Plausible Causative Mechanism for Dolutegravir Developmental Toxicity

多替拉韦发育毒性的可能致病机制

基本信息

批准号：
10671073
负责人：
Robert M Cabrera
金额：
$ 67.46万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671073
关键词：
Acquired Immunodeficiency Syndrome Adult Adverse event Affect Animal Model Animals Apoptosis Binding Biochemical Biological Assay Birth Blood Botswana Buffers Calcium Carbon Cations Cell Line Cell model Cells Child Clinical Cohort Studies Competitive Binding Conceptions Congenital Abnormality Data Development Developmental Process Developmental Toxicant Diet Dose Embryo Embryonic Development Embryonic Induction Erythrocytes Exposure to FOLR1 gene Fetal Tissues Folic Acid Folic Acid Antagonists HIV HIV Seropositivity Healthcare Human Immunofluorescence Immunologic Impairment In Vitro Incidence Infant Integrase Inhibitors Intervention Iron Label Link Manufacturer Measures Membrane Modeling Molecular and Cellular Biology Mothers Mus Neural Tube Closure Neural Tube Defects Neural Tube Development Neurologic Outcome Pathology Patients Pattern Pharmaceutical Preparations Physiological Placenta Plasma Pregnancy Pregnant Women Prevalence Proliferating Regimen Reporting Reproduction Research Research Proposals Risk Risk Factors Role Serum Specificity System Teratogens Testing Time Tissues Toxic effect Woman Work Zebrafish animal tissue antagonist antiretroviral therapy chelation child bearing clinically relevant developmental toxicity dosage embryo tissue experience folate-binding protein mouse model novel offspring placental mammal prenatal exposure programs rapid testing response surveillance study therapeutically effective trophoblast uptake

项目摘要

Abstract The human immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG) has emerged as a leading core agent. The DTG/Tivicay manufacturer reports (09/2018) that animal reproduction studies showed no evidence of adverse developmental outcomes, but an ongoing observational human cohort study in Botswana initially reported a 9-fold increase for neural tube defect (NTD) risk in offspring from mothers receiving DTG. With increased exposed births but no additional NTDs, a 6-fold increase for NTD risk in infants with early gestational exposure to DTG still remains. Recent concerns about teratogenicity have led to caution for DTG-based regimen use in women of child-bearing potential. We hypothesized that if DTG is teratogenic, then embryonic exposure to DTG will result in changes to one or more essential developmental processes, affecting functional mechanisms that have direct roles in neurulation and NTDs. We report a mechanism of action (MOA) for DTG teratogenicity and demonstrate specificity of this MOA in an animal model by rescue of DTG-induced developmental toxicity. Competitive binding data indicates DTG is a partial antagonist of folate receptors at clinically relevant concentrations. Data from the zebrafish model show developmental toxicity due to early embryonic exposure to DTG. Specificity of DTG developmental toxicity is demonstrated via rescue of DTG-induced developmental toxicity by supplemental folate. Folates and folate receptor are established modifiers of risk for NTDs, and these data indicate DTG is an antagonist of folate receptor and developmental toxicant at clinically relevant concentrations.

抽象的人类免疫缺陷病毒（HIV）整合酶抑制剂越来越多地用于治疗抗逆转录病毒疗法（ART）和多替拉韦（DTG）已成为领先的核心药物。这 DTG/Tivicay 制造商报告 (09/2018) 动物繁殖研究表明没有证据表明不利的发育结果，但博茨瓦纳正在进行的一项观察性人类队列研究最初报告称，母亲接受治疗后，后代患神经管缺陷 (NTD) 的风险增加了 9 倍 DTG。随着暴露出生人数的增加，但没有额外的 NTD，婴儿患 NTD 的风险增加了 6 倍妊娠早期暴露于 DTG 的情况仍然存在。最近对致畸性的担忧导致育龄妇女应谨慎使用基于 DTG 的治疗方案。我们假设如果 DTG 是致畸的，那么胚胎暴露于 DTG 将导致一种或多种必需物质发生变化发育过程，影响在神经形成和发育中具有直接作用的功能机制被忽视的热带病。我们报告了 DTG 致畸性的作用机制 (MOA)，并证明了其特异性这种 MOA 在动物模型中通过挽救 DTG 诱导的发育毒性。竞争性结合数据表明 DTG 在临床相关浓度下是叶酸受体的部分拮抗剂。数据斑马鱼模型显示出由于早期胚胎暴露于 DTG 导致的发育毒性。 DTG 发育毒性的特异性通过拯救 DTG 诱导的发育来证明。补充叶酸的毒性。叶酸和叶酸受体是 NTD 风险的既定调节剂，这些数据表明DTG在临床上是叶酸受体的拮抗剂和发育毒物相关浓度。