Aptamer Microbicide Development Program (MDP)

描述(申请人提供)：在没有艾滋病毒疫苗和避孕套使用不一致的情况下，艾滋病大流行的势头继续增强。性接触是感染的主要途径，妇女受到的影响不成比例。在这种情况下，迫切需要开发新的女性控制的预防技术，包括杀微生物剂。理想情况下，杀微生物剂应能预防HIV-1和其他常见的性传播感染(STI)，如单纯疱疹病毒(HSV)和人乳头瘤病毒(HPV)。这些产品应该是安全、有效、可接受和廉价的。它们也应该能够用于阴道和直肠间隔。这笔赠款的目的是使用适体技术来生产具有抗艾滋病毒-1、单纯疱疹病毒-2和人乳头瘤病毒16活性的单个候选杀微生物剂。之所以选择HSV-2和HPV-16，是因为已知它们会增加艾滋病毒-1传播的风险(HSV-2)或与宫颈癌和肛门癌的发展(HPV-16)有关。适配子是通过体外进化过程从大量复杂的组合文库中衍生出来的核酸配体，通常被称为指数富集型配体的系统进化(SELEX)。适配子具有与重要的蛋白质靶标结合的能力，具有高亲和力和生物学后果，包括降低病毒感染性。在这项提议中，我们将检验下列假设：(1)通过体外细胞攻击实验，可以开发出单独的抗病毒适配子，从而显示出对HIV-1、HSV-2和HPV-16的有效性；(2)在宫颈-阴道、肠道和肛门组织外植体系统中可以证明抗病毒的有效性，并且当单独或联合给药时，抗病毒适配子的作用不会改变；(3)当在挑战实验中使用多种病毒时，联合使用抗病毒适配子可以防止外植体系统的感染。这项研究将由牛津大学(适配子发现)、RNA-Tec(适配子优化和放大)和UCLA(组织外植体研究)的一个财团进行。

DESCRIPTION (provided by applicant): In the absence of a HIV vaccine, and with inconsistent use of condoms, the AIDS pandemic continues to gather momentum. Sexual exposure is the primary route of infection with women becoming disproportionately affected. In this setting, there is an urgent need to develop new female controlled prevention technologies including microbicides. Ideally, microbicides should provide protection against HIV-1 and other common sexually transmitted infections (STIs) such as herpes simplex virus (HSV) and human papilloma virus (HPV). These products should be safe, effective, acceptable and cheap to manufacture. They should also be able to be used in both the vaginal and rectal compartments. The purpose of this grant is to use aptamer technology to generate individual candidate microbicides with activity against HIV-1, HSV-2 and HPV-16. HSV-2 and HPV-16 have been chosen because they are known to increase the risk of HIV-1 transmission (HSV-2) or are linked to the development of cervical and anal cancer (HPV-16). Aptamers are nucleic acid ligands derived from massively complex combinatorial libraries by a process of in vitro evolution, often referred to as systematic evolution of ligands by exponential enrichment (SELEX). Aptamers have the capacity to bind to important protein targets with high affinity and biological consequences including reducing viral infectivity. In this proposal we will test the following hypotheses: (1) Individual antiviral aptamers can be developed that demonstrate efficacy against HIV-1, HSV-2, and HPV-16 using in-vitro cell challenge experiments, (2) Antiviral efficacy can be demonstrated in cervico-vaginal, intestinal, and anal tissue explant systems and is not altered when aptamers are given as single agents or in combination, and (3) Combinations of antiviral aptamers can prevent infection of explant systems when multiple viruses are used in challenge experiments. The study will be undertaken by a consortium based at Oxford University (aptamer discovery), RNA-Tec (aptamer optimization and scale-up) and UCLA (tissue explant studies).