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

基本信息

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
项目类别：
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

项目摘要

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.

提案摘要已知多种药物在怀孕期间使用时会致畸，导致流产或出生缺陷。怀孕。然而，许多其他药物的致畸性尚不清楚，特别是那些最近上市的药物上市。由于当前的 COVID-19 大流行/地方病，许多研究人员正在开发新的针对 SARS-CoV-2 的抗病毒药物。目前，已有三种抗病毒药物获批或紧急使用 FDA 授权的药物分别是 remdesivir、molnupiravir 和 Paxlovid。然而对其致畸性的研究尚不清楚稀缺。由于随着免疫逃逸变体的出现，COVID-19 仍然持续存在，许多人，包括那些有生育能力的人可能需要抗病毒治疗。以便医生能够提供适当的建议对于他们的患者，应该充分研究抗病毒药物的致畸性。此前，我们发明了基于小鼠和人类干细胞的 3D 形态发生模型，概括了早期的关键特征体外胚胎发生，可作为灵敏、特异检测各种致畸性的有效工具化学品。我们使用这些形态发生模型的初步研究表明，抗 COVID-19 药物，特别是瑞德西韦和莫努匹拉韦，在接近其浓度时会损害胚胎发生人体内的治疗血浆水平。这些观察结果需要进一步研究致畸性如本申请中所提议的，抗病毒药物的潜力。具体来说，我们将（1）表征分子新型抗病毒药物对形态发生模型的影响，（2）探索其可能的致畸机制新的抗病毒药物，以及（3）检查新的抗病毒药物对小鼠整个胚胎的致畸作用文化。所提出的实验应该产生与其致畸潜力相关的有价值的信息，例如浓度-效果关系和作用分子机制，并有助于设计和以有效的方式解释基于动物和人类的研究。