Lung fibrosis modeling and compound testing platform using fibrotic lung ECM that recreates the fibrotic disease environment to improve predictiveness and accelerate anti-fibrotic drug development

使用纤维化肺 ECM 的肺纤维化建模和复合测试平台，可重建纤维化疾病环境，以提高预测性并加速抗纤维化药物的开发

• 批准号: 10515017
• 负责人: John David O'Neill
• 金额: $ 95.05万
• 依托单位: XYLYX BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515017
• 关键词: 3-Dimensional; Animal Model; Animals; Basic Science; Biocompatible Materials; Biological Assay; Biology; Biomanufacturing; Biomechanics; Biotechnology; Cell Culture Techniques; Cells; Chronic lung disease; Coenzyme A; Collagen; Collagen Type I; Data Set; Decision Making; Dependence; Development; Diagnosis; Disease; Disease Progression; Disease model; Documentation; Drug Modelings; Drug Screening; Environment; Etiology; Experimental Models; Extracellular Matrix; FDA approved; Facility Controls; Fibroblasts; Gel; Gene Expression; Genes; Goals; Human; Hydrogels; In Vitro; International; Interstitial Lung Diseases; Intervention; Interview; Investigation; Knowledge; Legal patent; Life; Lung; Lung Transplantation; Lung diseases; Manuscripts; Marketing; Mechanics; Methods; Modeling; Organ Donor; Output; Pathogenesis; Patient-Focused Outcomes; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Physiological; Pirfenidone; Polystyrenes; Predictive Value; Process; Protein Secretion; Protocols documentation; Publications; Publishing; Pulmonary Fibrosis; Pulmonary alveolar structure; Quality Control; Reporting; Reproducibility; Research; Respiratory physiology; Risk; Sampling; Scientist; Small Business Innovation Research Grant; Specificity; Standardization; Structure of parenchyma of lung; Technology; Test Result; Testing; Time; Tissue Model; Tissues; Validation; Work; base; commercialization; comparative; cost; drug development; drug discovery; drug testing; fibrotic lung; high risk; human tissue; idiopathic pulmonary fibrosis; improved; in vitro Model; in vitro testing; in vivo; manufacturing process; metabolomics; mortality; multiple omics; nintedanib; novel; novel therapeutics; predictive modeling; product development; quality assurance; research and development; scale up; standard of care; stem; success; technological innovation; therapeutic development; transcriptome sequencing; transcriptomics; validation studies; verification and validation

PROJECT ABSTRACT Xylyx is developing a pulmonary fibrosis disease modeling and anti-fibrotic compound testing platform aimed at improving the physiological relevance and predictive value of in-vitro models for idiopathic pulmonary fibrosis (IPF) to power the investigation of IPF disease biology and accelerate development of drugs to treat IPF. Devastating, intractable, and life-threatening, IPF is an interstitial lung disease characterized by obliteration of pulmonary alveoli and progressive loss of respiratory function. Over 55,000 new cases of IPF are diagnosed each year. Median survival is 3–4 years, and annual mortality in the US exceeds 40,000. The etiology and pathogenesis of IPF remain unknown. Predictive animal and in-vitro models of IPF for basic science research and drug development are severely lacking, leaving a significant unmet need and market opportunity for a physiologically-relevant in-vitro platform that enables high-fidelity cell-based phenotypic studies of IPF. This SBIR Fast Track will support development and validation studies for commercialization of an IPF disease modeling and compound testing platform that recapitulates in vitro key features of the human IPF disease environment and has been shown to support fibrotic phenotype of human lung fibroblasts to improve cell-based assays in early-stage anti-fibrotic drug discovery. The technological innovation is the product’s human IPF fibrotic lung specificity stemming from proprietary methods for isolating acellular human IPF lung extracellular matrix (ECM) with the composition and biomechanics of human IPF lung tissue. Our ‘physiomimetic approach’ yields standardized human fibrotic lung cell culture substrates for predictive in-vitro models of IPF that enable more physiologic and thus more predictive studies, providing a major competitive advantage over existing products like collagen-coated polystyrene plates. The goal is validation and commercialization of standard human IPF lung ECM disease modeling and compound testing platform for predictive in-vitro models of IPF to greatly reduce dependence on animal models and enable more relevant results for IPF drug developers. Specific aims are to: (i) determine transcriptomic and metabolomic profiles of lung fibroblasts in human IPF and normal lung ECM hydrogels, (ii) evaluate quality and consistency of human IPF and normal lung ECM hydrogels, (iii) perform compound testing studies with IPF standard-of-care drugs. After successful completion of the Fast Track project, Xylyx will commercialize the IPF compound testing platform to scientists in pharmaceutical companies in need of predictive IPF disease models for drug discovery and screening, thus reducing the significant costs associated with late-stage attrition due to poor efficacy, and facilitating the development of improved treatment options for the more than 3 million sufferers of IPF worldwide. The product of this SBIR Fast Track will immediately enter the rapidly growing cell culture market segment in biopharma and drug development, valued at USD $6.4B in 2014 and estimated to reach USD $29.2B by 2024, and will support drug development aimed at the USD $3.0B IPF treatment market.

