Human pluripotent stem cell-based assessment of dolutegravir teratogenicity

提案摘要 2018年，美国食品和药物管理局（FDA）发布了关于度鲁特韦（dolutegravir）妊娠风险的警告， 抗逆转录病毒药物治疗人类免疫缺陷病毒（HIV）。这个警告是基于一个NIH- 在博茨瓦纳进行的一项由基金资助的观察性研究发现， 在怀孕前或怀孕早期接受度鲁特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，它仍然推荐度鲁特韦 作为包括育龄妇女在内的所有人群的首选艾滋病毒治疗。世卫组织的决定是基于 在其他观察性研究中，这表明尽管统计学上的发病率较高，但总体上 度鲁特韦的致畸风险相对较小，作为一种有效的抗HIV药物，其获益超过了致畸风险。 药然而，目前尚不清楚度鲁特韦的作用机制是什么， 诱发神经管缺陷，以及什么情况可能加剧度鲁特韦的致畸作用。 这种机制性的理解对于进一步的研究预测什么类型的患者有风险是必不可少的 dolutegravir的副作用。该项目的目的是调查致畸潜力 dolutegravir，使用我的实验室建立的人类胚胎干细胞的新检测平台。 具体来说，我们将（1）表征度鲁特韦对人类多能干细胞的分子影响 聚集体，（2）确定度鲁特韦是否通过叶酸拮抗作用引起致畸作用，和 (3)研究dolutegravir和其他抗HIV药物之间的协同作用。机械的见解 从拟议的实验中获得的，应有助于进一步的调查和努力，以尽量减少 度鲁特韦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.