Defining the impact of dolutegravir on the maternal metabolic environment and its implications on risk of congenital anomalies.

定义多替拉韦对母体代谢环境的影响及其对先天性异常风险的影响。

基本信息

批准号：
10657644
负责人：
Lena Serghides
金额：
$ 26.3万
依托单位：
UNIVERSITY HEALTH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657644
关键词：
Age Animals Anti-Retroviral Agents Botswana Carbon Clinical Complement Conceptions Congenital Abnormality Contracts Data Defect Diabetes Mellitus Dose Embryo Environment Exposure to Fetus First Pregnancy Trimester Folic Acid Folic Acid Deficiency General Population Glucose HIV HIV Seronegativity Human In Vitro Incidence Intervention Investigation Length Link Mediating Metabolic Metabolism Mitochondria Modeling Mothers Mus National Institute of Child Health and Human Development Neural Tube Defects Oxidative Stress Oxidative Stress Induction Pathway interactions Persons Plasma Pregnancy Pregnant Women Prevention Recommendation Regimen Reporting Resistance Resources Risk Risk Factors Risk Reduction Safety Sampling System Testing Therapeutic Toxic effect Uncertainty United States National Institutes of Health Weight Gain Woman World Health Organization animal data antiretroviral therapy biomarker selection blood glucose regulation candidate validation clinically relevant clinically significant congenital anomaly efavirenz embryo culture excessive weight gain experimental study fetal folic acid metabolism in vivo metabolic profile metabolomics mouse model neural model pregnant prepregnancy obesity prospective protective effect reproductive screening surveillance data

项目摘要

PROJECT SUMMARY/ABSTRACT: Dolutegravir (DTG)-based antiretroviral therapy (ART) is recommended by the World Health Organization for all people living with HIV, including pregnant women. Surveillance data from Botswana reported a 3-fold increased incidence of neural tube defects (NTDs) in women taking DTG from conception. Other studies have not detected this association although none were sufficiently powered. Concern over the clinical significance of the association between DTG and NTDs has created uncertainty in the treatment of women with HIV globally. Data from animal DTG fetotoxicity studies in our lab support the Botswana findings and suggest that DTG at a dose yielding clinically relevant plasma levels (1x-DTG) is associated with a modest but significantly increased risk of a variety of congenital defects including NTDs. Unexpectedly, we observe fewer fetal anomalies (similar to control) in mice treated with a 5x-DTG dose. Maternal folate deficiency, pre-gestational diabetes, and pre- pregnancy obesity are established NTD risk factors. Excessive weight gain is reported in persons initiating or switching to DTG. Excess weight gain and the underlying metabolic alterations could be a mechanism by which DTG increases NTD rates. We will use well-controlled animal studies and clinical samples from Botswana to perform an unbiased omics approach to identify potential pathways through which DTG may induce fetal defects. In addition, we will take a targeted approach, involving murine in vivo and embryo culture models, to investigate the impact of DTG on folate, glucose, and oxidative stress as potential pathways leading to DTG- associated fetal defects. In Aim 1 we will identify and validate maternal and fetal metabolic factors modified by DTG exposure that increase or reduce the risk for NTDs and other fetal anomalies by: (1) performing a metabolomics screen of pregnant mice and their fetuses treated with DTG-based ART (1x-DTG and 5x-DTG) or control for indicators of fetal anomaly risk or protection; (2) screening for metabolic differences in pregnant women with HIV on DTG-based ART from conception, compared with those on efavirenz-based ART from conception, and with HIV-negative pregnant women; (3) validating candidate metabolites using murine in vivo and embryo culture systems. In Aim 2 we will perform experimental studies to determine the mechanism(s) by which DTG increased the risk of fetal anomalies. We will examine the impact of DTG on: (1) folate metabolism; (2) glucose homeostasis; (3) oxidative stress and mitochondrial function, using murine in vivo and embryo culture systems. We will leverage resources of an existing prospective pregnancy study in Botswana (NIH/NICHD K23 HD088230-01A1 – PI: Dr. Zash), and take advantage of Dr. Serghides' robust mouse pregnancy model of ART safety, Drs. Copp and Greene's renowned expertise in models of NTDs, and the omics expertise of Metabolon, Dr. Jao, and Dr. Coburn to successfully complete this project. Our study will be the first to examine associations between DTG and metabolic alterations as a mechanism underlying DTG- associated congenital defects.

