Neutralization of HIV by Modified Lactobacilli

修饰乳杆菌中和 HIV

• 批准号: 6626089
• 负责人: PATRICK MARTIN
• 金额: $ 75.83万
• 依托单位: OSEL, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626089
• 关键词: AIDS education /prevention; CD4 molecule; Lactobacillus; biotechnology; cell line; communicable disease transmission; dosage forms; electroporation; female; gene delivery system; genetic manipulation; human immunodeficiency virus; mucosal immunity; surface antigens; technology /technique development; vagina; virus cytopathogenic effect; virus protein

DESCRIPTION: (Provided by Applicant) The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervicovaginal mucosa serving as the main site of viral entry in women. Realizing that the vaginal mucosa is colonized with large numbers of non-pathogenic lactobacilli, we propose an innovative approach toward blocking transmission of HIV that involves genetically modifying clinical isolates of lactobacillus to express proteins that bind and inactivate HIV prior to transmission to host tissues. We have been able to demonstrate that vaginal lactobacilli can be engineered to secrete a truncated form of the CD4 molecule (containing domains 1-2) that is capable of binding to the HIV virus and reducing the infectious titer in vitro. In so doing, we have provided the first demonstration of the expression of a complex disulfide-bonded, biologically active mammalian protein in lactobacillus. We now intend to transition this program into its early development phases to enable future clinical testing. Specifically, we propose the following aims: 1) express several other HIV binding proteins in L. jensenii and from efficacy data, select the optimal protein to carry forward; 2) integrate the ligand expression constructs into the chromosome of L. jensenii, using either selected inducible (e.g. alkaline shock) or strong, constitutive promoters (e.g. PcbsA) to drive expression from a single copy; and 3) develop pilot scale manufacturing process, including formulation, of these engineered lactobacilli. The successful completion of these proposed Phase II studies will position us for entry into clinical trials, where this novel ViroShield approach will meet its most rigorous evaluation. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：（由申请人提供）艾滋病毒传播的主要模式 全球通过异性恋接触，与宫颈阴道粘膜服务 作为妇女病毒进入的主要地点。意识到阴道粘膜是 用大量非致病性乳酸杆菌殖民，我们提出 阻止艾滋病毒传播的创新方法 基因修饰乳杆菌的临床分离株以表达蛋白质 在传播到宿主组织之前，这种结合并灭活HIV。我们有 能够证明可以设计阴道乳酸乳杆菌以分泌 CD4分子的截断形式（包含域1-2），能够 与HIV病毒结合并减少体外感染性滴度。在这样 这样做，我们提供了复杂表达的第一个演示 乳酸杆菌中的二硫键键合，生物活性的哺乳动物蛋白。我们 现在打算将该计划转变为早期发展阶段 启用未来的临床测试。具体来说，我们提出以下目的：1） 表达L. jensenii中的其他几种HIV结合蛋白，并发出功效 数据，选择以携带的最佳蛋白质； 2）整合配体 使用任一选定 可诱导（例如碱性休克）或​​强构启动子（例如PCBSA） 从单个副本中驱动表达； 3）开发飞行员量表 这些工程乳酸杆菌的制造过程，包括配方。 这些拟议的第二阶段研究的成功完成将使我们定位 对于进入临床试验，这种新颖的Viroshield方法将满足 它最严格的评估。 拟议的商业应用程序：不可用