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：
10461938
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/10461938
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 Dosage Forms Dose Embryo Embryonic Development 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 Name 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 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 base chelation child bearing clinically relevant developmental toxicity 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抗逆转录病毒疗法（ART）和DoluteGravir（DTG）已成为领先的核心药物。这 DTG/Tivicay制造商报告（09/2018），动物繁殖研究没有证据表明不利的发展结果，但在博茨瓦纳进行了一项持续的观察性人类同伙研究最初报告了接受母亲的后代的神经管缺陷（NTD）风险增加9倍 DTG。随着暴露出生的增加，但没有额外的NTD，婴儿的NTD风险增加了6倍随着妊娠暴露于DTG，仍然存在。最近对致畸性的担忧已导致谨慎在具有育儿潜力的女性中基于DTG的方案使用。我们假设如果DTG 是致病性的，然后暴露于DTG的胚胎会导致一个或多个必需品的变化发育过程，影响在神经和神经和 NTD。我们报告了一种作用机理（MOA），以表明DTG致病性，并证明了特异性通过营救DTG诱导的发育毒性，该MOA在动物模型中。竞争性约束力数据表明DTG是临床相关浓度下叶酸受体的部分拮抗剂。数据从斑马鱼模型中显示出由于早期胚胎暴露于DTG而引起的发育毒性。 DTG发育毒性的特异性通过营救DTG诱导的发育证明了补充叶酸的毒性。叶叶和叶酸受体是对NTD的风险修饰符建立的，这些数据表明DTG是叶酸受体的拮抗剂，在临床上是毒性的毒物相关浓度。