LASER ART for PreP

PreP 激光艺术

• 批准号: 10391567
• 负责人: Benson Edagwa
• 金额: $ 69.83万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-12 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391567
• 关键词: AIDS prevention; Adherence; Adverse event; Animal Model; Animals; Anti-Retroviral Agents; Area; Arts; Biological Availability; Biological Models; CD4 Positive T Lymphocytes; Cell Count; Cells; Characteristics; Chemicals; Chemistry; Conscious; Creativeness; Data; Data Set; Development; Dose; Drug Design; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Esterification; Esters; Female; Formulation; Freeze Drying; Frequencies; Funding; Future; Goals; HIV Infections; HIV-1; Half-Life; Health; Healthcare; Hematology; Histology; Human; Hydrolysis; Hydrophobicity; Immunologics; Individual; Industry; Infection; Injections; Interdisciplinary Study; Intramuscular Injections; Investigational New Drug Application; Laboratories; Lasers; Lead; Letters; Life; Link; Lipids; Macaca mulatta; Measures; Medicine; Metabolic; Modification; Mus; Names; Nebraska; Nucleotides; Pathway interactions; Penetrance; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacy (field); Plants; Plasma; Powder dose form; Preclinical Testing; Prevention; Process; Prodrugs; Production; Publications; Publishing; Quality Control; Rattus; Reproducibility; Research; Research Design; Research Personnel; Research Project Grants; Rest; Reticuloendothelial System; Rodent; Safety; Savings; Scheme; Science; Scientist; Sex Differences; Site; Substance Use Disorder; Suspensions; Tenofovir; Test Result; Testing; Tissues; Toxicology; Treatment Protocols; United States Food and Drug Administration; Universities; Validation; Viral Load result; Viral reservoir; Virus; Virus Replication; Work; antiretroviral therapy; base; bench to bedside; biomaterial compatibility; chemical synthesis; cost; design; disease transmission; drug modification; emtricitabine; expectation; high risk; humanized mouse; improved; innovation; interdisciplinary approach; large scale production; lipophilicity; macrophage; male; multidisciplinary; nanocrystal; nanoformulation; nanomedicine; novel; novel strategies; nucleoside monophosphate; particle; pharmacokinetics and pharmacodynamics; pill; pre-exposure prophylaxis; prevent; product development; scale up; surfactant; tool; translational study; uptake; viral resistance; viral transmission

Abstract This project contains a highly collaborative investigative team with interdisciplinary expertise with significant potential impact for HIV/AIDS prevention. The proposal includes pharmacologic, virologic, animal and product development studies designed to halt disease transmission through novel long-acting (LA) antiretrovirals. These are named LA slow effective release antiretroviral therapies (LASER ART) designed to facilitate HIV-1 prevention by intense bench to the clinic translational studies. Innovative interdisciplinary approaches contain a detailed research plan, extensive preliminary and broadly published supportive data. Creativity and innovativeness are offered placed at higher risk than a conventional research project. The work builds on the development of parenteral nanoformulations of chemically modified antiretroviral drugs designed to improve adherence. The drugs are currently offered once/day in pill form but will be converted to up to once a year administration. Support from expert pharmacologists and pharmaceutical scientists with University researchers are operative. The drugs include dolutegravir (DTG), emtricitabine (FTC) and tenofovir (TFV) created to extend their apparent drug half-life, efficacy and abilities to target viral reservoirs. They are, in measure, DTG and FTC and TFV prodrug + nucleotide (ProTides) designated “N” for nanoformulation, “M” for esterification and “P” for ProTides. The created NPFTC and NPTFV and NM2DTG demonstrate sustained plasma and tissue drug concentrations of > 90% inhibitory concentration from months to a year. Based on encouraging results, we seek funds to facilitate large scale development that would facilitate future human studies. The final formulations would be characterized by sustained prodrug hydrolysis with reduced injection volumes. The pathway forward follows established partnership with the Clinton Health Access Initiative and oversight by ViiV Healthcare and Gilead Sciences. The overarching goal is safety, reproducibility and “scale-up” that follows US Food and Drug Administration-approved current good manufacturing practices (cGMP). The specific aims are each supported by extensive published data sets forged through the multidisciplinary research. Creation and characterization focus on prodrug formulations, toxicology, and pharmacokinetics profiles follow a safe developmental action plan. The work is facilitated by a fully operational cGMP facility and rhesus macaque validations. The lead formulation will be developed with our CHAI partners. We posit that the creation of LASER ART DTG or FTC and TFV will have a profound impact on HIV prevention.

抽象的 该项目包含一个高度协作的调查团队，具有跨学科的专业知识，具有重要的 对预防艾滋病毒/艾滋病的潜在影响。该提案包括药理学、病毒学、动物和产品 旨在通过新型长效（LA）抗逆转录病毒药物阻止疾病传播的开发研究。 这些被命名为 LA 缓慢有效释放抗逆转录病毒疗法 (LASER ART)，旨在促进 HIV-1 通过大量的临床转化研究进行预防。创新的跨学科方法包括 详细的研究计划、广泛的初步和广泛发表的支持数据。创造力和 与传统研究项目相比，创新的风险更高。这项工作建立在 开发化学修饰的抗逆转录病毒药物的肠外纳米制剂，旨在改善 坚持。这些药物目前以药丸形式每天提供一次，但将改为每年一次 行政。专家药理学家和药物科学家以及大学研究人员的支持 正在运作。这些药物包括多替拉韦（DTG）、恩曲他滨（FTC）和替诺福韦（TFV），旨在延长 它们的明显药物半衰期、功效和针对病毒库的能力。从某种程度上来说，它们是 DTG 和 FTC TFV 前药 + 核苷酸 (ProTides)，纳米制剂指定为“N”，酯化指定为“M”，酯化指定为“P” 普罗泰德斯。创建的 NPFTC 和 NPTFV 以及 NM2DTG 展示了持续的血浆和组织药物 数月至一年的浓度 > 90% 抑制浓度。基于令人鼓舞的结果，我们 寻求资金以促进大规模开发，从而促进未来的人类研究。决赛 制剂的特点是持续前药水解并减少注射量。这 前进的道路遵循与克林顿健康访问计划建立的合作伙伴关系以及 ViiV 的监督 医疗保健和吉利德科学。总体目标是安全性、可重复性和效仿美国的“规模化” 美国食品和药物管理局批准的现行良好生产规范 (cGMP)。具体目标是 每一项都得到了通过多学科研究形成的广泛发表的数据集的支持。创造与 表征重点关注前药配方、毒理学和药代动力学特征，遵循安全标准 发展行动计划。全面运作的 cGMP 设施和恒河猴促进了这项工作 验证。主要配方将与我们的 CHAI 合作伙伴一起开发。我们假设创建 激光艺术 DTG 或 FTC 和 TFV 将对艾滋病毒预防产生深远影响。