Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy
靶向上皮 GM1 神经节苷脂的口服治疗先导蛋白治疗溃疡性结肠炎的临床前验证
基本信息
- 批准号:10198918
- 负责人:
- 金额:$ 48.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-20 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAffinityAnti-Inflammatory AgentsAntibodiesAzoxymethaneBindingBiochemicalBiologicalBiological AssayBiological Response Modifier TherapyBiophysicsBiopsyC-terminalC57BL/6 MouseCaco-2 CellsCellsCholera Toxin Protomer BCholera VaccineChronicClinical TrialsColectomyColitisColonCrohn&aposs diseaseDataDetectionDevelopmentDiseaseDisease remissionDoseDysplasiaE-CadherinEndoplasmic ReticulumEndoscopyEnteralEnzyme-Linked Immunosorbent AssayEpithelialEpithelial CellsExcisionExposure toFibrosisFormulationFrequenciesGanglioside GM1Gene ExpressionGenesGoalsHigh Pressure Liquid ChromatographyHistopathologyHumanImmuneImmune System DiseasesImmunohistochemistryImmunologic SurveillanceImmunosuppressive AgentsImpairmentIn VitroIndividualInflammationInflammatory Bowel DiseasesInterleukin-10IntestinesKnock-outKnockout MiceLamina PropriaLeadMalignant NeoplasmsMass Spectrum AnalysisModelingModificationMolecularMonitorMononuclearMucous MembraneMusNatural regenerationNicotianaOralOral AdministrationOrganoidsPathologyPathway interactionsPatientsPharmaceutical PreparationsPhase I Clinical TrialsPiroxicamPlantsPostoperative ComplicationsProcessProteinsRecombinantsRecording of previous eventsRecoveryRectumRefractoryRelapseResearchSafetyScanningSeriesSodium Dextran SulfateSpecimenSystemTNF geneTestingTherapeuticTherapeutic AgentsTherapeutic EffectTissuesTreatment EfficacyUlcerative ColitisVaccine AntigenValidationVariantanalogbasecell typeclinical carecolitis associated cancercomparative efficacycurative treatmentsefficacy studyefficacy validationepithelial injuryepithelial repairfirst-in-humanhealingholotoxinsimmunoregulationimprovedindexinginfection riskinflammatory disease of the intestineinflammatory markermouse modelmutantnovelnovel therapeutic interventionoverexpressionpre-clinicalprototyperesponseretrograde transportsafety studyscreeningtissue culturetumorigenesiswound healing
项目摘要
PROJECT SUMMARY
Currently, there is no curative medication available for ulcerative colitis (UC), a type of inflammatory bowel
disease affecting the innermost mucosal layer of the rectum and the colon. Although mucosal healing is a major
treatment goal, many patients fail to achieve mucosal healing with available UC drugs such as anti-inflammatory,
immuno-modulatory and anti-TNF agents. Since epithelial repair is a critical process towards mucosal healing,
an agent facilitating this process will provide a novel therapeutic strategy differentiating from existing clinical care
for UC. Our therapeutic lead is a variant of the oral cholera vaccine antigen cholera toxin B subunit (CTB), which
was modified with a C-terminal extension including an endoplasmic reticulum retention motif (CTBSEKDEL). We
have recently shown that oral administration of CTBSEKDEL, but not native CTB, facilitates colon epithelial repair
and mucosal healing in a dextran sodium sulfate (DSS)-induced acute colitis mouse model. Moreover, biweekly
oral administration of CTBSEKDEL significantly reduced tumorigenesis in the azoxymethane/DSS model of colitis-
associated cancer. Based on these findings, we hypothesize that CTBSEKDEL provides a prototype oral biologic
facilitating mucosal healing in UC. The goal of this translational R01 project is to optimize and validate the
therapeutic potential of CTBSEKDEL in preclinical UC models. Since CTBSEKDEL has already shown feasibility in an
acute colitis model, we will immediately proceed with further validation in chronic colitis models. In parallel, in
Aim 1, we will create CTBSEKDEL variants with modifications in the C-terminal sequence (CTB(X)H/KDEL) to improve
molecular stability upon spray dry for enteric-coated formulations. We will produce these proteins using a
Nicotiana benthamiana plant transient overexpression system and screen them based on a series of biochemical
and biophysical assays, as well as a mouse acute DSS colitis model. In Aim 2, we will validate the efficacy and
safety of CTBSEKDEL and a selected CTB(X)H/KDEL in two chronic colitis models based on repeated DSS exposure
in C57bl/6 mice and piroxicam-exposed IL-10 knockout mice, in comparison to an anti-TNFα antibody.
Therapeutic efficacy and safety will be determined by disease activity index, histopathology,
immunohistochemistry and molecular biological analysis of inflammation, crypt regeneration, epithelial barrier
recovery and fibrosis. In Aim 3, we will employ a human colon explant model to further validate the mucosal
healing potential of CTBSEKDEL and CTB(X)H/KDEL. Colon biopsy and colectomy tissues will be obtained from
patients with different disease history and biological backgrounds. Efficacy will be evaluated based on wound
healing-related gene expression and immunohistochemistry for epithelial proliferation/regeneration markers. Cell
type-specific responses will be investigated in colon lamina propria mononuclear cells and colonic organoids.
Collectively, the project will generate pivotal preclinical data supporting the development of a first-in-class oral
biologic candidate inducing colon epithelial repair for UC treatment towards a Phase I clinical trial.
