LASER ART for PreP

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，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。 这些疗法被命名为LA缓释抗逆转录病毒疗法(激光ART)，旨在促进HIV-1 预防由高强度工作台到临床的转化研究。创新的跨学科方法包括 详细的研究计划，广泛的初步和广泛公布的支持性数据。创造力和 创新被置于比传统研究项目更高的风险中。这项工作是建立在 化学修饰抗逆转录病毒药物肠外纳米制剂的开发 坚持不懈。这些药物目前以药丸的形式每天提供一次，但将转换为最多一年一次 行政管理。来自专业药理学家和药剂学家与大学研究人员的支持 都在运作中。这些药物包括多洛替格列韦(DTG)、恩曲他滨(FTC)和替诺福韦(TFV) 它们的表观药物半衰期、有效性和针对病毒库的能力。就衡量标准而言，它们是DTG和FTC 和TFV前药+核苷酸(ProTdes)，纳米制剂指定为“N”，酯化指定为“M”，而纳米制剂指定为“P” 前潮。创建的NPFTC和NPTFV和NM2DTG展示了持续的血浆和组织药物 从几个月到一年的&gt；90%的抑制浓度。基于令人鼓舞的结果，我们 寻求资金，以促进大规模发展，从而促进未来的人类研究。决赛 制剂的特点将是持续的前体药物水解和减少的注射量。这个 路径前进遵循与克林顿健康获取倡议建立的伙伴关系和欢跃的监督 医疗保健和吉利德科学公司。首要目标是安全性、可重复性和跟随美国的“扩大规模”。 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 每一项研究都得到了通过多学科研究形成的广泛出版的数据集的支持。创作和 前药配方、毒理学和药代动力学方面的特征描述遵循安全的 发展行动计划。这项工作是由一个全面运作的cGMP设施和恒河猴推动的 验证。铅配方将与我们的Chai合作伙伴一起开发。我们假设， 激光抗逆转录病毒治疗DTG或FTC和TFV将对艾滋病毒预防产生深远影响。

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.