SBIR Phase I: Feasibility of a Vaginal Ring for Delivery of Protein Drugs in HIV Prevention

这个小型企业创新研究(SBIR)第一阶段项目涉及到美国和国外的一个主要健康问题。目前，还没有长期的阴道递送装置可用于递送蛋白质，例如正在研究的预防艾滋病毒的蛋白质。我们的长期目标是通过使用可与目前仅用于避孕的其他产品相媲美的阴道给药环来防止艾滋病毒在人与人之间传播。这项提议的目的是开发一种概念验证原型阴道环，以演示5P12 RANTES蛋白的剂量水平，该蛋白可以使用环装置递送。中心假设是，基于亲和力的相互作用可以用来控制5P12 RANTES从阴道环的释放，能够提供3周及更长时间内免受艾滋病毒感染的保护。这项工作将完成两个目标：1)制备基于亲和力的5P12 RANTES释放阴道环；2)通过人T细胞上的受体阻断试验评价5P12 RANTES的释放和体外生物学活性。这个项目的更广泛的影响/商业潜力是巨大的。人类免疫缺陷病毒(HIV)的传播是一种流行病，全球每年的感染率约为250万。正在实施的减缓这一流行病的战略之一是通过在性交前对生殖器粘膜使用局部预防性药物来防止人与人之间的传播。达匹韦林和替诺福韦等小分子药物目前正在进行临床前和临床试验，方法是使用阴道凝胶或插入阴道环。小分子药物的主要局限性是它们对病毒产生抗药性的敏感性。5P12 RANTES是一种被证明可以防止艾滋病毒进入的蛋白质，对耐药性具有显著的抵抗力，目前正在对局部阴道分娩进行研究。在证明了可行性后，我们相信有可能创造出一种组合阴道环，它将提供避孕或替代激素治疗，并防止艾滋病毒经阴道传播。该环的未来版本可以提供其他蛋白质疗法，如针对HPV的疫苗和疗法。

This Small Business Innovation Research (SBIR) Phase I project concerns a major health concern both here in the US and abroad. Currently, no long-term vaginal delivery device is available for the delivery of proteins such as are being investigated for HIV prevention. Our long-term goal is to prevent person-to-person HIV transmission through the use of a vaginal drug delivery ring comparable to other products currently used only for contraception. The objective of this proposal is to develop a proof-of-concept prototype vaginal ring made to demonstrate the dosage levels of the protein 5P12 RANTES, which can be delivered using a ring device. The central hypothesis is that affinity-based interactions can be used to control release of 5P12 RANTES from a vaginal ring, capable of offering protection from HIV infections for 3 weeks and beyond. This work will be accomplished in two aims:1) Fabrication of affinity-based 5P12 RANTES releasing vaginal ring; and 2) Evaluation of 5P12 RANTES release and biological activity in vitro using a receptor blocking assay on human T-cells. The broader impact/commercial potential of this project is tremendous. The spread of human immunodeficiency virus (HIV) is an epidemic with a global infection rate of around 2.5 million per year. One of the strategies being implemented to slow this epidemic is preventing person-to-person transmissions through the use of topical preventative agents applied to the genital mucosa before intercourse. Small molecule drugs such as dapivirine and tenofovir are currently in pre-clinical and clinical trials through application of vaginal gels or insertion of vaginal rings. The major limitation of small molecule drugs is their susceptibility to developing viral resistance. 5P12 RANTES is a protein shown to prevent HIV entry, is remarkably impervious to drug resistance, and is being investigated for local vaginal delivery. Upon proving feasibility, we believe it possible to create a combination vaginal ring that would provide contraceptive or replacement hormone therapy and also protect against vaginal HIV transmission. Future versions of the ring could deliver other protein therapeutics such as vaccines and therapies against HPV.