Use of Modified Lactobacilli to Block HSV Transmission

描述（申请人提供）：生殖器疱疹是由单纯疱疹病毒2型（HSV-2）通过性传播引起的，虽然由单纯疱疹病毒1型（HSV-1）引起的病例比例较小，但正在增加。生殖器疱疹感染与一系列临床症状有关，包括许多严重的 自然 生殖器疱疹是一种常见的生殖器疱疹病毒，它的传播途径是生殖器疱疹的传播途径。 我们正在开发一种新的方法来阻止HSV在女性中的传播。 这种称为MucoCept HSV的方法涉及对乳酸杆菌的人阴道分离株进行遗传修饰，乳酸杆菌是在健康女性阴道粘膜微生物群中发现的常见细菌。这些细菌正在被修饰以产生诱饵HSV受体，其具有在HSV被传递到宿主细胞和组织之前在粘膜层内结合、捕获和包裹HSV的能力。 因此，这代表了一种新的和潜在的强大的方法，以防止HSV的传播。 如本申请中所概述的，我们提出遗传修饰阴道来源的乳杆菌以表达HSV受体HveC，其共价连接到细菌的细胞壁，或分泌到周围的生物膜基质中。 这种方法将使用我们小组已经用于在这些相同的乳酸杆菌菌株中成功表达其他异源哺乳动物蛋白的技术。 我们建议随后证明表达的HveC蛋白中和敏感培养细胞系的HSV感染性的能力。 如果成功实现，这些研究将使我们能够进行II期研究，以评估这些修饰细菌减少HSV体内传播的功效，以及优化HveC蛋白的稳定表达，作为该产品临床开发计划的主要组成部分。

DESCRIPTION (provided by applicant): Genital herpes infection is extremely common throughout the world and continues to increase in incidence, Genital herpes is caused by the sexual transmission of herpes simplex virus type 2 (HSV-2), although a smaller, but increasing, percentage of cases are caused by herpes simplex virus type 1 (HSV-1) Genital herpes infection is associated with a range of clinical sequlae, including many that are serious in nature. The lack of effective measures to impede HSV transmission underlies the widespread escalation of the genital herpes epidemic. We are developing a novel approach to block HSV transmission in women. This approach, termed MucoCept HSV, involves genetic modification of human vaginal isolates of lactobacilli, the common bacterium found within the vaginal mucosal microflora of healthy women. These bacteria are being modified to produce a decoy HSV receptor that has the capacity to bind, trap, and inactivate HSV within the mucosal layer before it is transmitted to host cell and tissues. As such, this represents a novel and potentially powerful approach to prevent the transmission of HSV. As outlined in the present application, we propose to genetically modify vaginal-derived lactobacilli to express the HSV receptor, HveC, either covalently attached to the cell wall of the bacterium, or secreted into the surrounding biofilm matrix. This approach will use technology that has already been used by our group for the successful expression of other heterologous mammalian proteins in these same strains of lactobacilli. We propose to subsequently demonstrate the capacity of the expressed HveC protein to neutralize HSV infectivity of susceptible cultured cell lines. If achieved successfully, these studies will position us to undertake Phase II studies to assess the efficacy of these modified bacteria to reduce HSV transmission in vivo, as well as to optimize stable expression of the HveC protein as a major component of the clinical development plan for this product.