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，我们提交了一项程序建议，以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局部菌壳。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传递到阴道和直肠内的粘膜表面。预计乳酸杆菌的遗传修饰的阴道分离株有望防止HIV进入或进入宿主细胞和组织，从而减少感染。这三个高度整合的项目包括1）一种设计和开发表达能够与HIV进行多价高持持续相互作用的CD4变体的乳酸杆菌的方法乳杆菌指导的抗ICAM衍生物作为抑制与细胞相关的HIV粘膜传播的一种新型手段。这些项目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，本应用程序中突出的三个独特项目已经完成了关键的“概念验证”研究，为该应用程序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HIV使用的保守功能机制，以实现其宿主的生产性感染。因此，这些方法不太可能被病毒蛋白的高突变性避免，这是HIV的重要特性，它损害了有效的预防疫苗的发展。