Deconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-09-26 DOI:10.1161/circresaha.124.323058
Eduardo Marbán
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Abstract

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.
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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。
美国食品和药物管理局批准的所有非编码 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。在再生医学工作的一次偶然演变中,我和我的同事颠倒了 RNA 药物的发现过程:首先,我们发现了可改变疾病的天然 ncRNA,然后用它们作为新合成 RNA 药物的模板。只有在生物活性得到证实后,才会对其机制进行探究。这一历程始于用于心脏再生的心肌细胞(CDCs)的开发。在首次人体试验中测试 CDC 时,我们发现它们是间接起作用的:CDC 分泌的细胞外囊泡中的 ncRNA 介导了治疗效果。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,对它们进行了体外和体内合成和筛选。那些具有特殊疾病调节生物活性的ncRNA激发了新的化学实体,这些实体符合食品药品管理局批准的ncRNA武器库的结构规范。细胞外囊泡衍生 RNA 生物启发药物开发"(CREDO)这一发现弧线产生了多种有前景的先导化合物,每种化合物都通过独特的、通常是新颖的机制发挥作用。这一过程依赖于新出现的见解来引导治疗开发。我们最初的研究重点--CDCs--目前已进入治疗杜氏肌营养不良症及其相关心肌病的第三阶段试验。但是,CDCs 的静脉给药策略和重复给药方案已被证明是临床成功的关键,而这两种策略和方案都源于系统的机理研究。与此同时,不断涌现的新发现也催生了多种无细胞候选疗法:CDC分泌的细胞外囊泡正处于临床前开发阶段,用于治疗室性心律失常,而CREDO构想的RNA药物正在转化中,用于治疗从心肌炎到硬皮病等各种疾病。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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