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: 10609532
• 负责人: John David O'Neill
• 金额: $ 96.14万
• 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/10609532
• 关键词: 3-Dimensional; Acceleration; 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; Multiomic Data; Organ Donor; Output; Paper; 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 Reduction; Sampling; Scientist; Small Business Innovation Research Grant; Specific qualifier value; Specificity; Standardization; Structure of parenchyma of lung; Technology; Test Result; Testing; Time; Tissue Model; Tissues; Validation; Work; commercialization; comparative; cost; drug development; drug discovery; drug testing; empowerment; fibrotic lung; high risk; human tissue; idiopathic pulmonary fibrosis; improved; in vitro Model; in vitro testing; in vivo; manufacture; manufacturing process; metabolomics; mortality; nintedanib; novel; novel therapeutics; predictive modeling; product development; quality assurance; research and development; scale up; standard of care; stem; success; supply chain; 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， 提高特发性肺纤维化体外模型的生理相关性和预测价值 (IPF)为IPF疾病生物学研究提供动力，并加速治疗IPF的药物开发。 IPF是一种破坏性、难治性和危及生命的间质性肺疾病，其特征是肺动脉闭塞， 肺泡和进行性呼吸功能丧失。超过55，000例IPF新发病例被诊断 每年.中位生存期为3-4年，美国的年死亡率超过40，000。病因及 IPF的发病机制尚不清楚。用于基础科学研究的IPF预测性动物和体外模型 和药物开发严重缺乏，留下了大量未满足的需求和市场机会， 生理学相关的体外平台，能够对IPF进行高保真的细胞表型研究。这 SBIR快速通道将支持IPF疾病商业化的开发和验证研究 模拟和化合物测试平台，可概括人类IPF疾病的体外关键特征 已经显示支持人肺成纤维细胞的纤维化表型，以改善基于细胞的 在早期抗纤维化药物发现的分析。技术创新是产品的人类IPF纤维化 肺特异性源自分离无细胞人IPF肺细胞外基质的专有方法 (ECM)与人类IPF肺组织的组成和生物力学相一致。我们的“生理模拟方法" 用于预测IPF体外模型的标准化人纤维化肺细胞培养基质， 生理学研究，因此更具预测性，与现有产品相比具有主要竞争优势 比如涂有胶原蛋白的聚苯乙烯板。目标是验证和商业化标准人类IPF 用于预测IPF体外模型的肺ECM疾病建模和化合物测试平台， 依赖于动物模型，并为IPF药物开发人员提供更相关的结果。具体目标是： (i)确定人IPF和正常肺ECM中肺成纤维细胞的转录组学和代谢组学特征 水凝胶，（ii）评价人IPF和正常肺ECM水凝胶的质量和一致性，（iii）进行 IPF标准治疗药物的化合物试验研究。在成功完成快速通道项目后， Xylyx将把IPF化合物测试平台商业化，提供给有需要的制药公司的科学家 用于药物发现和筛选的预测性IPF疾病模型，从而降低相关的重大成本 由于疗效不佳而导致晚期减员，并促进开发改善的治疗方案， 全世界有超过300万IPF患者。此SBIR快速通道的产品将立即进入 生物制药和药物开发领域快速增长的细胞培养市场，年价值64亿美元 预计到2024年将达到292亿美元，并将支持旨在实现30亿美元的药物开发 IPF治疗市场。