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Nanoscience-Inspired Acoustofluidic Assembly Lines for Gene and Cellular Therapies

受纳米科学启发的用于基因和细胞治疗的声流体装配线

基本信息

批准号：
10018943
负责人：
Steven John Jonas
金额：
$ 39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018943
关键词：
Acoustics Address Appointment Area Autologous Award CRISPR/Cas technology Candidate Disease Gene Cell Therapy Cell membrane Cells Chemicals Childhood Clinical DNA Sequence Alteration Disease Dose Engineering Extramural Activities Faculty Focus Groups Funding Opportunities Future Gene Delivery Gene Transfer Gene-Modified Generations Genes Growth and Development function Hematopoietic stem cells Hemoglobinopathies Human Infrastructure Institution Intervention Laboratories Lead Mechanics Medical Mentors Methods Microfluidics Mind Modification Mutation Nanotechnology Oncology Pathology Patient Care Pediatric Hematology Pediatrics Physicians Population Positioning Attribute Research Research Personnel Resources Scientist Sickle Cell Anemia Site Stem cell transplant Supportive care System Technology Testing Therapeutic Tissues Toxic effect Translating United States National Institutes of Health Variant Viral Vector Vision base career career development clinical application clinical practice clinical translation clinically relevant cost effective design disease-causing mutation experience falls gene correction gene therapy genome editing high reward high risk innovation insight materials science multidisciplinary nanocarrier nanoscience programs scale up stem cell biology stem cell population stem cells tenure track tool

项目摘要

Project Summary Stem cell-based gene therapies that leverage gene-editing approaches to address disease-causing mutations are emerging as viable medical interventions across a variety of pathologies. Current viral-vector-based and non-viral gene-transfer methods of delivering gene editing machinery, which involve either chemical or energetic disruption of cell membranes, are used routinely in laboratory settings, but fall short when scaled up for clinically relevant applications targetting the manufacture of therapeutic cell products. New methods that enable efficient, rapid, safe, and economical delivery of gene editing packages are needed to support the infrastructures that will be required to translate these gene therapies broadly for application in patient care. Our solution to this critical unmet need leverages innovations in gene editing and nanotechnology to render cell membranes transiently porous, enabling intracellular delivery of biomolecular cargoes. We will design and apply new methods that use acoustic waves generated within microfluidic systems (i.e., acoustofluidics) to mechanically disrupt cell membranes, facilitating the rapid and efficient delivery of CRISPR/Cas9 gene-editing components that are packaged into supramolecular nanocarriers. We use sickle cell disease, one of the most common hemoglobinopathies worldwide, as an initial clinical target for evaluating the proposed platform as it arises from a well-defined genetic mutation that can be targetted for site-specific correction in hematopoietic stem cells with gene editing systems such as CRISPR/Cas9. Successful execution of this research will pave the way for technologies that enable rapid and sustainable processing of stem cell-based gene therapies at clinically- applicable doses – effectively establishing scalable, good manufacturing practice-compatible assembly lines for manufacturing gene modified therapeutic cell products to treat a wide variety of disesases and will streamline the clinical deployment of future cellular therapies.

项目摘要基于干细胞的基因疗法，利用基因编辑方法来解决致病突变正在成为各种病理的可行医疗干预措施。目前基于病毒载体的递送基因编辑机制的非病毒基因转移方法，其涉及化学或能量细胞膜的破坏，在实验室环境中常规使用，但在临床上按比例扩大时，相关应用，其目标是制造治疗性细胞产品。新的方法，需要快速、安全和经济地交付基因编辑包，以支持需要将这些基因疗法广泛地应用于患者护理。我们的解决方案，未满足的需求利用基因编辑和纳米技术的创新，使细胞膜瞬时多孔的，使得能够在细胞内递送生物分子货物。我们将设计和应用新的方法，在微流体系统内产生的声波（即，声流体学）以机械地破坏细胞膜，促进CRISPR/Cas9基因编辑组件的快速有效递送，包装在超分子纳米载体中。我们使用镰状细胞病，最常见的疾病之一全球范围内的血红蛋白病，作为评价拟议平台的初始临床目标，因为它源于一种明确定义的基因突变，可以靶向造血干细胞中的位点特异性校正，基因编辑系统，例如CRISPR/Cas9。这项研究的成功实施将为以下方面铺平道路：能够在临床上快速和可持续地处理基于干细胞的基因疗法的技术- 适用剂量-有效建立可扩展的、与良好制造规范兼容的装配线，制造基因修饰的治疗性细胞产品以治疗多种疾病，未来细胞疗法的临床应用