originally designed and optimized for small molecules and recent failures in MT clinical trials have been attributed to dosing inconsistencies. For other drugs, dosing has been addressed and improved through the adoption of formulation approaches from the pharmaceutical sciences and drug delivery approaches from engineering. My goals over the next five years are to: (i) understand the key requirements for successful MT delivery, (ii) introduce pharmaceutical sciences and engineering-based drug delivery approaches to formulate and subsequently improve the delivery of MTs, and (iii) highlight the utility of MT delivery systems in enabling MT treatment of diseases/disorders that affect distinct tissues, such as infections on the skin or infection in the gastrointestinal tract. My program will focus on defining and subsequently addressing the MT-specific formulation and delivery challenges. We will address gaps in knowledge that have limited the rational development of MT-specific delivery systems related to basic questions such as how important is delivery of MTs to the right place, at the right time, and at the right dose. My program will be the first to attempt a systematic approach to asking and answering these key questions towards improved formulation and delivery of MTs.