项目摘要/摘要：世界卫生组织推荐基于Dolutegravir（DTG）的抗逆转录病毒疗法（ART）所有患有艾滋病毒的人，包括孕妇。博茨瓦纳的监视数据报告了3倍从概念中摄取DTG的妇女中神经管缺陷（NTD）的增加。其他研究也有尽管没有足够的动力，但未发现这种关联。对临床意义的关注 DTG和NTD之间的关联在全球艾滋病毒妇女的治疗中造成了不确定性。我们实验室中动物DTG胎儿毒性研究的数据支持博茨瓦纳的发现，并建议DTG在A 剂量产生临床相关的血浆水平（1x-DTG）与适中有关，但显着增加包括NTD在内的各种先天性缺陷的风险。出乎意料的是，我们观察到更少的胎儿异常（相似）在用5倍-DTG剂量治疗的小鼠中控制）。母体叶酸缺乏，妊娠前糖尿病和前怀孕肥胖是NTD危险因素。在开始的人或切换到DTG。体重增加过多，基本的代谢改变可能是一种机制 DTG提高了NTD率。我们将使用来自博茨瓦纳到的良好控制动物研究和临床样本执行公正的OMICS方法来识别DTG可能影响胎儿的潜在途径缺陷。此外，我们将采用一种有针对性的方法，涉及体内和胚胎培养模型的鼠，研究DTG对叶酸，葡萄糖和氧化应激的影响，作为导致DTG-的潜在途径相关的胎儿缺陷。在AIM 1中，我们将确定并验证由MATER和胎儿代谢因素修改的因素 DTG暴露会增加或降低NTD和其他胎儿异常的风险：（1）执行A 用DTG ART（1X-DTG和5X-DTG）处理的怀孕小鼠及其胎儿的代谢组学筛查控制胎儿异常风险或保护指标；（2）筛查怀孕的代谢差异与来自efavirenz的艺术相比构思和HIV阴性孕妇；（3）使用体内鼠验证候选代谢物和胚胎培养系统。在AIM 2中，我们将进行实验研究，以确定由 DTG增加了胎儿异常的风险。我们将研究DTG对：（1）叶酸代谢的影响；（2）葡萄糖稳态；（3）使用鼠体内和胚胎的氧化应激和线粒体功能培养系统。我们将利用博茨瓦纳现有的预期怀孕研究的资源（NIH/NICHD K23 HD088230-01A1 - PI：ZASH博士），并利用Serghides博士的强大鼠标艺术安全的怀孕模型，博士。 COPP和Greene在NTD模型中著名的专业知识以及OMICS Metabolon，Jao博士和Coburn博士的专业知识成功完成了该项目。我们的研究将是首先检查DTG与代谢改变之间的关联作为DTG-的基础机制相关的先天性缺陷。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model.

DOI：
10.1016/j.ebiom.2023.104762
发表时间：
2023-09
期刊：
EBIOMEDICINE
影响因子：
11.1
作者：
Mohan, Haneesha;Nguyen, Jessica;Mackenzie, Ben;Yee, Audrey;Laurette, Evelyn Yukino;Sanghvi, Tanvi;Tejada, Oscar;Dontsova, Valeriya;Leung, Kit-Yi;Goddard, Cameron;De Young, Taylor;Sled, John G.;Greene, Nicholas D. E.;Copp, Andrew J.;Serghides, Lena
通讯作者：
Serghides, Lena

Interaction between dolutegravir and folate transporters and receptor in human and rodent placenta.

DOI：
10.1016/j.ebiom.2021.103771
发表时间：
2022-01
期刊：
EBioMedicine
影响因子：
11.1
作者：
Gilmore JC;Hoque MT;Dai W;Mohan H;Dunk C;Serghides L;Bendayan R
通讯作者：
Bendayan R

In response to the Letter to the Editor by Romach et al. re our publication "Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels".

DOI：
10.1016/j.ebiom.2021.103334
发表时间：
2021-04
期刊：
EBioMedicine
影响因子：
11.1
作者：
Mohan H;Guzman Lenis M;Laurette EY;Tejada O;Sanghvi T;Leung KY;Cahill LS;Sled JG;Delgado-Olguín P;Greene NDE;Copp AJ;Serghides L
通讯作者：
Serghides L

A Pharmacokinetic Dose-Optimization Study of Cabotegravir and Bictegravir in a Mouse Pregnancy Model.

DOI：
10.3390/pharmaceutics14091761
发表时间：
2022-08-24
期刊：
PHARMACEUTICS
影响因子：
5.4
作者：
Mohan, Haneesha;Atkinson, Kieran;Watson, Birgit;Brumme, Chanson J.;Serghides, Lena
通讯作者：
Serghides, Lena

Dolutegravir and rat whole embryo culture.