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， 调节口腔微生物组以预防龋齿。龋齿的特点是 当食物中的糖接触到 牙齿生物膜（菌斑）。估计影响42%的儿童，59%的青少年和92%的 美国的成年人，龋齿是人类最普遍的慢性疾病。龋齿可能是 伴有严重的合并症和并发症，包括疼痛、疼痛、牙科 败血症甚至死亡龋齿导致生活质量下降， 每年损失54亿美元的生产力。尽管美国每年花费超过1240亿美元， 目前预防龋齿的方法，包括刷牙/牙线和氟化物应用， 在过去的十年里，在降低人口中龋齿的总体患病率方面收效甚微。 因此，更有效的预防龋齿措施仍然是一个尚未满足的关键需求。 在过去的二十年里，人们越来越认识到口腔微生物组在口腔疾病中的作用。 龋病的发病机制，揭示龋病的发展和进展是伴随着 通过特定细菌种类比例的变化。变形链球菌是一种 口腔微生物的发生成员和龋齿的主要病原体， 人类而一些能够选择性杀死S.变异人已经 如果没有确定，其影响可能是短暂的。作为替代方案，Vulcan Biologics提出了一种 持久和稳定地重新编程口腔微生物组以减少 或消除S的流行。变异人这种方法的基础是结合应用 噬菌体 专门针对细菌但不影响真核细胞的病毒 选择的细菌，应该提供益生菌的效果和营养素（益生元），是特定的 保护性益生菌。详细地说，这种三管齐下的联合武器方法 涉及：i）使用毒性噬菌体靶向口腔内的特定小生境， 微生物组，应该是去殖民化的目标，在这种情况下，S。变异，二）管理 工程化或进化的替代保护性益生菌，例如乳杆菌属，是 植入口腔生态位，和iii）提供益生元或益生元组合， 独特地有益于定殖菌株以促进粘附和长期植入。这 非殖民化/非殖民化（非殖民化-侦察）战略有可能取得成功， 以前调节微生物组的尝试都失败了： 已建立的微生物群落对新来者的永久植入。