A Novel Probiotic for the Treatment of Sjogren's Syndrome

一种治疗干燥综合症的新型益生菌

• 批准号: 10253624
• 负责人: Gary Fanger
• 金额: $ 99.87万
• 依托单位: RISE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253624
• 关键词: Affect; Animal Model; Antigens; Arthritis; Artificial Saliva; Atrophic; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; Bacterial Infections; Biological Assay; Biological Markers; Biology; Cell Death; Cells; Clinical; Clinical Research; Clinical Trials; Connective Tissue; Consent; Contracts; Cyclic GMP; Data; Development; Diabetes Mellitus; Diarrhea; Disease; Documentation; Dose; Drug Kinetics; Enteral; Epithelial Cells; Equipment; Excipients; Experimental Models; Filtration; Food; Freeze Drying; Funding; Genome; Goals; Grant; Harvest; Histocompatibility Antigens Class II; Homeostasis; Human; Human Volunteers; I-antigen; Immune; Immune mediated destruction; Immunologics; Immunomodulators; Immunosuppressive Agents; Individual; Infiltration; Inflammatory; Infrastructure; Investments; Label; Lacrimal gland structure; Lactococcus; Life; Lubricants; Lymphoma; Mediating; Medical; Methods; Modeling; Mucous Membrane; Mus; Ocular Prosthesis; Operon; Oral; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Preparation; Probiotics; Procedures; Process; Production; Property; Proteins; Recombinants; Regulatory T-Lymphocyte; Replacement Therapy; Resistance; Running; Safety; Salivary Glands; Salmonella; Schedule; Secure; Ships; Sjogren' s Syndrome; Small Business Innovation Research Grant; Specificity; Symptoms; Testing; Therapeutic; Time; Toxicology; Up-Regulation; Vaccines; Woman; adaptive immune response; base; body system; capsule; chronic autoimmune disease; clinical candidate; clinical development; colonization factor antigens; commercialization; cost; design; drug development; drug production; enterotoxigenic Escherichia coli; first-in-human; gastrointestinal; high efficiency particulate air filter; immunoregulation; improved; meetings; microbiome; mouse model; novel; oral tolerance; pharmacokinetics and pharmacodynamics; phase 2 study; prevent; product development; research clinical testing; response; scale up; treatment effect; vaccine trial; vector

Project Summary Our goal is to develop a novel, immunologically enhanced L. lactis probiotic-based therapeutic for the treatment of Sjögren’s Syndrome (SjS). SjS is a progressive, chronic autoimmune disease characterized by inflammatory cell infiltration of the salivary and lacrimal glands, resulting in acinar epithelial cell atrophy, cell death, and loss of exocrine function 1-6. At least half of SjS patients develop extraglandular inflammatory disease and have a wide range of systemic clinical manifestations that can affect any organ system, including connective tissue, and 5-10% of patients develop life-threatening lymphoma 7, 8. SjS is a debilitating disease affecting as many as 3.1 million individuals in the U.S. 9, 10, with women being nine times more likely to be afflicted with SjS than men 5, 10, 11. Treatment of SjS remains a significant unmet medical need. Current treatment relies on replacement therapies such as artificial saliva and eye lubricants or immunosuppressive agents12, 13. Because of the multiple antigens involved in this disease process, i.e., α-fodrin 14-17, ribonuclear protein Ro/SSA 14, 48, 49, La/SSB 14, 48, 49, and M3R 18, 49, 50, oral tolerance methods become problematic. Thus, the capacity to stimulate regulatory cells independent of knowing the antigen specificity for the disease poses as an attractive therapeutic approach. Originally conceived as a human diarrheal vaccine, we found that colonization factor antigen I (CFA/I) from human enterotoxigenic E. coli (ETEC) is effective at inducing auto-Ag-specific T regulatory cells when administered orally as either a purified protein or delivered via a Salmonella or L. lactis bacterial delivery system 19-21, 61. To avoid challenges associated with producing large quantities of CFA/I protein and improve the mucosal pharmacokinetic (PK) and pharmacodynamic (PD) properties of CFA/I following oral administration, we developed and characterized a vector-containing L. lactis-CFA/I expressing product (referred to as VTC- CFA) and evaluated its efficacy in multiple autoimmune models. Indeed, VTC-CFA was effective at reducing clinical symptoms in a SjS animal model, along with experimental models of RA, diabetes, and MS 22-24. Prior Phase I and II SBIR funding has enabled us to effectively advance VTC-CFA towards clinical testing by developing our clinical candidate that expresses CFA/I from a genome-integrated operon, validating non- clinical biology, and completing upstream and downstream process development. As part of these efforts, we held an FDA pre-IND meeting to finalize our IND-enabling plans and align our CMC/manufacturing strategy. This application is designed to complete VTC-CFA IND enabling studies and file an IND with the FDA. The key aims of this proposal are: 1) complete VTC-CFA GLP toxicology studies, 2) establish cGMP manufacturing infrastructure, 3) perform cGMP manufacturing for drug substance, 4) Fill capsules under cGMP conditions for drug product, and 5) file an IND with the FDA for VTC-CFA. Successful commercialization of VTC-CFA will provide a profound medical advancement for treating SjS.

