Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Circ Res. 2024 Sep 27;135(8):877-885. doi: 10.1161/CIRCRESAHA.124.323058. Epub 2024 Sep 26.
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.
所有获得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途径。在再生医学工作的偶然发展中，我和我的同事们颠倒了 RNA 药物发现的过程：首先，我们确定了天然的疾病调节 ncRNA，然后将它们用作新的合成 RNA 药物的模板。只有在证明了生物活性之后，我们才会探究其机制。这项工作始于心脏球体衍生细胞（CDCs）的心脏再生研究。在一项首次人体试验中测试 CDCs 时，我们发现它们是间接起作用的：CDCs 分泌的细胞外囊泡中的 ncRNA 介导了治疗效果。这些 ncRNA 绝大多数是未知功能的片段。我们从 CDC 分泌的细胞外囊泡中选择了几种丰富的 ncRNA 种类，在体外和体内对它们进行了合成和筛选。那些具有特殊疾病修饰生物活性的 ncRNA 激发了新的化学实体，这些实体符合美国食品药品监督管理局批准的 ncRNA 武器库的结构规范。这个发现过程——细胞衍生的 RNA 来自细胞外囊泡以用于受启发的药物研发，或 CREDO——产生了各种有前途的先导化合物，每种化合物都通过独特的、通常是新颖的机制发挥作用。该过程依赖于涌现的见解来塑造治疗的发展。我们最初研究的重点——CDCs——现在正在进行针对杜氏肌营养不良症及其相关心肌病的 3 期测试。但是，证明对临床成功至关重要的 CDCs 的静脉内给药策略和重复给药方案都源于系统的机制研究。与此同时，涌现的见解导致了多种无细胞治疗候选物：CDC 分泌的细胞外囊泡正在进行用于室性心律失常的临床前开发，而基于 CREDO 理念的 RNA 药物正在翻译用于从心肌炎到硬皮病等各种疾病。