项目摘要 Xylyx正在开发肺纤维化疾病建模和抗纤维化化合物测试平台 改善特发性肺纤维化的体外模型的物理相关性和预测价值 （IPF）为IPF疾病生物学的投资提供动力，并加快药物的开发来治疗IPF。 IPF是毁灭性，棘手和威胁生命的，是一种间质性肺部疾病 肺肺泡和呼吸功能的进行性丧失。诊断出超过55,000例新IPF病例 每年。中位生存期为3 - 4年，美国的年死亡率超过40,000。病因和 IPF的发病机理仍然未知。基础科学研究的IPF的预测动物和体外模型 严重缺乏药物开发，留下了巨大的未满足需求和市场机会 与生理上的体外平台相关，可实现基于IPF的高保真性细胞表型研究。这 SBIR快速轨道将支持IPF疾病商业化的开发和验证研究 建模和复合测试平台，概括了人类IPF疾病的体外关键特征 环境已被证明支持人肺成纤维细胞的纤维化表型，以改善基于细胞的基于细胞 早期抗纤维化药物发现中的测定。技术创新是该产品的人类IPF纤维化 肺特异性是由隔离大量人类IPF肺部细胞外基质的专有方法 （ECM）具有人类IPF肺组织的组成和生物力学。我们的“生理方法”产生 标准化的人类纤维化肺细胞培养物，用于IPF的预测性IPF的体外模型 生理学，因此更具预测性研究，比现有产品提供了主要的竞争优势 像胶原蛋白涂层的聚苯乙烯板一样。目标是验证和商业化标准人IPF 肺ECM疾病建模和复合测试平台，用于预测IPF的维特罗模型，以大大减少 对动物模型的依赖，并为IPF药物开发人员带来更相关的结果。具体目的是： （i）确定人IPF和正常肺ECM中肺成纤维细胞的转录组和代谢组学特征 水凝胶，（ii）评估人IPF和正常肺ECM水凝胶的质量和一致性，（III）执行 使用IPF标准药物的化合物测试研究。成功完成快速项目后， Xylyx将向有需要的制药公司的科学家商业化IPF化合物测试平台 预测性IPF疾病模型用于药物发现和筛查，从而降低了相关的显着成本 由于效率差而导致后期属性，并支持改进的治疗选择的发展 全世界IPF的300万患者。 SBIR快速轨道的产物将立即进入 生物制药和药物开发中快速增长的细胞培养市场细分市场，价值6.4B美元 2014年，到2024年估计将达到29.2B美元，并将支持针对3.0b美元的药物开发 IPF治疗市场。