Human pluripotent stem cell-based assessment of dolutegravir teratogenicity

建议书摘要 2018年，美国食品和药物管理局发布了关于多洛替格韦怀孕风险的警告， 用于治疗人类免疫缺陷病毒(HIV)的抗逆转录病毒药物。这一警告是基于美国国立卫生研究院的- 博茨瓦纳资助的一项观察性研究，发现严重神经管的发生率明显更高 怀孕前或怀孕早期服用多洛替格列韦的妇女所生婴儿的缺陷。 尽管如此，世界卫生组织(WHO)在2019年宣布，它仍然建议使用多洛替格韦 作为所有人口，包括育龄妇女的首选艾滋病毒治疗。谁的决定是基于 在其他观察性研究上，表明尽管统计上发病率较高，但总体 多洛替格列韦的致畸风险相对较小，作为一种有效的抗艾滋病毒药物，其益处超过了这一点 药物治疗。然而，目前尚不清楚多洛替格雷对 诱导神经管畸形以及何种情况可能加重多洛替格雷的致畸作用。 这种机械性的理解对于预测哪些类型的患者有风险的进一步研究是必不可少的 避免多洛替格雷的不良影响。拟议项目的目标是研究其致畸潜力。 使用我的实验室建立的新的人类胚胎干细胞测试平台。 具体地说，我们将(1)表征多洛替格列韦对人类多能干细胞的分子影响 聚集体，(2)确定多洛替格列韦是否通过叶酸拮抗引起致畸作用，以及 (3)研究多洛替格雷与其他抗HIV药物的协同作用。机械论的见解 从拟议的实验中获得的信息应该有助于进一步的调查和努力将 多洛替格雷暴露的潜在致畸风险。

Proposal Abstract In 2018, the Food and Drug Administration issued a warning about pregnancy risk of dolutegravir, an antiretroviral medication to treat human immunodeficiency virus (HIV). This warning was based on an NIH- funded observational study in Botswana, which found a significantly higher incidence of severe neural tube defects in babies born to women who received dolutegravir before pregnancy or early in the first trimester. Nevertheless, the World Health Organization (WHO) announced in 2019 that it still recommends dolutegravir as preferred HIV treatment for all populations, including women of reproductive age. WHO's decision is based on additional observational studies, suggesting that in spite of statistically higher incidence, the overall teratogenic risk of dolutegravir is relatively small and is outweighed by the benefit as an effective anti-HIV medication. However, it is currently unclear what mechanisms are involved in the action of dolutegravir to induce neural tube defects and what circumstances may exacerbate the teratogenic effects of dolutegravir. Such mechanistic understanding is essential for further studies to anticipate what types of patients are at risk from adverse impact of dolutegravir. The goal of the proposed project is to investigate the teratogenic potential of dolutegravir, using the novel assay platform of human embryonic stem cells that my lab established. Specifically, we will (1) characterize molecular impact of dolutegravir in human pluripotent stem cell aggregates, (2) determine whether dolutegravir causes teratogenic effects through folic acid antagonism, and (3) investigate synergistic effects between dolutegravir and other anti-HIV medications. Mechanistic insights obtained from the proposed experiments should help further investigations and endeavors to minimize potential teratogenic risks from dolutegravir exposures.