Highly Acidifying Intravaginal Rings with Lactobacillus Probiotics to Treat Bacterial Vaginosis

含乳酸菌益生菌的高度酸化阴道环可治疗细菌性阴道病

• 批准号: 10699458
• 负责人: Keiichiro Kushiro
• 金额: $ 30.65万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699458
• 关键词: Adherence; Animal Model; Animals; Antibiotics; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Blinded; Buffers; Cells; Chlamydia; Clindamycin; Combined Modality Therapy; Data; Development; Dose; Ensure; Environment; Epidemic; Female; Formulation; Foundations; Freeze Drying; Frequencies; Gardnerella vaginalis; Gelatin; Glycogen; Goals; Gonorrhea; Growth; HIV; Human Papillomavirus; Lactic acid; Lactobacillus; Lead; Macaca; Macaca nemestrina; Marketing; Measurement; Methods; Metronidazole; Microbe; Mucous body substance; Odors; Organism; Phase; Physiological; Placebos; Population; Powder dose form; Predisposition; Premature Birth; Primates; Probiotics; Production; Public Health; Recurrence; Reproducibility; Resistance; Risk; Safety; Sampling; Sexually Transmitted Diseases; Small Business Innovation Research Grant; Smell Perception; Swab; Testing; Time; Toxic effect; Toxicology; Trichomonas Infections; Vagina; Vaginal Cream; Vaginal Gel; Vaginal Ring; Woman; Work; adverse birth outcomes; adverse pregnancy outcome; bacterial community; bacterial resistance; capsule; cervicovaginal; combinatorial; cost; density; design; dysbiosis; effective therapy; experience; in vivo; low and middle-income countries; manufacture; manufacturing cost; microbicide; microbiome; microbiome composition; microbiota; novel; pathogen; prevent; sexually active; vaginal microbiome; vaginal microbiota

Abstract Millions of women in the U.S. suffer from bacterial vaginosis (BV), a vaginal condition initiated by marked overgrowth of polymicrobial bacterial populations that can suppress protective lactobacilli. Healthy lactobacilli (LB), in particular lactobacillus crispatus, secrete lactic acid (LA) that acidifies the vagina and acts as a broad- spectrum microbicide that protects against many types of pathogens and also can suppress polymicrobial communities of BV species that produce little or no lactic acid. We do not know what initiates episodes of BV, but we do know that BV strongly increases risks of many sexually transmitted infections including HIV, and increases risks of premature births. At any given time, about 1/3 of sexually active women in the U.S. and world-wide have BV. Antibiotics can provide transient relief from the foul-smelling discharge caused by BV but they do not prevent BV from recurring (sometimes at a frequency up to twice a month). There is no product on the market that can provide sustained protection against BV. We and others have shown that LA can potently inactivate many types of BV-associated bacteria as well as many types of pathogens that cause sexually transmitted infections. Since LA is abundant in the healthy vaginas of women with protective LB, particularly in women with Lactobacillus crispatus (L.c), it has the potential to serve as a safe, non-antibiotics microbicide. We have recently determined the rate at which healthy lactobacilli continuously produce LA and hence for the first time know the rate at which lactic acid should be supplied to the vagina to treat and prevent BV. This in turn guided our development of an LA-releasing intravaginal ring (LA-IVR) that can provide sustained release of LA over 30 days at the rate needed to treat and prevent BV while not suppressing healthy LB. We have further synthesized macaque-sized LA-IVR that, when inserted into the macaque vagina, could lower the vaginal pH substantially without causing any toxicity. Building on our promising work, we seek to combine this LA-IVR with a L.c probiotics in the form of capsules containing lyophilized L.c powder, in order to achieve a synergistic alteration to the vaginal environment to best promote the re-establishment of a L.c-dominated microflora. In Aim 1, we plan to identify a lead strain of L.c based on growth rates as well as acidification rates and extent, then formulate them into lyophilized powders and load into capsules. In Aim 2, we will fabricate the macaque-sized LA-IVRs, and test whether combinatorial treatment of sustained LA release by this IVR with the L.c probiotics capsules can suppress BV-like bacterial species in pigtail macaques. Successful demonstration of safety and efficacy in this highly relevant large animal model would support the design requirements of an optimal LB-LA-IVR that Mucommune can advance through IND-enabling activities. The simplicity of our LA-IVR and L.c loaded capsule designs ensures both ease of production and likely very low manufacturing costs of the eventual product, which in turn should maximize potential public health impact and commercial viability of the product both in the U.S. and in low and middle income countries worldwide.

摘要 美国数以百万计的女性患有细菌性阴道病(BV)，这是一种由Mark引发的阴道疾病 可以抑制保护性乳酸菌的多菌群过度生长。健康乳酸菌 (Lb)，特别是皱纹乳杆菌，分泌乳酸(LA)，使阴道酸化，并作为广泛的- 光谱杀菌剂，可抵抗多种病原体，也可抑制多种微生物 产乳酸很少或不产乳酸的BV物种群落。我们不知道是什么引发了BV的发作， 但我们确实知道，BV强烈增加了许多性传播感染的风险，包括艾滋病毒，以及 会增加早产的风险。在任何给定的时间，大约三分之一的美国和 全世界都有BV。抗生素可以暂时缓解BV引起的恶臭排放，但 它们不能防止BV复发(有时频率高达每月两次)。上面没有任何产品 能够对BV提供持续保护的市场。我们和其他人已经证明，洛杉矶可以有效地 灭活多种类型的BV相关细菌以及导致性行为的多种病原体 传播感染。由于LA在具有保护性LB的妇女的健康阴道中大量存在，尤其是在 对于患有卷曲乳杆菌(L.C)的妇女来说，它有可能成为一种安全的、非抗生素的杀菌剂。 我们最近测定了健康的乳酸菌持续产生乳酸的速率，因此对于 第一次知道治疗和预防BV的乳酸应该以多快的速度进入阴道。此入站 转而指导我们开发了一种释放LA的阴道内环(LA-IVR)，它可以提供持续的 以治疗和预防BV所需的速度在30天内释放LA，同时不抑制健康的LB。我们 进一步合成了猕猴大小的LA-IVR，当插入猕猴阴道时，可以降低 阴道酸碱度基本不会造成任何毒性。在我们前景看好的工作的基础上，我们寻求将这一点结合起来 LA-IVR与L.C益生菌以胶囊形式含有冻干L.C粉末，以实现 协同改变阴道环境，最大限度地促进以L.C为主的阴道重建 微生物区系。在目标1中，我们计划根据生长速度和酸化速度确定L.C的一个主要菌株。 然后将它们制成冻干粉并装入胶囊中。在目标2中，我们将制造 猕猴大小的LA-IVR，并测试这种IVR与 L.C益生菌胶囊对小尾猴体内类BV菌种有抑制作用。成功的演示 这种高度相关的大型动物模型的安全性和有效性将支持 最优的LB-LA-IVR，Mu公社可以通过支持IND的活动来推进。我们LA-IVR的简单性 和L.C装载胶囊的设计确保了生产的简便性和可能非常低的制造成本 最终产品，这反过来又应该最大化潜在的公共健康影响和商业可行性 产品在美国和全球中低收入国家均有销售。