Teratogenicity assessment of new antiviral drugs using 3D morphogenesis models

使用 3D 形态发生模型评估新型抗病毒药物的致畸性

• 批准号: 10741474
• 负责人: YUSUKE MARIKAWA
• 金额: $ 15.65万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741474
• 关键词: 2019-nCoV; 3-Dimensional; Adopted; Adult; Adverse effects; Affect; Animals; Antiviral Agents; Brain; COVID-19; COVID-19 pandemic; Cells; Chemicals; Clinical Trials; Congenital Abnormality; DNA-Directed RNA Polymerase; Data; Development; Drug usage; Embryo; Embryonic Development; Embryonic Structures; Event; Exclusion; Exposure to; FDA Emergency Use Authorization; Gene Expression; Genes; Grant; Heart; Human; Immune; Impairment; In Vitro; Incidence; Investigation; Link; Marketing; Metabolic; Methods; Mitochondrial RNA; Modeling; Molecular; Molecular Analysis; Molecular Mechanisms of Action; Morphogenesis; Morphology; Mus; Patients; Pattern; Paxlovid; Persons; Pharmaceutical Preparations; Phosphorylation; Physicians; Plasma; Pregnancy; Research Personnel; Risk; Somites; Spontaneous abortion; Structure; Teratogenic effects; Teratogens; Testing; Therapeutic; Toxicokinetics; Toxicology; Variant; Viral; Virus; chemical property; child bearing; design; embryo culture; experimental study; grasp; human pluripotent stem cell; human stem cells; in vivo; innovation; invention; molnupiravir; novel; pharmacologic; pregnant; remdesivir; stem cells; three dimensional cell culture; tool; transcriptome sequencing; transcriptomics; whole genome

Proposal Abstract Various drugs are known to be teratogenic, causing miscarriages or birth defects, when used during pregnancy. However, teratogenicity is unclear for many other drugs, particularly those that were recently marketed. Because of the ongoing COVID-19 pandemic/endemic, many investigators are developing new antiviral drugs against SARS-CoV-2. Currently, three antivirals are approved or granted the emergency use authorization by the FDA, namely remdesivir, molnupiravir, and Paxlovid. Yet studies on their teratogenicity are scarce. As COVID-19 still persists with the emergence of immune escape variants, many people, including those of childbearing potential, may require antiviral treatment. For physicians to provide proper advice for their patients, the teratogenicity of the antivirals should be studied sufficiently. Previously, we invented the mouse and human stem cell-based 3D morphogenesis models, which recapitulate the key features of early embryogenesis in vitro and can serve as effective tools to sensitively and specifically detect various teratogenic chemicals. Our Preliminary Studies using these morphogenesis models suggest that the anti-COVID-19 drugs, particularly remdesivir and molnupiravir, impair embryogenesis at the concentrations close to their therapeutic plasma levels in human. These observations necessitate further investigations into the teratogenic potential of the antivirals, as proposed in this application. Specifically, we will (1) characterize the molecular impact of the new antivirals on the morphogenesis models, (2) explore the possible teratogenic mechanisms of the new antivirals, and (3) examine the teratogenic effects of the new antivirals with the mouse whole embryo culture. The proposed experiments should yield valuable information pertinent to their teratogenic potential, such as the concentration-effect relationship and molecular mechanisms of actions, and help in the design and interpretation of animal- and human-based studies in an effective manner.

提案摘要 众所周知，当在怀孕期间使用时，各种药物都具有致畸性，导致流产或出生缺陷。 怀孕然而，致畸性是不清楚的许多其他药物，特别是那些最近 销售。由于持续的COVID-19大流行/地方病，许多研究人员正在开发新的 抗SARS-CoV-2的抗病毒药物目前，三种抗病毒药物被批准或授予紧急使用 FDA授权的三种药物，即Remdesivir、Molnupiravir和Paxlovid。然而，关于其致畸性的研究 稀少。由于COVID-19仍然存在免疫逃逸变体的出现，许多人，包括 有生育能力的患者可能需要抗病毒治疗。对于医生提供适当的建议， 因此，对抗病毒药物的致畸性应进行充分的研究。在此之前，我们发明了 基于小鼠和人类干细胞的3D形态发生模型，它概括了早期干细胞的关键特征， 胚胎发生，可以作为一种有效的工具，敏感和特异地检测各种致畸 化学品我们使用这些形态发生模型的初步研究表明，抗COVID-19 药物，特别是Remdesivir和Molnupiravir，在接近其浓度时损害胚胎发生。 人的治疗血浆水平。这些观察结果需要进一步研究致畸性 抗病毒药物的潜力，如本申请中提出的。具体而言，我们将（1）表征分子 新的抗病毒药物对形态发生模型的影响，（2）探讨可能的致畸机制， 新的抗病毒药物，和（3）用小鼠全胚胎检查新的抗病毒药物的致畸作用 文化拟议的实验应产生与其致畸潜力有关的宝贵信息， 如浓度效应关系和作用的分子机制，并帮助设计和 以有效的方式解释基于动物和人类的研究。