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: 10662445
• 负责人: Neil A Fanger
• 金额: $ 97.88万
• 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/10662445
• 关键词: Acute; Allergens; Allergic; Antigens; Asthma; Autoimmune Diseases; Autoimmunity; Automobile Driving; Bacteria; Benchmarking; Blood Chemical Analysis; CCR6 gene; CD4 Positive T Lymphocytes; Cells; 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; Marketing; Measures; Mediating; Modeling; Monitor; Mus; Operon; Oral; Oral Administration; Patients; Persons; Pharmacology and Toxicology; Phase; Physiological; Probiotics; 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; cell bank; clinical candidate; desensitization; dust mite allergy; environmental allergen; genome sequencing; irritation; manufacture; mouse model; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; prophylactic; 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作为治疗哮喘的新型耐受诱导益生菌平台。 根据CDC的数据，美国有超过2500万人患有哮喘。全球近3.5亿 人们患有哮喘，每年有超过30万人死于这种疾病（CDC）。 因为哮喘从根本上说是一种免疫失调的疾病，所以目前的许多哮喘治疗方法都是 免疫抑制剂，包括类固醇。虽然这些药物对控制哮喘症状有效， 对于许多患者，这种作用是暂时的，具有相当大的副作用，并且需要持续给药。 哮喘“发作”是由各种环境刺激引发的，其中最常见的是 空气过敏原脱敏协议是存在的，但考虑到大多数 哮喘患者具有多种通常未鉴定的过敏原。因此，迫切需要新的治疗方法， 使哮喘患者能够耐受他们自己的“个性化”过敏原。 最近，我们的项目组开发了一种新的乳酸乳球菌（Lactococcus lactis，L。表达IL-35的乳酸菌研究菌株 （VTC-L35）26.口服给予VTC-L35有效地降低了以下疾病的发生率和疾病严重程度： 在胶原诱导的关节炎的小鼠模型中的预防和治疗方案中的炎症 模型（CIA）。VTC-L35在CIA小鼠中诱导CCR 6+和CCR 6 − CD 39 + CD 4 + Treg细胞。调查他们的 诱导表明，CCR 6+和CCR 6 − Foxp 3 +/或− CD 39 + CD 4 + T细胞都是免疫调节的来源。 由VTC-L35诱导的IL-10。 我们相信，在存在个体的环境过敏原的情况下口服施用VTC-L35将 诱导抗原特异性调节细胞并恢复对个体过敏原的耐受性，从而逆转哮喘 症状为了验证我们的方法，我们计划证明口服给予VTC-L35， 低量屋尘螨（HDM）抗原的存在可预防过敏性和气道症状， 小鼠模型随后，我们将开发和验证基因组整合的临床菌株。高级别 这项快速跟踪SBIR应用的目的是：1）证明我们的VTC-L35研究菌株诱导 在小鼠HDM过敏模型中的耐受性，没有可检测的短期毒性; 2）开发和表征 从基因组整合操纵子表达人IL-35的VTC-L35临床候选物;和3）开发非- 支持VTC-L35 IND批准的GLP和GLP临床前数据集。 该提案的完成将建立一种新的表达IL-35的益生菌平台， 广泛治疗哮喘、过敏症，甚至一系列自身免疫性疾病。