Development of a Live Topical Microbicide for Women

描述(申请人提供)：OSEL，Inc.是一家专门从事细菌疗法开发的生物制药公司。该公司的主导产品LACTIN-V是一种自然产生的人类阴道乳杆菌分离物，目前正在进行第二阶段临床试验，以检验其在预防复发尿路感染和细菌性阴道病(BV)方面的安全性和有效性。这两种感染的特征都是产生过氧化氢(H2O2)的乳酸菌枯竭，这种乳酸菌通常可以保护阴道免受机会性病原体的感染。流行病学研究还表明，阴道乳酸菌的丧失与异性传播HIV-1和其他性传播感染的风险增加有关。LACTIN-V代表了一种预防阴道感染的生态方法，方法是用一种定植的、产生过氧化氢的乳杆菌菌株重建保护阴道的菌群。 第二代乳杆菌产品，也是这项提案的主题，是一种产生过氧化氢的詹森氏乳杆菌的人类阴道分离株，这种乳杆菌已经经过基因增强，能够结构性地分泌高水平的有效艾滋病毒进入抑制剂氰韦林-N(CV-N)。这种活的、自我更新的杀微生物剂可能提供一种有效但廉价的方法来提供基于蛋白质的杀微生物剂，并解决女性控制的方法的迫切需要，以阻止艾滋病毒-1的异性传播。 在这份R21提案中，我们将从一组生物工程菌株中选择一种杀菌剂开发候选菌株，这些生物工程菌株含有稳定整合到简氏乳杆菌染色体上的优化的CV-N表达盒。我们将使用中国恒河猴(Macaca Mulatta)模型进行临床前安全性和有效性研究，包括原位CV-N表达、免疫毒性和对抗粘膜病毒传播的有效性。此外，我们建议评估与转基因生物的药物开发有关的潜在监管问题，并优化该产品的配方和制造工艺。在与FDA进行IND前咨询后，我们将提交IND的探索性申请，然后在提案的R33阶段启动两项探索性的0期研究，以评估重组L.jensenii菌株对健康女性志愿者使用抗生素后的安全性、耐受性、先天性生殖道免疫因子、阴道定植和机体清除的影响。

DESCRIPTION (provided by applicant): Osel, Inc. is a biopharmaceutical company specializing in the development of bacterial therapeutics. The company's lead product, LACTIN-V, is a naturally occurring human vaginal isolate of Lactobacillus crispatus presently undergoing phase II clinical trials to examine its safety and efficacy in preventing recurrent urinary tract infections and bacterial vaginosis (BV). Both of these infections are characterized by a depletion of hydrogen peroxide (H2O2)-producing lactobacilli that normally protect the vagina from infection by opportunistic pathogens. Epidemiological studies also suggest that loss of vaginal lactobacilli is associated with an increased risk of heterosexual HIV-1 transmission and other sexually transmitted infections. LACTIN-V represents an ecological approach to prevent vaginal infections by re-establishing the protective vaginal flora with a colonizing, H2O2-producing Lactobacillus strain. A second-generation Lactobacillus product, and the topic of this proposal, is a human vaginal isolate of H2O2-producing L. jensenii that has been genetically enhanced to constitutively secrete high levels of the potent HIV entry inhibitor cyanovirin-N (CV-N). This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and addresses the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. In this R21 proposal, we will select a microbicide development candidate from a collection of bioengineered strains that contain optimized CV-N expression cassettes stably integrated into the L. jensenii chromosome. We will employ a Chinese rhesus macaque (Macaca mulatta) model that affords persistent vaginal colonization of L. jensenii to conduct preclinical safety and efficacy studies, including in situ CV-N expression, immunotoxicity, and efficacy against mucosal viral transmission. Furthermore, we propose to evaluate potential regulatory issues concerning the pharmaceutical development of a genetically modified organism, and to optimize the formulation and manufacturing processes for this product. Following a pre-IND consultation with the FDA, we will file an exploratory IND application and then initiate two exploratory phase 0 studies in the R33 phase of the proposal to assess the effects of the recombinant L. jensenii strain on safety, tolerability, innate genital tract immune factors, vaginal colonization, and clearance of the organism after antibiotic administration in healthy female volunteers.