CNS-Derived Fetal Extracellular Vesicles for the Non-Invasive Diagnosis of Fetal CNS CMV Infection

CNS 来源的胎儿细胞外囊泡用于胎儿 CNS CMV 感染的无创诊断

基本信息

批准号：
10494139
负责人：
Laura Goetzl
金额：
$ 19.59万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10494139
关键词：
Affect Amniocentesis Antibodies Avidity BCL2 gene Biological Assay Biological Markers Birth Blood Blood - brain barrier anatomy Brain Cells Clinical Clinical Research Clinical Trials Counseling Data Detection Development Diagnosis Diagnostic Diagnostic Procedure Down Syndrome Drug Exposure Early identification Early treatment Effectiveness Evaluation Fetal Alcohol Syndrome Fetus First Pregnancy Trimester Funding Future Gestational Age Goals Immune response Immunoglobulin G Immunoglobulin M Infant Infection Inflammation Injury Matched Case-Control Study Maternal-Fetal Medicine Units Network Methods MicroRNAs Modeling Morbidity - disease rate Nervous System Trauma Neuraxis Neurologic Oral Outcome Parents Participant Placenta Predictive Value Pregnancy Primary Infection Proteins Public Health RNA marker Randomized Controlled Trials Sampling Second Pregnancy Trimester Serum Solid Sorting - Cell Movement Source Statistical Methods Statistical Models Surface TNFRSF1A gene Testing Therapeutic Trials Time Treatment Efficacy Vertical Disease Transmission Vesicle Virus Diseases Zika Virus accurate diagnosis base biobank congenital cytomegalovirus cost effective therapy exosome extracellular vesicles fetal fetal diagnosis fetal infection high reward high risk individualized medicine inflammatory marker long-term sequelae maternal serum microRNA biomarkers nanovesicle nonhuman primate noninvasive diagnosis novel perinatal injury pre-clinical predict clinical outcome prevent protein biomarkers randomized trial response screening seroconversion side effect synaptopodin targeted biomarker targeted treatment transcription factor treatment strategy ultrasound valacyclovir

项目摘要

Abstract Congenital cytomegalovirus (CMV) infection affects 1 in every 150 infants born in the US and is responsible for more long-term sequelae than either Down syndrome or Fetal Alcohol Syndrome. Despite this, there are no current diagnostic methods to individualize early treatment towards those pregnancies most likely to benefit nor existing methods to non-invasively follow treatment efficacy. Traditional methods of ultrasound and amniocentesis delay accurate diagnosis of congenital CMV until mid-gestation and may not detect fetal infection early enough to prevent developmental sequelae. Exosomes/extracellular vesicles are nanovesicles that package and protect proteins and freely cross the blood brain barrier and the placenta bearing specific and discriminatory surface markers from their cell of origin. Purification of vesicles from maternal blood using markers unique to the fetal brain non-invasive evaluation of neurologic morbidity from CMV infection. We hypothesize that nanovesicles can be isolated from maternal serum that contain both protein markers of neurologic injury and inflammation and miRNA markers specific to mechanisms of CMV. We further hypothesize that changes in exosome levels of these target biomarkers will correlate with clinical outcomes. Successful completion of the aims of this proposal has to potential to transform the clinical approach to congenital viral infections. Nanovesicles may be able to detect pre-clinical injury prior to the development of ultrasound findings – enabling earlier treatment prior to irreversible damage and therefore potentially increasing the effectiveness of any treatment strategy. The results would determine if novel assays developed under this proposal can be used to predict morbidity, clinically to counsel parents and in future therapeutic trials to follow response. The ultimate goal is to guide individualized treatment in affected pregnancies while limiting unnecessary drug exposure/side effects in unaffected pregnancies.

抽象的在美国，每 150 名出生的婴儿中就有 1 人患有先天性巨细胞病毒 (CMV) 感染，与唐氏综合症或胎儿酒精综合症相比，它会造成更多的长期后遗症。尽管如此，目前还没有针对个体化早期治疗的诊断方法。那些最有可能受益的怀孕或现有的非侵入性后续治疗方法传统的超声和羊膜穿刺术延迟了准确诊断。先天性 CMV 直到妊娠中期，可能无法及早发现胎儿感染以预防外泌体/细胞外囊泡是包装和发育的纳米囊泡。保护蛋白质并自由穿过血脑屏障和带有特定和从母体血液中纯化囊泡的来源细胞的区别性表面标记。使用胎儿大脑独特的标记物对 CMV 引起的神经系统发病率进行无创评估我们追求可以从含有的母体血清中分离出纳米囊泡。神经损伤和炎症的蛋白质标记物以及特定的 miRNA 标记物我们进一步发现这些目标的外泌体水平的变化。生物标志物将与临床结果的成功完成相关。该提案有可能改变先天性病毒感染的临床方法。纳米囊泡可能能够在超声波发展之前检测临床前损伤研究结果——在不可逆转的损害之前实现早期治疗，因此有可能提高任何治疗策略的有效性，结果将决定是否新颖。根据该提案开发的测定可用于预测发病率，并在临床上提供咨询父母和在未来的治疗试验中跟踪反应的最终目标是指导。对受影响的妊娠进行个体化治疗，同时限制不必要的药物暴露/副作用对未受影响的妊娠的影响。