A Novel IL-35 Expressing Probiotic Platform for Inducing Allergen Specific Tolerance

用于诱导过敏原特异性耐受的新型 IL-35 表达益生菌平台

• 批准号: 10450744
• 负责人: Neil A Fanger
• 金额: $ 97.95万
• 依托单位: VIRTICI, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450744
• 关键词: Acute; Allergens; Allergic; Americas; Antigens; Asthma; Autoimmune Diseases; Autoimmunity; Automobile Driving; Bacteria; Benchmarking; Blood Chemical Analysis; CCR6 gene; CD4 Positive T Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chromosomes; Clinic; Clinical; Collagen Arthritis; Colony-forming units; Country; Data Set; Dermatophagoides Antigens; Development; Disease; Dose; Event; Extrinsic asthma; FOXP3 gene; Freeze Drying; Genome; Genomics; Goals; Growth; Health; Hematology; Histopathology; House mice; Human; Hypersensitivity; Immune; Immune System Diseases; Immune Tolerance; Immunologics; Immunosuppressive Agents; Incidence; Individual; Inflammation; Interleukin-10; Intestines; Lactococcus lactis; Measures; Mediating; Modeling; Monitor; Mus; Operon; Oral; Oral Administration; Patients; Persons; Pharmacology and Toxicology; Phase; Physiological; Probiotics; Prophylactic treatment; Protocols documentation; Pyroglyphidae; Reaction; Regulatory T-Lymphocyte; Research; Respiratory Signs and Symptoms; Severity of illness; Small Business Innovation Research Grant; Source; Steroids; Stimulus; Symptoms; T memory cell; Therapeutic; Toxic effect; Toxicology; Treatment Protocols; airborne allergen; asthma exacerbation; asthmatic; base; cell bank; clinical candidate; desensitization; dust mite allergy; environmental allergen; genome sequencing; irritation; mouse model; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; pyroglyphid; side effect; symptom treatment; therapeutic target; trafficking; whole genome

Project Summary Our goal is to develop VTC-L35 as a novel tolerance-inducing probiotic platform for the treatment of asthma. According to the CDC, more than 25 million people in America suffer from asthma. Globally, nearly 350 million people suffer from asthma, with more than 300,000 annual deaths attributed to the disease (CDC). Because asthma is fundamentally a disease of immune dysregulation, many current asthma treatments are immunosuppressive agents, including steroids. While these are effective at managing asthma symptoms for many patients, the effects are temporary, have considerable side-effects, and require constant administration. Asthma “attacks” are triggered by a variety of environmental stimuli, the most common of which are aeroallergens. Desensitization protocols exist but are intensive and impractical given the fact that most asthmatics have multiple, often unidentified, allergens. As a result, new therapies are desperately needed to tolerize asthmatics against their own “personalized” allergens. Recently, our project team developed a novel Lactococcus lactis (L. lactis) research strain expressing IL-35 (VTC-L35)26. Oral administration of VTC-L35 effectively reduced the incidence and disease severity of inflammation in both prophylactic and treatment protocols in the mouse model of collagen-induced arthritis model (CIA). VTC-L35 induced CCR6+ and CCR6− CD39+ CD4+ Treg cells in CIA mice. Inquiry into their induction revealed that both CCR6+ and CCR6− Foxp3+/or− CD39+ CD4+ T cells act as the source of the IL-10 induced by VTC-L35. We believe that oral administration of VTC-L35 in the presence of an individual’s environmental allergens will induce antigen-specific regulatory cells and restore tolerance to an individual’s allergens, reversing asthma symptoms. To validate our approach, we plan to demonstrate that oral administration of VTC-L35 in the presence of low amounts of house dust mite (HDM) antigens prevents allergic and airway symptoms in a mouse model. Subsequently, we will develop and validate a genome-integrated clinical strain. The high-level aims of this Fast-track SBIR application are to 1) demonstrate that our VTC-L35 research strain induces tolerance in a mouse HDM allergy model with no detectable short-term toxicity; 2) develop and characterize a VTC-L35 clinical candidate expressing human IL-35 from a genome-integrated operon; and 3) develop non- GLP and GLP preclinical datasets to support VTC-L35 IND approval. Completion of this proposal will establish a novel IL-35-expressing probiotic platform that can be applied to treat asthma, allergies broadly and even an array of autoimmune diseases.

项目摘要 我们的目标是开发VTC-L35作为一种新型耐受性的益生菌平台，用于治疗哮喘。 据疾病预防控制中心（CDC）称，美国有超过2500万人患有哮喘。在全球范围内，将近3.5亿 人们患有哮喘，每年30万人死亡归因于该疾病（CDC）。 由于哮喘从根本上是一种免疫失调的疾病，因此许多当前的哮喘治疗是 免疫抑制剂，包括类固醇。虽然这些有效地管理 许多患者（暂时性）具有相当大的副作用，需要持续给药。 哮喘的“攻击”是由各种环境刺激触发的，其中最常见的是 空气过敏剂。存在脱敏协议，但鉴于大多数 哮喘患者具有多种，通常不明的过敏原。结果，迫切需要新的疗法 对自己的“个性化”过敏原耐受哮喘患者。 最近，我们的项目团队开发了一种新型的乳酸乳酸菌（L.乳酸乳酸）研究菌株，表达IL-35 （VTC-L35）26。口服VTC-L35有效地降低了事件和疾病严重程度 胶原蛋白诱导关节炎小鼠模型中预防性和治疗方案的炎症 模型（CIA）。 VTC-L35在CIA小鼠中诱导CCR6+和CCR6- CD39+ CD4+ Treg细胞。询问他们 诱导表明CCR6+和CCR6- FOXP3+/OR- CD39+ CD4+ T细胞充当了 VTC-L35诱导的IL-10。 我们认为，在个人环境过敏原的存在下，VTC-L35的口服给药 诱导抗原特异性调节细胞并恢复对个体过敏原的耐受性，逆转哮喘 症状。为了验证我们的方法，我们计划证明在 存在低量的房屋灰尘螨（HDM）抗原可防止过敏和气道症状 鼠标模型。随后，我们将开发和验证基因组集成的临床菌株。高级 此快速轨道SBIR应用的目的是1）证明我们的VTC-L35研究菌株会引起 小鼠HDM过敏模型中的耐受性，没有可检测到的短期毒性； 2）发展和表征 VTC-L35临床候选者从基因组集成的歌剧中表达人IL-35； 3）发展非 GLP和GLP临床前数据集支持VTC-L35 IND批准。 该提案的完成将建立一个新颖的表达IL-35益生菌平台，可以应用于 治疗哮喘，广泛的过敏甚至一系列自身免疫性疾病。