Combining Bacteriophage-Mediated Decolonization with Microbial Engraftment to Foster Sustained Supragingival Microbiome Modulation for Enhanced Anti-Cariogenic Therapy

将噬菌体介导的去定植与微生物植入相结合，促进龈上微生物组的持续调节，以增强抗龋齿治疗

• 批准号: 10307172
• 负责人: Michael Sandor Koeris
• 金额: $ 1.1万
• 依托单位: VULCAN BIOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2021-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307172
• 关键词: Abscess; Adherence; Adolescent; Adult; Affect; Awareness; Bacteria; Bacteriophages; Biological; Caries prevention; Cessation of life; Child; Chronic Disease; Communities; Dental; Dental Enamel; Dental caries; Development; Dietary Sugars; Engineering; Engraftment; Etiology; Eukaryotic Cell; Fluorides; Fostering; Human; Lactobacillus; Lytic; Measures; Mediating; Methods; Nutrient; Oral; Pain; Pathogenesis; Population; Prevalence; Probiotics; Productivity; Quality of life; Research; Resistance; Role; Sepsis; Streptococcus mutans; Technology; Therapeutic; Virulent; Virus; arm; base; comorbidity; dental agent; dental biofilm; member; microbial; microbial community; microbiome; oral microbial community; oral microbiome; pathogenic bacteria; prebiotics; prevent; small molecule; synthetic biology

Vulcan Biologics plans to harness the power of synthetic biology to enable persistent and stable modulation of the oral microbiome for the prevention of dental caries. Caries are characterized by the acidification and degradation of tooth enamel when dietary sugars come into contact with dental biofilms (plaque). Affecting an estimated 42% of children, 59% of adolescents, and 92% of adults in the U.S., dental caries is the most prevalent chronic disease in humans. Caries can be accompanied by serious comorbidities and complications, including pain, abscesses, dental sepsis, and even death. Caries contribute to diminished quality of life and account for an estimated $5.4 billion in lost productivity each year. Despite U.S. spending in excess of $124 billion each year, current methods to prevent caries, including brushing/flossing and fluoride applications, have done little to reduce the overall prevalence of caries in the population in the last decade. Thus, more effective measures to prevent dental caries remain a critical unmet need. The last two decades have brought an increasing awareness of the role of the oral microbiome in dental caries pathogenesis, revealing that caries development and progression are accompanied by changes in the proportions of particular bacterial species. Streptococcus mutans is a naturally occurring member of the oral microbiota and the principal etiological agent of dental decay in humans. While a few small molecules capable of selectively killing S. mutans have been identified, their effects are likely to be short-lived. As an alternative, Vulcan Biologics proposes a tripartite approach for the persistent and stable reprogramming of the oral microbiome to reduce or eliminate the prevalence of S. mutans. This approach is based on combining the application of bacteriophages— —with viruses that exclusively target bacteria but do not affect eukaryotic cells selected bacteria that should provide a probiotic effect and nutrients (prebiotics) that are specific to the protective probiotic bacteria. In detail, this three-pronged, combined-arms approach involves: i) the use of virulent bacteriophages to target the specific niche within the oral microbiome that should be decolonized for the target, in this case S. mutans, ii) administration of an engineered or evolved replacement protective probiotic, e.g. Lactobacillus spp., to be engrafted into the oral niche, and iii) provisioning of a prebiotic or combination of prebiotics that uniquely benefit the colonizing strains to promote adherence and long-term engraftment. This decolonization/recolonization (Decon-Recon) strategy has the potential to succeed where previous attempts to modulate the microbiome have failed: overcoming the resistance of established microbial communities to the permanent engraftment of newcomers.

Vulcan Biologics 计划利用合成生物学的力量来实现持久和稳定的 调节口腔微生物群以预防龋齿的特点是。 当饮食中的糖与牙釉质接触时，牙釉质会酸化和降解。 牙齿生物膜（牙菌斑）估计影响 42% 的儿童、59% 的青少年和 92% 的人。 在美国成年人中，龋齿是人类最常见的慢性疾病。 伴有严重的合并症和并发症，包括疼痛、脓肿、牙科 脓毒症，甚至死亡会导致生活质量下降，并导致死亡。 尽管美国每年的支出超过 1240 亿美元，但每年的生产力损失却高达 54 亿美元。 今年，目前预防龋齿的方法，包括刷牙/使用牙线和氟化物应用， 过去十年来，在降低人群中龋齿的总体患病率方面几乎没有采取任何措施。 因此，更有效的预防龋齿的措施仍然是一个未得到满足的关键需求。 过去二十年，人们越来越认识到口腔微生物组在健康方面的作用。 揭示龋齿的发病机制，揭示龋齿的发生、进展是相伴的 通过改变特定细菌种类的比例，变形链球菌是一种自然的细菌。 口腔微生物群的存在成员和蛀牙的主要病因 虽然一些能够选择性杀死变形链球菌的小分子已被研究出来。 作为替代方案，Vulcan Biologics 提出了一种替代方案。 三方方法对口腔微生物组进行持久和稳定的重编程，以减少 或消除变形链球菌的流行。该方法基于结合应用。 噬菌体——与 专门针对细菌但不影响真核细胞的病毒 选定的应提供益生菌作用的细菌和特定的营养物质（益生元） 详细来说，这种三管齐下的联合方法。 涉及： i) 使用剧毒噬菌体来靶向口腔内的特定生态位 应针对目标进行去定植的微生物组，在本例中为变形链球菌，ii) 施用 工程或进化的替代性保护性益生菌，例如乳酸菌 植入口腔生态位，以及 iii) 提供益生元或益生元组合， 对定植菌株有独特的促进粘附和长期定植的作用。 非殖民化/再殖民化（Decon-Recon）战略有可能在以下领域取得成功： 之前调节微生物组的尝试都失败了：克服微生物的抵抗力 建立微生物群落以永久植入新来者。