Human pluripotent stem cell-based assessment of dolutegravir teratogenicity

建议文摘

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.