Predevelopment of VV8220, a Gut-selective CRAC Channel Therapeutic for Ulcerative Colitis

VV8220 的预开发，一种针对溃疡性结肠炎的肠道选择性 CRAC 通道疗法

基本信息

批准号：
10484704
负责人：
Milton L Greenberg
金额：
$ 30万
依托单位：
VIVREON BIOSCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10484704
关键词：
Acute Adoptive Transfer Affect Ames Assay Animal Model Anti-Inflammatory Agents Antigens Bacteria Biological Biological Markers Biological Sciences Capital Cardiovascular system Cell model Cells Chemicals Chemistry Chronic Colitis Colon Cytochrome P450 Development Disease Disease remission Dosage Forms Dose Drug Interactions Drug Kinetics Drug Side Effects Excretory function Exhibits Family Feedback Financial cost Funding Gastrointestinal tract structure Gene Expression Genes Genetic Transcription Goals Histopathology Immunosuppression In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Investments Lamina Propria Lead Lesion Leukocytes Life Maintenance Measurement Mediating Metabolism Minor Mission Modeling Mus National Institute of Allergy and Infectious Disease Nuclear Oral Oral Administration Pathogenicity Pathologic Pathway interactions Patients Peroxidases Persons Pharmaceutical Preparations Pharmacology Phase Plasma Positioning Attribute Preparation Program Development Property Quality of life Rectum Regimen Regulatory T-Lymphocyte Remission Induction Risk Risk Management Safety Signal Transduction Skin Small Business Innovation Research Grant Sodium Dextran Sulfate Stress T-Lymphocyte Tablets Testing Therapeutic Time Topical agent Toxicology Treatment Efficacy Ulcer Ulcerative Colitis absorption autoimmune inflammation capsule channel blockers chronic inflammatory disease clinical candidate clinical development clinical remission dextran sulfate sodium induced colitis disorder control drug action drug candidate drug testing efficacy study efficacy validation enzyme activity expectation fight against follow-up genotoxicity immunoregulation improved in vivo indexing infection risk inhibitor interest intestinal barrier leukocyte activation mRNA Expression medication safety monocyte mouse model next generation novel novel therapeutic intervention patient population physical property prevent programs receptor response scale up side effect small molecule targeted treatment therapeutic candidate therapeutically effective transcription factor treatment duration

项目摘要

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAID PA-21-259 Project Summary Ulcerative colitis (UC) is the most common form of inflammatory bowel disease affecting up to one in 5,000 individuals. The pathologic inflammation occurs in the inner lining of the colon and rectum due to an inappropriate response of resident leukocytes to normally tolerated bacteria and other pro-inflammatory material in the gut. This results in potentially life-threatening ulcerative lesions and significant disruption to quality of life. Currently indicated small molecule and biologic drugs are not effective in all patients, or many patients become unresponsive to therapies over time, and additional treatment options are needed. One promising and novel therapeutic approach to controlling UC is to restrict anti-inflammatory drug action to the inner lining of the gut where the local inflammatory response is most extreme, thereby simultaneously limiting systemic anti- inflammatory side effects of the drug. An orally available drug with such gut-restricted properties would be acting similarly to topical agents applied to the skin to control autoimmune inflammation of the skin. The leukocyte Ca2+ release activated Ca2+ (CRAC) channel is operative on gut monocytes and T cells (primary cellular drivers of UC) and is triggered by leukocyte receptors for foreign antigens. The CRAC pathway regulates many pro- inflammatory genes in these cells through activation of NFAT and NF-B transcriptional activity. These attributes make the CRAC channel a suitable target for development of a gut-restricted small molecule drug. Vivreon's small molecule lead CRAC channel blocker, VV8220, exhibits physical properties consistent with a gut restricted oral drug candidate, including strong potency and limited systemic exposure upon oral dosing. Here we propose to perform further predevelopment studies with VV8220 to characterize and confirm its suitability as a gut-restricted oral drug candidate for treatment of UC. In Aim 1 (ADME/DMPK studies) we will assess its direct effects on cytochrome P450 family (CYP) enzyme activities and mRNA expression, its cardiovascular liability via an in vitro hERG channel blockade test, its genotoxic potential via an Ames test, and its in vivo pharmacokinetics. In Aim 2 we will evaluate its efficacy in two mouse models. First is the DSS model involving disruption of the intestinal barrier and consequent flora-driven UC. The second involves adoptive transfer of inflammatory naïve T cells into recipient mice lacking suppressive Treg cells that normally control a gut inflammatory response (Adoptive T cell model). The two model results will be assessed by a Disease Activity Index, histopathology and by measurement of the UC inflammatory biomarker myeloperoxidase (MPO) in gut lamina propria. Successful completion of these Aims will position the VV8220 program to advance into IND-enabling studies like advanced toxicology testing, chemistry scale up and dose-range finding with Phase II SBIR and external funding.

Vivreon 生物科学有限公司 4940 卡罗尔峡谷路，Ste 110 圣地亚哥, CA 92121 milton@vivreonbiosciences.com NIAID PA-21-259 项目概要溃疡性结肠炎 (UC) 是最常见的炎症性肠病，影响高达五千分之一的人由于不适当的治疗，病理性炎症发生在结肠和直肠的内壁。常驻白细胞对肠道中正常耐受的细菌和其他促炎物质的反应。这导致潜在危及生命的溃疡性病变并显着破坏目前的生活质量。表明小分子和生物药物并非对所有患者都有效，或者许多患者变得随着时间的推移，对治疗没有反应，需要一种有希望的新颖的治疗选择。控制 UC 的治疗方法是将抗炎药物的作用限制在肠道内壁局部炎症反应最极端，同时限制了全身抗具有这种肠道限制特性的口服药物将发挥作用。与应用于皮肤以控制皮肤自身免疫性炎症的外用制剂类似，白细胞 Ca2+。释放激活的 Ca2+ (CRAC) 通道对肠道单核细胞和 T 细胞（主要细胞驱动因子）起作用 UC) 并由外来抗原的白细胞受体触发。CRAC 途径调节许多亲-抗原。通过激活 NFAT 和 NF-κB 转录活性来抑制这些细胞中的炎症基因。使 CRAC 通道成为开发肠道限制性小分子药物的合适靶点。 Vivreon 的小分子先导 CRAC 通道阻断剂 VV8220 表现出与肠道一致的物理特性限制性口服候选药物，包括口服给药时的强效和有限的全身暴露。我们建议使用 VV8220 进行进一步的预开发研究，以表征并确认其适用性用于治疗 UC 的肠道限制性口服候选药物在目标 1（ADME/DMPK 研究）中，我们将评估其直接作用。对细胞色素 P450 家族 (CYP) 酶活性和 mRNA 表达及其心血管责任的影响体外 hERG 通道阻断试验、艾姆斯试验的遗传毒性潜力及其体内药代动力学。在目标 2 中，我们将评估其在两种小鼠模型中的功效，首先是涉及破坏的 DSS 模型。肠道屏障和随后的菌群驱动的 UC。第二个涉及炎症幼稚的过继转移。将 T 细胞注入缺乏通常控制肠道炎症反应的抑制性 Treg 细胞的受体小鼠中（过继性 T 细胞模型）将通过疾病活动指数、组织病理学和通过测量肠道固有层中的 UC 炎症生物标志物髓过氧化物酶 (MPO) 成功。完成这些目标将使 VV8220 项目能够进入 IND 支持的研究，例如高级研究利用 II 期 SBIR 和外部资金进行毒理学测试、化学放大和剂量范围发现。