项目摘要
目前,溃疡性结肠炎(UC)是一种炎症性肠病,
影响直肠和结肠最内层粘膜的疾病。虽然粘膜愈合是主要的
治疗目标,许多患者未能实现粘膜愈合与可用的UC药物,如抗炎,
免疫调节剂和抗TNF剂。由于上皮修复是粘膜愈合的关键过程,
促进这一过程的药物将提供一种与现有临床护理不同的新的治疗策略,
为UC。我们的治疗先导是口服霍乱疫苗抗原霍乱毒素B亚单位(CT B)的变体,
用包括内质网滞留基序(CTBSEKDEL)的C-末端延伸修饰。我们
最近表明口服CTBSEKDEL而不是天然CTB促进结肠上皮修复
葡聚糖硫酸钠(DSS)诱导的急性结肠炎小鼠模型中的粘膜愈合。此外,双周
CTBSEKDEL的口服给药显著降低了结肠炎的氧化偶氮甲烷/DSS模型中的肿瘤发生。
相关癌症基于这些发现,我们假设CTBSEKDEL提供了一种原型口腔生物制剂,
促进UC的粘膜愈合。本翻译R 01项目的目标是优化和验证
CTBSEKDEL在临床前UC模型中的治疗潜力。由于CTBSEKDEL已经在一个
在急性结肠炎模型中,我们将立即在慢性结肠炎模型中进行进一步验证。同时,在
目的1,我们将创建在C-末端序列中具有修饰的CTBSEKDEL变体(CTB(X)H/KDEL),以改善CTBSEKDEL的功能。
肠溶包衣制剂喷雾干燥后的分子稳定性。我们将使用一种
本氏烟草植物瞬时过表达系统的建立及一系列生化指标的筛选
和生物物理测定,以及小鼠急性DSS结肠炎模型。在目标2中,我们将验证疗效,
基于重复DSS暴露的两种慢性结肠炎模型中CTBSEKDEL和选定CTB(X)H/KDEL的安全性
在C57 BL/6小鼠和吡罗昔康暴露的IL-10敲除小鼠中,与抗TNF α抗体进行比较。
疗效和安全性将通过疾病活动指数、组织病理学、
炎症、隐窝再生、上皮屏障免疫组织化学和分子生物学分析
恢复和纤维化。在目标3中,我们将采用人结肠外植体模型来进一步验证粘膜
CTBSEKDEL和CTB(X)H/KDEL的愈合潜力。结肠活检和结肠切除术组织将从
不同疾病史和生物学背景的患者。将根据伤口评价疗效
愈合相关基因表达和上皮增殖/再生标记物的免疫组织化学。细胞
将在结肠固有层单核细胞和结肠类器官中研究类型特异性应答。
总的来说,该项目将产生关键的临床前数据,支持开发一流的口服
诱导结肠上皮修复的生物候选物,用于UC治疗的I期临床试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nobuyuki Matoba其他文献
Nobuyuki Matoba的其他文献
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{{ truncateString('Nobuyuki Matoba', 18)}}的其他基金
Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy
靶向上皮 GM1 神经节苷脂的口服治疗先导蛋白治疗溃疡性结肠炎的临床前验证
- 批准号:
10596495 - 财政年份:2020
- 资助金额:
$ 48.14万 - 项目类别:
Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy
靶向上皮 GM1 神经节苷脂的口服治疗先导蛋白治疗溃疡性结肠炎的临床前验证
- 批准号:
10055139 - 财政年份:2020
- 资助金额:
$ 48.14万 - 项目类别:
Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy
靶向上皮 GM1 神经节苷脂的口服治疗先导蛋白治疗溃疡性结肠炎的临床前验证
- 批准号:
10379384 - 财政年份:2020
- 资助金额:
$ 48.14万 - 项目类别:
Core C: PREVENT Program Pharmacokinetics and Pharmacodynamics Services Core
核心 C:预防计划药代动力学和药效学服务核心
- 批准号:
8769376 - 财政年份:2014
- 资助金额:
$ 48.14万 - 项目类别:
Plant-produced Actinohivin as a Candidate HIV Microbicide
植物产生的放线菌素作为候选 HIV 杀菌剂
- 批准号:
7892885 - 财政年份:2010
- 资助金额:
$ 48.14万 - 项目类别:
Plant-produced Actinohivin as a Candidate HIV Microbicide
植物产生的放线菌素作为候选 HIV 杀菌剂
- 批准号:
8484618 - 财政年份:2010
- 资助金额:
$ 48.14万 - 项目类别:
Plant-produced Actinohivin as a Candidate HIV Microbicide
植物产生的放线菌素作为候选 HIV 杀菌剂
- 批准号:
8685097 - 财政年份:2010
- 资助金额:
$ 48.14万 - 项目类别:
Plant-produced Actinohivin as a Candidate HIV Microbicide
植物产生的放线菌素作为候选 HIV 杀菌剂
- 批准号:
8509580 - 财政年份:2010
- 资助金额:
$ 48.14万 - 项目类别:
Plant-produced Actinohivin as a Candidate HIV Microbicide
植物产生的放线菌素作为候选 HIV 杀菌剂
- 批准号:
8085869 - 财政年份:2010
- 资助金额:
$ 48.14万 - 项目类别:
Expression of Decontructed HIV-1 Virus-Like Particles in Bioengineered Plants
解构的 HIV-1 病毒样颗粒在生物工程植物中的表达
- 批准号:
7367919 - 财政年份:2007
- 资助金额:
$ 48.14万 - 项目类别:
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