Synthetic mRNA-mediated reversible immunocontraception

合成 mRNA 介导的可逆免疫避孕

• 批准号: 10474919
• 负责人: Deborah J Anderson
• 金额: $ 68.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474919
• 关键词: Synthetic; mRNA; mediated; reversible; immunocontraception

Project summary Currently 72% of women who practice contraception use hormonal methods, but there is frequent dissatisfaction with these methods, due to quality of life and safety concerns. Therefore, there is a clear need for new approaches to non-hormonal female contraceptives that are easy to use, woman-applied, and have a controllable duration of action. Reversible immunocontraception offers a non-hormonal solution, where anti- sperm antibodies are introduced into the female reproductive tract (FRT) and inhibit sperm function. This approach, though, has a number of challenges including: discovery of a specific and effective monoclonal antibody (mAb) against a human sperm antigen, and a safe and reliable method for introduction of mAbs that is temporally and spatially controllable. For this grant application, reproductive biology expertise and a molecular toolbox has been brought together to overcome these challenges. An anti-sperm antibody has been identified with well-characterized mechanisms of action that impact fertility, and an innovative method has been identified to deliver the antibody to the FRT. Here a synthetic mRNA-based approach is proposed to deliver a sperm agglutinating and mucus trapping antibody to the FRT. To date, the ability to express high levels of antibody for over 28 days with a single administration of mRNA in the FRT of sheep has been demonstrated. Delivery is achieved through direct, rapid, aerosol exposure of the FRT epithelium to naked mRNA in water. Persistence of the antibody in secretions was achieved through the incorporation of a GPI-linker into the heavy chain of the antibody. This combination allows for rapid delivery and expression, and for controllable persistence of the protective mAb in secretions. In the R61 phase, the mechanism of delivery under relevant conditions will be optimized and explored; antibody design questions will also be addressed that will allow for tunable persistence of the antibody in mucus secretions. In the R33 phase, pharmacokinetic experiments will be performed in macaques, as well as continued antibody optimization. Last, sperm challenge experiments will be performed in vivo to demonstrate efficacy. The long-term goal is to develop a cost-effective mRNA-based approach for expressing anti-sperm antibodies in the FRT. The short-term goals are to optimize the approach, answer mechanistic questions, and demonstrate pre-clinical feasibility in the macaque model. If successful, a new paradigm for contraception will be demonstrated, one that can be combined with the co-expression of anti-STI antibodies, such as those against HIV and HSV-2.

项目摘要 目前，有72％的练习避孕妇女使用荷尔蒙方法，但经常不满意 通过这些方法，由于生活质量和安全问题。因此，明显需要新的 易于使用，女性申请并具有的非激素女性避孕药的方法 可控的行动持续时间。可逆免疫感应提供了一种非荷尔蒙溶液，其中抗 将精子抗体引入女性生殖道（FRT）并抑制精子功能。这 但是，方法有许多挑战，包括：发现特定有效的单克隆 针对人类精子抗原的抗体（mAb），以及一种引入mAb的安全可靠方法 在时间和空间上可控制。对于此赠款应用，生殖生物学专业知识和分子 工具箱已经聚集在一起以克服这些挑战。已经鉴定出一种抗植物抗体 具有影响生育能力的作用机制，已经确定了一种创新的方法 将抗体输送到FRT。在这里提出了一种基于合成mRNA的方法来提供精子 凝集和粘液捕获FRT的抗体。迄今为止，表达高水平的抗体的能力 在28天的时间里，已经证明了绵羊FRT中的一个mRNA管理。交货是 通过直接，快速的气溶胶暴露于水中的裸mrna。持久性 分泌物中的抗体是通过将GPI链链接到重链中实现的 抗体。这种组合允许快速传递和表达，以及可控的持久性 分泌物中的保护性mab。在R61阶段，相关条件下的交付机理将是 优化和探索；还将解决抗体设计问题，这将允许可调的持久性 粘液分泌中的抗体。在R33阶段，将在 猕猴以及持续的抗体优化。最后，精子挑战实验将在 体内证明功效。长期目标是开发一种基于经济有效的mRNA方法 在FRT中表达抗植物抗体。短期目标是优化方法，答案 机械性问题，并在猕猴模型中证明了临床前的可行性。如果成功，一个新的 将展示用于避孕的范式，可以与反Sti的共表达结合 抗体，例如抗艾滋病毒和HSV-2的抗体。