项目概要 我们的目标是开发一种新型的、免疫增强的、基于乳酸乳球菌益生菌的治疗方法 干燥综合征（SjS）的治疗是一种进行性、慢性自身免疫性疾病，其特征是。 炎症细胞浸润唾液腺和泪腺，导致腺泡上皮细胞萎缩，细胞 死亡和外分泌功能丧失 1-6 至少一半的 SjS 患者出现腺外炎症。 疾病并具有广泛的全身临床表现，可以影响任何器官系统，包括 结缔组织，5-10% 的患者会发展为危及生命的淋巴瘤 7, 8。SjS 是一种使人衰弱的疾病 影响美国多达 310 万人 9, 10，其中女性患病的可能性是女性的九倍 受 SjS 影响的男性分别为 5、10、11。 SjS 的治疗仍然是一个重大的未满足的医疗需求，目前的治疗依赖于替代疗法。 例如人工唾液和眼部润滑剂或免疫抑制剂12、13。由于存在多种抗原 参与该疾病过程，即 α-fodrin 14-17、核糖核蛋白 Ro/SSA 14、48、49、La/SSB 14、48、49 和 M3R 18, 49, 50，口服耐受方法因此成为问题，刺激调节细胞的能力。 独立于了解疾病的抗原特异性而构成一种有吸引力的治疗方法。 最初被设想为人类腹泻疫苗，我们发现定植因子抗原 I (CFA/I) 人产肠毒素大肠杆菌 (ETEC) 在以下情况下可有效诱导自身抗原特异性 T 调节细胞： 作为纯化蛋白口服或通过沙门氏菌或乳酸乳球菌递送 系统 19-21, 61. 避免与生产大量 CFA/I 蛋白相关的挑战并提高 口服给药后 CFA/I 的粘膜药代动力学 (PK) 和药效学 (PD) 特性， 我们开发并表征了含有载体的乳酸乳球菌-CFA/I表达产物（称为VTC- CFA）并评估了其在多种自身免疫模型中的功效，事实上，VTC-CFA 可有效减少。 SjS 动物模型以及 RA、糖尿病和 MS 22-24 实验模型中的临床症状。 I 期和 II 期 SBIR 资金使我们能够有效推进 VTC-CFA 走向临床测试 开发我们的临床候选药物，从基因组整合的操纵子表达 CFA/I，验证非 临床生物学，并完成上游和下游工艺开发作为这些努力的一部分，我们。 举行了 FDA IND 前会议，以最终确定我们的 IND 授权计划并调整我们的 CMC/制造战略。 该申请旨在完成 VTC-CFA IND 启用研究并向 FDA 提交 IND 密钥。 该提案的目标是：1) 完成 VTC-CFA GLP 毒理学研究，2) 建立 cGMP 生产 基础设施，3) 进行原料药的 cGMP 制造，4) 在 cGMP 条件下填充胶囊 药品，以及 5) 向 FDA 提交 VTC-CFA 的 IND 申请。 VTC-CFA 的成功商业化将为治疗 SjS 提供深远的医学进步。