Lactobacilli as a Delivery Vehicle for Microbicides

乳酸杆菌作为杀菌剂的输送载体

• 批准号: 6805402
• 负责人: Qiang Xu
• 金额: $ 109.09万
• 依托单位: OSEL, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805402
• 关键词: HIV infections; Lactobacillus; antiAIDS agent; biotechnology; biotherapeutic agent; communicable disease control; communicable disease transmission; cooperative study; drug design /synthesis /production; drug vehicle; topical drug application

DESCRIPTION (provided by applicant): In response to PAR-03-137, we are submitting a program proposal to design and develop a series of potent and highly selective protein-based topical microbicides. The unifying theme of the application is the use of non-pathogenic mucosal bacteria, lactobacilli, to deliver these proteins to mucosal surfaces within the vagina and rectum. The administration of genetically modified vaginal isolates of lactobacilli, expressing protein microbicides, is anticipated to prevent access or entry of HIV into host cells and tissues, thereby reducing infection. The three highly integrated projects include 1) an approach to design and develop lactobacilli expressing CD4 variants capable of a multivalent high-avidity interaction with HIV, as a means of trapping and inactivating HIV particles within the mucosa, 2) a program to produce lactobacilli expressing RANTES analogs that function as chemokine receptor antagonists and block HIV entry into cells and tissues of the host and 3) a project centered on lactobacillus-directed delivery of anti-ICAM derivatives as a novel means of inhibiting cell-associated mucosal transmission of HIV. These projects all will be supported by central core facilities, including administrative, microbiology, and primate safety study cores. Importantly, the three unique projects highlighted in this application have already completed key "proof-of-concept" studies that set the stage for the advanced research and development activities outlined in this application. Furthermore, all three approaches target conserved functional mechanisms used by HIV to achieve a productive infection of its host. As such, these approaches are less likely to be circumvented by the high mutability of viral proteins, an important property of HIV that has impaired the development of effective preventative vaccines.

描述（由申请人提供）：为了响应 PAR-03-137，我们正在提交一份计划提案，旨在设计和开发一系列有效且高度选择性的基于蛋白质的局部杀菌剂。该应用的统一主题是使用非致病性粘膜细菌（乳酸杆菌）将这些蛋白质递送到阴道和直肠内的粘膜表面。施用表达蛋白质杀菌剂的转基因乳杆菌阴道分离株预计可防止艾滋病毒进入宿主细胞和组织，从而减少感染。这三个高度集成的项目包括 1) 一种设计和开发表达 CD4 变体的乳杆菌的方法，该变体能够与 HIV 进行多价高亲和力相互作用，作为在粘膜内捕获和灭活 HIV 颗粒的一种手段，2) 一个生产表达 CD4 的乳杆菌的程序RANTES 类似物作为趋化因子受体拮抗剂并阻止 HIV 进入宿主细胞和组织，3) 一个以乳酸菌定向递送抗 ICAM 衍生物为中心的项目，作为一种新型药物抑制 HIV 细胞相关粘膜传播的方法。这些项目都将得到中央核心设施的支持，包括行政、微生物学和灵长类动物安全研究核心。重要的是，本申请中强调的三个独特项目已经完成了关键的“概念验证”研究，为本申请中概述的高级研发活动奠定了基础。此外，所有三种方法都针对艾滋病毒用于实现宿主有效感染的保守功能机制。因此，这些方法不太可能被病毒蛋白的高突变性所规避，而病毒蛋白的高突变性是艾滋病毒的一个重要特性，阻碍了有效预防性疫苗的开发。