All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. The journey began with the development of cardiosphere-derived cells (CDCs) for cardiac regeneration. While testing CDCs in a first-in-human trial, we discovered they worked indirectly: ncRNAs within CDC-secreted extracellular vesicles mediate the therapeutic benefits. The vast majority of such ncRNAs are fragments of unknown function. We chose several abundant ncRNA species from CDC-secreted extracellular vesicles, synthesized and screened each of them in vitro and in vivo. Those with exceptional disease-modifying bioactivity inspired new chemical entities that conform to the structural conventions of the Food and Drug Administration-approved ncRNA armamentarium. This discovery arc-Cell-Derived RNA from Extracellular vesicles for bioinspired Drug develOpment, or CREDO-has yielded various promising lead compounds, each of which works via a unique, and often novel, mechanism. The process relies on emergent insights to shape therapeutic development. The initial focus of our inquiry-CDCs-are now themselves in phase 3 testing for Duchenne muscular dystrophy and its associated cardiomyopathy. But the intravenous delivery strategy and the repetitive dosing protocol for CDCs, which have proven key to clinical success, both arose from systematic mechanistic inquiry. Meanwhile, emergent insights have led to multiple cell-free therapeutic candidates: CDC-secreted extracellular vesicles are in preclinical development for ventricular arrhythmias, while the CREDO-conceived RNA drugs are in translation for diseases ranging from myocarditis to scleroderma.

中文翻译：

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解构再生医学：从细胞疗法的机制研究到新型生物启发 RNA 药物。


所有美国食品药品监督管理局批准的非编码 RNA （ncRNA） 药物 （n≈20） 都通过反义等机制靶向已知的致病分子通路。在再生医学工作的偶然演变中，我和我的同事颠倒了 RNA 药物发现过程：首先我们确定了天然的疾病修饰 ncRNA，然后将它们用作新合成 RNA 药物的模板。只有在生物活性得到证明后，才探究机制。这段旅程始于开发用于心脏再生的心脏球衍生细胞 （CDC）。在首次人体试验中测试 CDC 时，我们发现它们间接起作用：CDC 分泌的细胞外囊泡内的 ncRNA 介导治疗益处。绝大多数此类 ncRNA 是功能未知的片段。我们从 CDC 分泌的细胞外囊泡中选择了几种丰富的 ncRNA 物种，在体外和体内合成和筛选了它们。那些具有特殊疾病修饰生物活性的生物实体激发了新的化学实体，这些实体符合美国食品和药物管理局批准的 ncRNA 武器库的结构约定。这种发现弧线 - 来自细胞外囊泡的细胞来源的 RNA，用于生物启发药物开发，或 CREDO- 已经产生了各种有前途的先导化合物，每种化合物都通过一种独特且通常是新颖的机制起作用。该过程依赖于新兴的见解来塑造治疗开发。我们调查的最初重点 - CDC - 现在本身处于杜氏肌营养不良症及其相关心肌病的 3 期测试中。但是，已被证明是临床成功的关键的 CDC 的静脉给药策略和重复给药方案都源于系统的机制调查。 与此同时，新兴的见解导致了多种无细胞治疗候选药物：CDC 分泌的细胞外囊泡正处于室性心律失常的临床前开发阶段，而 CREDO 构想的 RNA 药物正在转化用于从心肌炎到硬皮病的各种疾病。