Programming gene and engineered-cell therapies with synthetic biology.
Programming gene and engineered-cell therapies with synthetic biology.
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DOI：
10.1126/science.aad1067
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发表时间：
2018-02-09
期刊：
影响因子：
--
通讯作者：
Weiss R
中科院分区：
文献类型：
--
作者：
Kitada T;DiAndreth B;Teague B;Weiss R
基因和工程细胞疗法有望通过基因修饰细胞来完成治疗任务，从而治疗疾病。尽管该领域在治疗单基因疾病和血液系统恶性肿瘤方面取得了一些成功，但目前的方法仅限于过度表达一种或几种转基因，限制了这种方法可以治疗的疾病，并导致对安全性和有效性的潜在担忧。合成的基因网络可以调节剂量、时间、基因表达的定位和治疗活性，以响应小分子和疾病生物标志物。这种可编程的基因和工程细胞疗法将为无法治愈或难以治疗的疾病提供新的干预手段。基因和工程细胞疗法为无法治愈或难以治疗的疾病提供了新的治疗方式。第一代基因和工程细胞疗法已经用于临床，包括针对腺苷脱氨酶缺乏症的体外基因替代疗法，针对某些类型的白血病和淋巴瘤的嵌合抗原受体CAR) T细胞疗法，针对遗传性视网膜缺损的腺相关病毒基因疗法，以及针对地中海贫血、镰状细胞病、血友病和脊髓性肌萎缩症的研究性疗法。尽管这些早期的成功，安全问题可能会阻碍这些方法的广泛采用：例如，治疗性基因产品在狭窄的治疗窗口中过度表达可能是有毒的，而T细胞的过度激活可能是致命的。更复杂的控制细胞活动将使我们能够可靠地“编程”具有治疗行为的细胞，从而导致更安全，更有效的基因和工程细胞疗法以及新的治疗方法。合成生物学的最新进展使新的基因和工程细胞疗法成为可能。这些发展包括工程生物传感器，可以检测疾病生物标志物，如microrna和细胞表面蛋白；对外源小分子作出反应的遗传传感器；以及与细胞的各种成分相互作用、编辑DNA、调节RNA和与内源性信号网络连接的新方法。这些新的生物模块本身具有治疗潜力，也可以作为复杂的合成基因电路的基石，精确控制治疗功能的强度、时间和位置。这种对细胞行为的先进控制将促进治疗方法的发展，解决疾病的潜在分子原因，并在生物分子靶点以前被认为是不可药物的情况下提供可行的治疗策略。”最近的出版物展示了几种通过结合基本传感器、调节和效应模块来设计复杂治疗性遗传程序的策略。这些策略包括i)控制分娩后治疗活性的外部小分子调控，ii)仅在患病细胞和组织中激活治疗活性的细胞特异性生物标志物传感器，和/或维持身体系统稳态的反馈控制回路。例如，治疗系统包括一个基因回路，它能感知两种特定的细胞表面标记物，仅在目标癌细胞存在时激活CAR - T细胞；一个回路，它能程序化地将胰腺祖细胞分化为胰岛素分泌样细胞；一个基因网络，它能感知银屑病相关细胞因子的数量，仅在发作时释放免疫调节蛋白。这些概念验证系统可能会带来比现有疗法更安全、更有效的新疗法。合成生物学和相关领域的快速发展使治疗性基因回路越来越接近临床。在哺乳动物遗传电路建模和模拟方面的持续努力将减少需要测试的电路变体的数量，以实现期望的行为。用于测试基因回路的平台也在不断进化，越来越接近于基因回路运行的实际人类环境。人类类器官、芯片组织和全血模型将在更生理相关的环境中实现更高通量的电路表征和优化。核酸递送的进展将提高治疗性核酸引入靶细胞的安全性和效率，免疫调节的新方法将抑制或减轻不必要的免疫反应。总之，这些进步将加速基于合成生物学的基因和工程细胞疗法的发展和采用。基因编码的治疗程序可以调节剂量。通过感知和处理外部管理信号以及细胞特异性和全身性疾病生物标志物来定位或定时治疗功能。这些合成基因网络可能导致基因和工程细胞疗法更安全、更有效，并且可以治疗比目前方法更广泛的疾病。
Gene and engineered-cell therapies promise to treat diseases by genetically modifying cells to carry out therapeutic tasks. Although the field has had some success in treating monogenic disorders and hematological malignancies current approaches are limited to overexpression of one or a few transgenes constraining the diseases that can be treated with this approach and leading to potential concerns over safety and efficacy. Synthetic gene networks can regulate the dosage timing and localization of gene expression and therapeutic activity in response to small molecules and disease biomarkers. Such programmable” gene and engineered-cell therapies will provide new interventions for incurable or difficult-to-treat diseases. Gene and engineered-cell therapies promise new treatment modalities for incurable or difficult-to-treat diseases. First-generation gene and engineered-cell therapies are already used in the clinic, including an ex vivo gene-replacement therapy for adenosine deaminase deficiency, chimeric antigen receptor CAR) T cell therapies for certain types of leukemias and lymphomas, an adeno-associated virus gene therapy for inherited retinal dig:swaps, and investigational therapies for -thalassemia, sickle cell disease, hemo-philia, and spinal muscular atrophy. Despite these early successes, safety concerns may hamper the broader adoption of some of these approaches: For example, overexpression of a therapeutic gene product with a narrow therapeutic window may be toxic, and excessive activation of T cells can be fatal More-sophisticated controlover cellular activity would allow us to reliably program” cells with therapeutic behaviors, leading to safer and more effective gene and engineeted-cell therapies as well as new treatments. Recent advances in synthetic biology are enabling new gene and engineered-cell therapies. These developments indude engineered