Mucosal tissue explants as surrogates for in vivo efficacy of microbicides

粘膜组织外植体作为杀菌剂体内功效的替代物

基本信息

批准号：
8288004
负责人：
Carolina Herrera
金额：
$ 17.23万
依托单位：
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288004
关键词：
Address Affect Animal Model Animals Anti-Retroviral Agents Antiretroviral drug resistance Antiviral Agents Biopsy Cervical Chimera organism Clinical Trials Colorectal Development Dose Drug Kinetics Drug resistance Future Goals HIV HIV Infections Histocompatibility Testing Human Individual Infection Laboratories Macaca mulatta Measurement Measures Methods Mission Modeling Monkeys Mucous Membrane Mutation Nature Pharmaceutical Preparations Pharmacodynamics Pharmacology Point Mutation Reverse Transcriptase Inhibitors Route SIV Series Sexual Transmission Tenofovir Testing Tissue Model Tissues Vagina Validation Vertebral column Viral Viral Physiology Work base economic value fitness improved in vivo inhibitor/antagonist innovation iterative design microbicide model development nonhuman primate novel pinacolyl methylphosphonic acid prevent programs rectal research study resistance mutation response simian human immunodeficiency virus tool

项目摘要

DESCRIPTION (provided by applicant): The HIV microbicide field is dependent upon testing in non-human primates (NHPs) as the only relevant model to study infection. However, the predictive accuracy of NHP studies of efficacy in humans has not been validated and as such the economic value is unknown. Hence, refinement of this model and development of a novel correlate of efficacy in humans that will reduce the potential use of NHPs is key for the global progress of microbicides and specifically of the Microbicide Innovation Program's mission. This proposal addresses these issues by testing the hypothesis that ex vivo tissue explant cultures can provide a potential surrogate of in vivo efficacy through measurement of intra-tissular drug pharmacology and ex vivo infection/protection. This will be investigated using combined expertise in modeling mucosal tissue infection and measurement of antiretroviral (ARV) drug pharmacokinetics and pharmacodynamics in tissue. The proposal will focus on a reverse transcriptase inhibitor, PMPA (tenofovir), and an entry inhibitor, maraviroc, used alone and in combination as candidate microbicides. In the R21 component of the proposal we will demonstrate the robustness of our ex vivo explant models for analysis of pharmacological parameters and ex vivo infection independently of the origin (human or NHP) and the type of mucosa (cervicovaginal or colorectal). This will be investigated through two Specific Aims: 1) to define ex vivo pharmacological dose-responses (pharmacokinetics and pharmacodynamics) in human and rhesus macaque mucosal tissue explants; 2) to define whether the viral backbone affects pharmacological correlates of activity. The next step of our proposal in the R33 component will involve validation of the model as a surrogate for prediction of in vivo efficacy of ARV drugs as vaginal and colorectal microbicides. Here the two Specific Aims are: 3) to assess whether activity of drugs titrated in vivo can be predicted with ex vivo challenge models: 4) to correlate ex vivo and in vivo protection and drug dosing in NHPs. The iterative design of the overall proposal will allow us to assess correlates between intra-tissular pharmacological dosing and efficacy at all levels: tissue type, origin of tissue, route of dosing and challenge, and nature of experiment (ex vivo, in vivo). These correlates will define "conversion factors" of microbicides efficacy between the NHP model and in humans, which will be key for the rational development of existing and future candidate microbicides.

描述（由申请人提供）：HIV杀菌剂领域取决于非人类灵长类动物（NHP）作为研究感染的唯一相关模型。但是，NHP对人类疗效的研究的预测准确性尚未得到验证，因此经济价值尚不清楚。因此，对这种模型的改进以及人类有效性的新型相关性的发展，这将减少NHP的潜在使用是微生物剂，特别是Microbicide Innovation Program的使命的全球进步的关键。该建议通过检验以下假设来解决这些问题，即离体组织外植体培养物可以通过测量血管内药物学和体内感染/保护来提供体内疗效的潜在替代。这将在对粘膜组织感染和抗逆转录病毒（ARV）药物药代动力学和组织中的药效学的测量中进行建模方面进行研究。该提案将集中于逆转录酶抑制剂PMPA（Tenofovir）和入口抑制剂Maraviroc，单独使用并组合用作候选菌心。在该提案的R21组成部分中，我们将证明我们的体内外植体模型的鲁棒性，用于分析药理学参数和离体感染，独立于起源（人类或NHP）以及粘膜的类型（子宫颈癌或结肠直肠）。这将通过两个具体目的进行研究：1）定义人和恒河猴猕猴粘膜组织外植体中的体内药理剂量回答（药代动力学和药效学）； 2）定义病毒主链是否影响活性的药理相关性。我们在R33组件中提案的下一步将涉及该模型的验证，作为预测ARV药物为阴道和结直肠菌皮的体内疗效的替代物。这里的两个具体目的是：3）评估是否可以通过体内挑战模型来预测体内滴定的药物的活性：4）与NHP中的体内和体内保护和药物剂量相关联。总体建议的迭代设计将使我们能够评估各个级别的血动内药理学剂量和功效之间的相关性：组织类型，组织的起源，剂量和挑战的途径以及实验的性质（Ex vivo，vivo，invivo）。这些相关性将定义NHP模型和人类中微生物疗效的“转化因子”，这将是现有和未来候选杀菌剂合理发展的关键。