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，其中天然或人工工程化的细胞分泌治疗 蛋白质被移植到身体上作为生物药物工厂，是一种有吸引力的 长期治疗血友病、糖尿病和肝病等慢性疾病的方法 紊乱然而，“现成的”治疗性细胞对宿主具有免疫原性，并且必须是免疫原性的。 免受宿主免疫系统的侵害细胞封装已经成为一种有吸引力的 策略移植这些细胞没有慢性免疫抑制。在这里，细胞被放置在 在免疫隔离装置中，所述免疫隔离装置将细胞与细胞的组分物理分离， 免疫系统，同时提供氧气和营养。可回收的宏观细胞- 封装器件（宏器件）在这种情况下是有吸引力的，因为它们提供了更安全的 临床翻译之路不幸的是，一个独立的宏设备，保持功能， 由于两个核心挑战，长期（>6个月）的人类尚未实现：1） 对植入器械的异物反应导致炎症和纤维化，以及2） 被包裹的细胞的氧气和营养物质供应不足。在此，我们建议 建立在生物材料设计，微制造， 生物电子和细胞工程从我们的团队开发一个先进的“智能” 具有集成电子元件的宏器件平台，克服了 当前设备设计的局限性。首先，我们将开发一种工程细胞系， 适合长期封装并适合临床转化。着陆垫内 这些细胞将确保稳定的转基因表达，从而允许广泛控制治疗性细胞因子。 蛋白质分泌（Aim 1）。另外，我们将开发一种生物电子宏器件， 为这些细胞在体内的长期移植提供了平台。我们的设备将结合新的 具有均匀/受控的孔径和增强的氧传输性能的膜。在 与此同时，我们将开发新的表面涂层技术，以尽量减少纤维化，并确保长期- 移植物存活率。我们将整合质子交换膜和光电 组分以允许a）原位氧产生，和B）光学基因活化以允许 通过包封的细胞对蛋白质产生的可重复控制（目的2）。最后，我们将测试 该装置在B6小鼠中使用模型蛋白（SEAP）来测试细胞的长期存活， 蛋白质递送的外部控制。我们将开发该设备作为一个平台， 因子VIII用于治疗血友病A（Aim 3）作为模型疾病。如果成功， 该平台将代表细胞治疗领域的质的技术进步。