Development of a Live Topical Microbicide for Women

描述（由申请人提供）：Osel，Inc.是一家生物制药公司，专门从事细菌疗法的开发。该公司的主导产品LACTIN-V是一种天然存在的卷曲乳杆菌人类阴道分离物，目前正在进行II期临床试验，以检查其预防复发性尿路感染和细菌性阴道病（BV）的安全性和有效性。这两种感染的特征是产生过氧化氢（H2 O2）的乳酸杆菌的耗尽，这些乳酸杆菌通常保护阴道免受机会性病原体的感染。流行病学研究还表明，阴道乳酸杆菌的损失与异性间HIV-1传播和其他性传播感染的风险增加有关。LACTIN-V代表了一种生态学方法，通过用定殖的、产生H2 O2的乳酸杆菌菌株重建保护性阴道植物群来预防阴道感染。 第二代乳杆菌产品，以及本提案的主题，是一种产生H2 O2的人阴道分离乳杆菌。jensenii，其已被遗传增强以组成性地分泌高水平的有效HIV进入抑制剂cyanovirin-N（CV-N）。这种活的、自我更新的杀微生物剂可以提供一种有效但廉价的手段来提供基于蛋白质的杀微生物剂，并解决了对女性控制的方法的迫切需要，以阻断HIV-1的异性传播。 在这个R21的建议，我们将选择一个杀微生物剂的发展候选人，从一个生物工程菌株的集合，含有优化的CV-N表达盒稳定整合到L。詹氏染色体我们将采用中国恒河猴（Macaca mulatta）模型，该模型可提供L. Jensenii进行临床前安全性和有效性研究，包括原位CV-N表达、免疫毒性和抗粘膜病毒传播的有效性。此外，我们建议评估有关转基因生物药物开发的潜在监管问题，并优化该产品的配方和生产工艺。在与FDA进行IND前咨询后，我们将提交探索性IND申请，然后在提案的R33阶段启动两项探索性0期研究，以评估重组L。Jensenii菌株对健康女性志愿者给予抗生素后的安全性、耐受性、先天生殖道免疫因子、阴道定植和生物体清除的影响。

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.