SMART BIOELECTRONIC IMPLANTS FOR CONTROLLED DELIVERY OF THERAPEUTIC PROTEINS IN VIVO AND ITS APPLICATION IN LONG-TERM TREATMENT OF HEMOPHILIA A

用于体内治疗性蛋白质控制输送的智能生物电子植入物及其在血友病 A 长期治疗中的应用

• 批准号: 10615840
• 负责人: DANIEL G ANDERSON
• 金额: $ 60.47万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615840
• 关键词: Address; Allogenic; American; Animal Model; Beta Cell; Biocompatible Materials; Biological; Biomedical Engineering; Biotechnology; Cell Line; Cell Survival; Cell Therapy; Cell Transplantation; Cell physiology; Cell secretion; Cells; Cellular Structures; China; Chronic; Chronic Disease; Clinical; Development; Device Designs; Devices; Diabetes Mellitus; Disease; Disease model; Dose; Drug Delivery Systems; Drug Modulation; Drug Targeting; Economics; Electronics; Elements; Emerging Technologies; Encapsulated; Engineering; Ensure; Factor VIII; Fibrosis; Foreign Bodies; Foreign-Body Reaction; Frustration; Gases; Gene Activation; Generations; Genetic; Glucose; Graft Survival; Hemophilia A; Human; Human Engineering; Hybrid Cells; Hypoxia; Immune; Immune response; Immune system; Immunosuppression; Implant; In Situ; Inflammation; Light; Liver diseases; Maintenance; Medicine; Membrane; Microcapsules drug delivery system; Microfabrication; Modeling; Modification; Monitor; Mus; Nature; Nutrient; Optics; Oxygen; Permeability; Pharmaceutical Preparations; Population; Porosity; Pre-Clinical Model; Preclinical Testing; Production; Property; Protein Secretion; Proteins; Protons; Risk; Rodent; Scientific Advances and Accomplishments; Silicones; Source; Techniques; Technology; Testing; Therapeutic; Time; Transplantation; Work; Xenograft procedure; betacell therapy; bioelectronics; biomaterial compatibility; capsule; cellular engineering; clinical translation; density; design; epigenetic silencing; flexibility; immune function; immunogenic; implantable device; implantation; improved; in vivo; islet; mouse model; nonhuman primate; novel; optogenetics; oxygen transport; prevent; protein transport; response; solid state; stable cell line; standard of care; surface coating; technology development; therapeutic protein; transgene expression; wireless

Cell-based therapies, where naturally or artificially engineered cells secreting therapeutic proteins are grafted onto the body to act as biological drug factories, are an attractive approach for long-term treatment of chronic diseases such as hemophilia, diabetes and liver disorders. However, ‘off the shelf’ therapeutic cells are immunogenic to the host and must be protected from the host immune system. Cell-encapsulation has emerged as an attractive strategy to transplant these cells without chronic immunosuppression. Here, cells are placed in an immune-isolating device which physically separates the cells from the components of the immune system while providing access to oxygen and nutrients. Retrievable macroscale cell- encapsulation devices (macrodevice), are attractive in this context as they provide a safer path to clinical translation. Unfortunately, a standalone macrodevice that remains functional in humans over long-periods (>6 months) is yet to be realized due to two core challenges: 1) a foreign-body reaction to the implanted device causing inflammation and fibrosis, and 2) inadequate supply of oxygen and nutrients to the encapsulated cells. Here, we propose to build on several promising recent advances in biomaterials design, microfabrication, bioelectronics and cell engineering from our team to develop an advanced “smart” macrodevice platform with integrated electronic components which overcomes the major limitations of current device designs. First, we will develop an engineered cell line which is amenable to long term encapsulation and suitable for clinical translation. Landing pads within these cells will ensure stable transgene expression, allowing for broad control of therapeutic protein secretion (Aim 1). Separately, we will develop a bioelectronic macrodevice as a platform for long- term transplant of these cells in vivo. Our device will incorporate novel membranes with uniform/controlled pore-sizes and enhanced oxygen transport properties. In parallel, we will develop new surface coating techniques to minimize fibrosis and ensure long- term graft survival. We will integrate proton exchange membranes and optoelectronic components to allow a) in-situ oxygen generation, and b) optical gene activation to allow for triggerable control of protein production by the encapsulated cells (Aim 2). Finally, we will test the device in B6 mice using a model protein (SEAP) to test for long term survival of cells and external control of protein delivery. We will develop the device as a platform to delivery of Factor VIII for the treatment of Hemophilia A (Aim 3) as a model disease. If successful, the platform will represent a qualitative technological advancement in the field of cell therapy.

基于细胞的疗法，自然或人工设计的细胞分泌疗法 蛋白质被嫁接到人体上以充当生物药物工厂，是一种吸引人 长期治疗慢性疾病，例如血友病，糖尿病和肝脏 疾病。但是，“离架子”的治疗细胞对宿主具有免疫原性，必须是 免受宿主免疫系统的保护。细胞包裹已成为一种吸引人的 在没有慢性免疫抑制的情况下移植这些细胞的策略。在这里，将细胞放置 在一种免疫隔离装置中，该设备将细胞从物理上分开 免疫系统，同时提供氧气和养分。可检索的宏观细胞 - 封装设备（Macrodevice）在此上下文中很有吸引力，因为它们提供了更安全的 临床翻译的途径。不幸的是，一个独立的宏观电视节目 由于两个核心挑战：1） 外国体体对植入装置的反应，导致感染和纤维化，2） 氧气和养分不足向包裹的细胞供应。在这里，我们建议 建立在生物材料设计的最新诺言，微加工， 来自我们团队的生物电子学和细胞工程，以开发高级“智能” 具有集成电子组件的宏观电视平台，它克服了主要的 当前设备设计的局限性。首先，我们将开发一条工程的单元线 适合长期封装，适合临床翻译。里面的降落垫 这些细胞将确保稳定的转化表达，从而可以广泛控制治疗 蛋白质分泌（目标1）。另外，我们将开发出生物电子宏观电视作为一个 这些细胞在体内长期移植的平台。我们的设备将包含小说 具有均匀/受控孔径和增强氧运输特性的膜。在 并行，我们将开发新的表面涂料技术，以最大程度地减少纤维化并确保长期 术语移植生存。我们将整合质子交换机制和光电子 允许a）原位氧的成分，b）光学基因激活以允许 可触发封装细胞对蛋白质产生的控制（AIM 2）。最后，我们将测试 使用模型蛋白（SEAP）测试B6小鼠中的设备，以测试细胞的长期存活和 蛋白质递送的外部控制。我们将开发设备作为交付的平台 VIII的因子治疗血友病A（AIM 3）作为模型疾病。如果成功， 平台将代表细胞疗法领域的定性技术进步。