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: 10356225
• 负责人: Nicole Bergman
• 金额: $ 84.26万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356225
• 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; 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.

项目概要/摘要 此第一阶段/第二阶段 STTR 快速通道提案响应 2018/2019 NCATS SBIR/STTR 的号召 研究重点是开发技术，以便“能够为疾病提供新的治疗方法和治愈方法” 更快地治疗患者”。改变生活的基因编辑载体、癌症杀伤病毒和生命的生产 目前保存疫苗依赖于传统的细胞培养技术。许多基于病毒和细胞的 基于的疗法已成为癌症、遗传相关失明、 免疫缺陷，以及先天性代谢缺陷。在这个令人兴奋的领域，许多疗法正在开发中 正在等待测试的名单上。然而，目前基于细胞培养的生产成本高昂且进展缓慢 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，一个 目前数量需要一年才能生产，成本为1-200万美元。因此，花费 400,000 美元 最近批准的基因药物为每位患者花费 1,400,000 美元并不奇怪。这些价格标签根本不 为社会带来可持续发展。如果发生大流行，需要数年时间才能生产足够剂量的疫苗 通过当前的生产方式保护 70 亿世界人口。因此，提高效率和 生产细胞系的培养速度是制造基因编辑载体、溶瘤细胞的共同目标 病毒和疫苗。我们与 XDemics Corporation、加州理工学院的联合研究工作， 和希望之城国家医疗中心，改进了细胞培养方法。基于一个 众所周知，氧气输送是增加细胞密度、活力和病毒的最受速率限制的过程 我们从高度生产中创造了一种新型高密度细胞呼吸器 (HDCR)（美国专利号 10,053,660） 透氧材料，可以廉价地模制成大片材，并具有集成的细胞保留功能 结构，用于贴壁或悬浮细胞的有效膜氧合。我们的假设是 通过 HDCR 消除剪切应力和低流量介质输送，这是通过解耦实现的 通过细胞膜氧合进行气体交换，将有助于提高产量、降低成本并提高产量 治疗性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 假设并制作了优化原型。在此，我们提出第一阶段研究来优化 设计用于细胞生长的 HDCR 并演示病毒的产生。拟议的第二阶段研究将包括 研究和开发多种病毒载体的生产工艺，包括 AAV 和免疫载体 溶瘤痘病毒/疫苗。我们预计 HDCR 将通过以下方式颠覆载体和病毒生产领域： 效率提高 10 倍以上，生产速度提高 2-10 倍以上。我们的长期目标是 将临床相关数量的病毒药物和疫苗的生产速度从几年缩短到 几个月。降低基因治疗载体、基于细胞的免疫疗法和疫苗的成本将 加速开发治疗癌症、基因缺陷和传染病的新疗法。