LASER ART for PreP

PreP 激光艺术

• 批准号: 10259156
• 负责人: Benson Edagwa
• 金额: $ 71.02万
• 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/10259156
• 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; Gap Junctions; 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; virology

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.

摘要 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， 对艾滋病毒/艾滋病预防的潜在影响。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 预防由紧张的工作台向临床转化的研究。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性数据。创新和 与传统的研究项目相比，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胃外纳米制剂， 坚持。这些药物目前以药丸形式每天提供一次，但将转换为每年一次 局药理学专家和制药科学家与大学研究人员的支持 是有效的。这些药物包括度鲁特韦（DTG），恩曲他滨（FTC）和替诺福韦（TFV），用于延长 它们的表观药物半衰期、功效和靶向病毒储库的能力。它们分别是DTG和FTC 和TFV前药+核苷酸（ProTides），对于纳米制剂指定为“N”，对于酯化指定为“M”，并且对于纳米制剂指定为“P”。 ProTides.创建的NPFTC和NPTFV和NM 2DTG证明了持续的血浆和组织药物 > 90%抑制浓度，持续数月至一年。基于令人鼓舞的结果，我们 寻求资金，以促进大规模的发展，这将有助于未来的人类研究。最终 制剂的特征在于持续的前药水解和减少的注射体积。的 前进的道路遵循与克林顿健康获取倡议建立的伙伴关系和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“规模扩大”， 美国食品药品监督管理局批准的现行药品生产质量管理规范（cGMP）。具体目标是 每一个都得到了通过多学科研究形成的广泛的已发表数据集的支持。创建和 表征侧重于前药制剂，毒理学和药代动力学特征遵循安全的 发展行动计划。这项工作是由一个全面运作的cGMP设施和恒河猴促进 验证。将与我们的CHAI合作伙伴一起开发主要配方。我们认为， 激光ART DTG或FTC和TFV将对艾滋病毒预防产生深远影响。