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 此第一阶段/第二阶段快速通道提案响应2018/2019年NCATS SBIR/STTR的号召 优先研究开发技术，以使“疾病的新疗法和疗法能够被提供给 让病人更快就诊。生产改变生命的基因编辑载体、致癌病毒和生命- 目前，节省疫苗依赖于传统的细胞培养技术。一些基于病毒和细胞的- 基于基础的疗法已经成为癌症、遗传性失明、 免疫缺陷和先天新陈代谢障碍。在这个令人兴奋的领域，许多治疗方法正在开发中 都在等待测试的名单上。然而，目前以细胞培养为基础的生产成本高，速度慢。 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， 目前生产需要一年的数量，成本为100-200万美元。因此，40万美元的成本 最近批准的基因药物每名患者140万美元并不令人惊讶。这些价签根本不是 社会可持续发展。如果发生大流行，将需要数年时间才能生产出足够剂量的疫苗 以现有的生产方式保护70亿世界人口。因此，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、溶瘤的共同目标 病毒和疫苗。我们在XDemics公司、加州理工学院的联合研究工作， 和希望之城国家医疗中心，导致了一种改进的细胞培养方法。基于一个 已知的事实是氧气输送是增加细胞密度、活力和病毒的最限速过程 生产我们创造了一种新型的高密度单元呼吸器(HDCR)(美国专利号10,053,660) 透氧材料，可以廉价地模制成大片，具有集成的电池保持性 架构，用于贴壁或悬浮细胞的高效膜氧合。我们的假设是 消除剪应力和通过HDCR的低流动介质输送，通过脱钩实现 通过细胞的膜氧化进行气体交换，将允许提高产量，降低成本，并增加 治疗性病毒载体和病毒的生产速度。我们有初步数据证实这一点 并产生了用于优化的原型。在此，我们建议进行第一阶段研究，以优化 设计用于细胞生长和演示病毒生产的HDCR。拟议的第二阶段研究将包括 研究和开发包括AAV和免疫病毒在内的多种病毒载体的生产工艺 溶瘤痘病毒/疫苗。我们预计，HDCR将通过以下方式扰乱媒介和病毒生产领域 使生产效率提高10倍，生产速度提高2-10倍。我们的长期目标是 加快临床相关数量的病毒药物和疫苗的生产，从几年到 月份。降低基因治疗载体、细胞免疫疗法和疫苗的成本将 加快开发治疗癌症、基因缺陷和传染病的新疗法。