biological sensors that can detect disease biomarkers such as microRNAs and cell-surface proteins; genetic sensors that respond to exogenous small molecules; and new methods for interacting with various components of the cell—editing DNA, modulating RNA, and interfacing with endogenous signaling networks. These new biological modules have therapeutic potential on their own and can also serve as building blocks for sophisticated synthetic gene circuits” that precisely control the strength, timing, and location of therapeutic function. This advanced control over cellular behavior will facilitate the development of treatments that address the underlying molecular causes of disease as well as provide viable therapeutic strategies in situations where the biomolecular targets have been previously considered undruggable.” Recent publications have demonstrated several strategies for designing complex therapeutic genetic programs by combining basic sensor, regulatory, and effector modules. These strategies include i) external small-molecule regulation to control therapeutic activity postdelivery, ii) sensors of cell-specific biomarkers that activate therapeutic activity only in diseased cells and tissues, and/or feedback control loops that maintain homeostasis of bodily systems. Example therapeutic systems include a genetic circuit that senses two specific cell-surface markers to activate CAR T cells only in the presence of target cancer cells, a circuit that programmatically differentiates pancreatic progenitor cells into insulin-secreting -like cells, and a gene network that senses the amount of psoriasis-associated cytokines to release immune-modulatory proteins only during flare-ups. These proof-of-concept systems may lead to new treatments that are dramatically safer and more effective than current therapies. Rapid progress in synthetic biology and related fields is bringing therapeutic gene circuits ever closer to the clinic. Ongoing efforts in modeling and simulating mammalian genetic circuits will reduce the number of circuit variants that need to be tested to achieve the desired behavior. The platforms used to test genetic circuits are also evolving to more closely resemble the actual human environment in which the circuits will operate. Human organoid, tissue-on-a-chip, and whole-blood models will enable higher-throughput circuit characterization and optimization in a more physiologically relevant setting. Progress in nucleic acid delivery will improve the safety and efficiency with which therapeutic nucleic acids are introduced to target cells, and new methods for immunomodulation will suppress or mitigate unwanted immune responses. Together, these advances will accelerate the development and adoption of synthetic biology-based gene and engineered-cell therapies. Genetically encoded therapeutic programs can regulate the dosage. localization, or timing of therapeutic function by sensing and processing externally administered signals as well as cell-specific and systemic disease biomarkers. These synthetic gene networks may lead to gene and engineered-cell therapies that are safer and more effective and that can address a broader class of diseases than current approaches.
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在药物发现的边界，片上的器官。
DOI：
10.1038/nrd4539
发表时间：
2015-04
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
Esch EW;Bahinski A;Huh D
通讯作者：
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DOI：
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发表时间：
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期刊：
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