Development of an Orally Available Therapeutic for Neutralizing C. difficile Toxin B

感染艰难梭菌是引起腹泻的最常见且日益流行的原因。在……里面 在美国，艰难梭菌感染(CDI)的病例估计每年有50万例，并导致 估计有15,000到30,000人死亡。据认为，这些案件每年的成本超过48亿美元。 CDI继续导致不适、严重疾病，有时甚至死亡，尽管有几条可用的线路 治疗。目前的治疗方法包括抗生素、粪便移植和抗体。该抗体代表 通过中和艰难梭菌分泌的毒素而不是杀死细菌或细菌来治疗CDI的新方法 停止它们的生长。抗体的一个局限性是它需要通过注射而不是 口服药。 这项拟议研究的长期目标是开发一种结合和中和的新疗法 艰难梭菌产生的毒素，可以口服。这种治疗是基于一种新型的纳米CLAMP 一种在结构上与抗体相似的蛋白质，具有中和艰难梭菌毒素的潜力。然而，相比于 有了抗体，纳米CLAMP对消化酶的破坏性影响更具抵抗力。 对消化酶的抗药性可能使患者能够口服这种药物，避免痛苦的注射。 当前提案的目标是 1.筛选具有TcdB中和活性和可发展生物物理特性的含铅抗TcdB纳米CLAMP 属性。 2.评价肠溶胶囊中抗TcdB纳米CLAMP的剂量-暴露关系。 3.评价艰难梭菌急性感染和复发小鼠模型的疗效。

Infection with the bacterium C. difficile is the most common and increasingly prevalent cause of diarrhea. In the United States, cases of C. difficile infection (CDI) are estimated to number 500,000 annually and to result in an estimated 15,000 to 30,000 deaths. The cost of these cases is thought to exceed $4.8 billion annually. CDI continues to cause discomfort, serious illness and sometimes death despite several available lines of treatment. Current treatments include antibiotics, fecal transplant, and an antibody. The antibody represents a new approach to treating CDI by neutralizing toxins secreted by C. difficile rather than killing the bacteria or stopping their growth. One limitation of the antibody is that it needs to be delivered via an injection instead of taken by mouth. The long-term objective of the proposed research is to develop a new treatment that binds to and neutralize the toxins made by C. difficile and that may be taken by mouth. The treatment is based on a novel nanoCLAMP protein similar to antibodies in its structure and potential to neutralize C. difficile toxin. However, compared with antibodies, nanoCLAMPs are much more resistant to the destructive effect of digestive enzymes. Resistance to digestive enzymes may enable patients to take this medicine orally and avoid a painful injection. The objectives of the current proposal are to 1. Select lead anti-TcdB nanoCLAMPs with TcdB-neutralizing activity and developable biophysical properties. 2. Assess dose-exposure relationship for anti-TcdB nanoCLAMPs in enteric capsules. 3. Evaluate efficacy in acute and recurrence mouse models of C. difficile infection.