High Density Cell Respirator (HDCR) for the production of vectors, viruses and vaccines

用于生产载体、病毒和疫苗的高密度细胞呼吸器 (HDCR)

• 批准号: 10415227
• 负责人: Nicole Bergman
• 金额: $ 83.06万
• 依托单位: XDEMICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415227
• 关键词: Architecture; Blindness; Businesses; California; Cell Adhesion; Cell Culture Techniques; Cell Density; Cell Line; Cell Therapy; Cells; Cellular immunotherapy; Cities; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Communicable Diseases; Data; Defect; Development; Devices; Disease; Dose; Event; Excision; Film; Funding; Future; Gases; Gene Transduction Agent; Genes; Genetic Engineering; Genetic Medicine; Genetic Vectors; Goals; Growth; Harvest; Immunologic Deficiency Syndromes; Inborn Errors of Metabolism; Industry Standard; Injections; Institutes; Institution; Investigation; Joints; Legal patent; Life; Liquid substance; Malignant Neoplasms; Mediating; Medical center; Medicine; Membrane; Methodology; Methods; Molds; Names; National Center for Advancing Translational Sciences; Nonprofit Organizations; Nutrient; Oncogenes; Oncolytic; Oncolytic viruses; Orthopoxvirus; Oxygen; Patients; Pattern; Permeability; Phase; Phase I/II Trial; Population; Poxviridae; Price; Process; Production; Productivity; Reagent; Research; Research Priority; Respirators; Savings; Scientist; Silicone Elastomers; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Societies; Speed; Suspensions; Technology; Testing; Therapeutic; Therapeutic Agents; Thinness; Time; Vaccines; Viral; Viral Vaccines; Viral Vector; Virus; Waiting Lists; Work; adeno-associated viral vector; base; cancer therapy; cell growth; cellular transduction; clinically relevant; cost; cost effective; density; design; engineered stem cells; fighting; gene therapy; gene transfer vector; hydrophilicity; improved; manufacturing process; melanoma; new technology; novel; novel therapeutics; oncolytic virotherapy; pandemic disease; particle; phase 1 study; phase 2 study; polydimethylsiloxane; prototype; research and development; shear stress; transmission process; vector; vector genome; wasting

PROJECT SUMMARY/ABSTRACT This Phase I/II STTR Fast Track proposal responds to the call from the 2018/2019 NCATS SBIR/STTR Research Priorities to develop technologies so that “new treatments and cures for disease can be delivered to patients more quickly”. The production of life-altering gene editing vectors, cancer killing viruses, and life- saving vaccines currently depends on traditional cell culture techniques. A number of virus-based and cell- based therapies have become clinical treatments for cancer, for genetically-related blindness, for immunodeficiency, and for inborn errors of metabolism. In this exciting field, many therapies being developed are on waitlists to be tested. However, current cell culture-based production is costly and slow to attend the existing demand. For instance, a clinical trial for AAV-based gene editing requires 10 viral particles, a quantity currently requiring a year for production and costing 1-2 million dollars. Thus, the cost of $400,000 to $1,400,000 per patient for recently approved gene medicines is not surprising. These price tags simply are not sustainable for society. In the event of a pandemic, it would take years to generate sufficient doses of vaccines to protect the 7 billion world population by current production methods. Thus, increasing the efficiency and speed of culture of production cell lines are common goals for manufacturing of gene editing vectors, oncolytic viruses, and vaccines. Our joint research efforts at XDemics Corporation, the California Institute of Technology, and the City of Hope National Medical Center, have resulted in an improved method of cell culture. Based on a known fact that oxygen delivery is the most rate-limiting process for increasing cell density, viability, and virus production we created a novel high density cell respirator (HDCR) (US Patent no. 10,053,660) from highly oxygen permeable material that can be inexpensively molded into large sheets, with integrated cell retention architecture, for efficient membrane oxygenation of adherent or suspension cells. Our hypothesis is that elimination of shear stress and the low flow media delivery through the HDCR, enabled by the decoupling of gas exchange via membrane oxygenation of cells, will allow for improved yield, decreased cost, and increased speed of production of therapeutic viral vectors and viruses. We have preliminary data confirming this hypothesis and have produced prototypes for optimization. Herein we propose Phase I studies to optimize the design of the HDCR for cell growth and demonstrate virus production. Proposed Phase II studies will consist of research and development of production processes for multiple viral vectors, including AAV and immuno- oncolytic poxvirus/vaccine. We expect that the HDCR will disrupt the field of vector and virus production, by allowing >10 times greater efficiency and >2-10 times greater speed of production. Our long-term goal is to speed up production of clinically-relevant quantities of viral medicines and vaccines from years down to months. Decreasing the cost of gene therapy vectors, cell-based immunotherapies, and vaccines will accelerate development of novel therapies for treating cancers, gene defects, and infectious diseases.

项目摘要/摘要 此阶段I/II STTR快速提案对2018/2019 NCATS SBIR/STTR的电话的响应 开发技术的研究重点，以便“可以将新的疾病治疗方法交付给 患者更快”。改变生命的基因编辑载体，癌症杀死病毒和生命 - 当前储蓄疫苗取决于传统的细胞培养技术。许多基于病毒的细胞和细胞 基于遗传相关的失明，基于癌症的疗法已成为临床治疗 免疫缺陷和新陈代谢错误。在这个令人兴奋的领域，开发了许多疗法 在候补名单上进行测试。但是，当前基于细胞培养的生产是昂贵而慢的 现有需求。例如，基于AAV的基因编辑的临床试验需要10个病毒颗粒，A 目前需要一年的生产和耗资1-200万美元的数量。那是40万美元的费用 最近批准的基因药物的每名患者$ 1,400,000并不奇怪。这些价格标签根本不是 对社会的可持续发展。如果发生大流行，则需要数年才能产生足够的疫苗 通过当前的生产方法来保护70亿世界人口。这提高了效率和 生产细胞系的培养速度是制造基因编辑载体的常见目标 病毒和疫苗。我们在加利福尼亚理工学院Xdemics Corporation的联合研究工作， 希望城市国家医疗中心（National Medical Center）导致了一种改进的细胞培养方法。基于a 已知的事实是，氧递送是增加细胞密度，活力和病毒的最限制过程 生产我们从高度创建了一种新型的高密度细胞呼吸器（HDCR）（美国专利10,053,660） 氧气可渗透的材料，可以廉价地模制成大板，并具有集成的细胞保留 结构，用于粘附或悬浮细胞的有效膜氧化。我们的假设是 通过HDCR消除剪切应力和低流量介质的传递 通过细胞的膜氧化的气体交换将允许提高产量，成本降低并增加 热病毒载体和病毒的生产速度。我们有初步数据证实了这一点 假设并产生了用于优化的原型。本文中，我们建议I阶段研究以优化 HDCR的设计用于细胞生长并证明病毒产生。拟议的第二阶段研究将包括 多种病毒载体的生产过程的研究和开发，包括AAV和免疫 - 溶瘤病毒/疫苗。我们预计，HDCR会破坏媒介和病毒产生的领域， 允许效率高10倍，生产速度> 2-10倍。我们的长期目标是 加快与临床上相关的病毒药物和疫苗的生产加速 月份。降低基因疗法载体，基于细胞的免疫疗法和疫苗的成本将 加速用于治疗癌症，基因缺陷和传染病的新型疗法的发展。