Vascularized Islet transplantation NICHE with local immunosuppression for the treatment of type 1 diabetes

血管化胰岛移植 NICHE 结合局部免疫抑制治疗 1 型糖尿病

• 批准号: 10417410
• 负责人: Alessandro Grattoni
• 金额: $ 71.27万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417410
• 关键词: Address; Adverse effects; Affect; Allogenic; Anoxia; Beta Cell; Biodistribution; Biometry; Blood Vessels; Caring; Cell Survival; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Clinical; Clinical Research; Collaborations; Custom; Data; Diabetes Mellitus; Disease; Drug Delivery Systems; Drug Kinetics; Engraftment; Environment; Event; Exposure to; Future; Goals; Graft Rejection; Homing; Hormones; Hydrogels; Hypoxia; Immune; Immunosuppression; Immunosuppressive Agents; Implant; In Situ; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Islets of Langerhans Transplantation; Life; Longevity; Longitudinal Studies; Membrane; Mesenchymal Stem Cells; Microspheres; Modeling; Nanoporous; Nutrient; Organ; Organ Transplantation; Oxygen; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Polymers; Positioning Attribute; Publishing; Pump; Quality of life; Regimen; Research; Rest; Safety; Site; Supporting Cell; System; Technology; Testing; Therapeutic; Thinness; Tissue Engineering; Toxic effect; Translating; Transplantation; Transplantation Immunology; Vascularization; Work; allotransplant; base; clinical development; clinical investigation; clinical translation; clinically translatable; conditioning; design; diabetic; diabetic rat; efficacy evaluation; engineered stem cells; euglycemia; flexibility; immunoregulation; immunosuppressed; improved; innovation; islet; islet allograft; minimally invasive; neovascularization; pharmacokinetic model; post-transplant; prototype; stem cells; subcutaneous; tumor-immune system interactions

Cell encapsulation technologies are poised to improve conventional islet transplantation to more effectively manage type I diabetes. Currently, lifelong whole-body immunosuppression is administered to avoid immune rejection of the transplant, despite the associated life-threatening adverse effects. Clinical studies reveal that transplants eventually fail due to lack of vascular support for nutrients and oxygen supply and host immune rejection. To address all these critical needs and supported by preliminary studies, we propose the NICHE, an innovative subcutaneous vascularized encapsulation system with local elution of immunosuppressants to protect transplanted cells from immune rejection. The NICHE presents dual transcutaneously refillable reservoirs, for drug and cells, respectively, separated by a nanoporous membrane. Local immunosuppressant delivery confines drugs to the graft site where immune attack occurs, minimizing exposure to the rest of the body, thus avoiding systemic immunosuppression and associated adverse effects. The NICHE cell reservoir is fully vascularized with functional vessels, recreating an ideal physiological environment conducive for maintaining long-term viability and function of transplanted cells. We hypothesize that the NICHE will provide a vascularized environment with local immunosuppressant delivery for successful long-term islet engraftment to restore euglycemia in diabetic hosts. In aim 1, we will study the ability of mesenchymal stem cells to induce vascularization within the NICHE as well as modulate the NICHE immune microenvironment to be conducive for islet transplantation in diabetic rats. This will be followed in aim 2 by the biodistribution analysis of immunosuppressants locally eluted in the NICHE and the assessment of immunomodulation and pharmacokinetics in diabetic rats. In aim 3, the NICHE efficacy in providing a suitable environment for successful islet engraftment to restore euglycemia in diabetic rats will be assessed over 1 year, in parallel to a longitudinal study of NICHE microenvironment remodeling. The proposed studies are based on our team’s extensive expertise in implantable drug and cell delivery systems, tissue engineering, research and clinical transplantation, transplant immunology, type 1 diabetes, as well as supportive preliminary data and previously published work. Importantly, the NICHE is designed prioritizing clinical considerations of efficacy, safety and user acceptability. Transcutaneous cell and drug refilling allow for ease of drug replenishment when needed, thus extending implant lifespan potentially for the lifetime of patients. Further, the thin and compact size of the NICHE, which is smaller than the encapsulation implants under clinical investigation, is favorable for user acceptability. Successful completion of the proposed work will provide a broadly applicable encapsulation system with localized immunosuppressant delivery for long- term protection of transplanted islets, as well as minimize adverse effects associated with immunosuppressive drugs. This could translate to a clinical breakthrough for deployment of cell therapies beyond islets, including stem cell-derived β cells, to treat diabetes as well as other diseases.

细胞包封技术有望改善传统的胰岛移植， 1型糖尿病的治疗目前，终身全身免疫抑制剂被施用以避免免疫缺陷。 移植排斥，尽管有相关的危及生命的不良反应。临床研究表明， 由于缺乏营养和氧气供应的血管支持以及宿主免疫，移植最终失败。 排斥反应为了满足所有这些关键需求，并得到初步研究的支持，我们提出了生态位， 创新的皮下血管化包封系统，可局部洗脱免疫抑制剂以保护 免疫排斥的移植细胞NICHE提供了双transmitted可再填充的水库， 药物和细胞，分别由纳米多孔膜隔开。局部免疫抑制剂给药范围 将药物转移到发生免疫攻击的移植部位，最大限度地减少对身体其他部位的暴露，从而避免 全身免疫抑制和相关的副作用。NICHE细胞库完全血管化， 功能性血管，重建有利于维持长期生存能力的理想生理环境 和移植细胞的功能。我们假设小生境将提供一个血管化的环境， 局部免疫抑制剂给药，用于成功的长期胰岛移植，以恢复正常 在糖尿病宿主中。在aim1中，我们将研究间充质干细胞诱导血管化的能力， 以及调节NICHE免疫微环境以有利于胰岛移植 在糖尿病大鼠中。随后在目标2中进行局部洗脱免疫抑制剂的生物分布分析 以及糖尿病大鼠中免疫调节和药代动力学的评估。在目标3中， NICHE在为成功的胰岛移植提供合适环境以恢复优泌肽方面的功效 糖尿病大鼠将在1年内进行评估，同时进行NICHE微环境的纵向研究 重塑这项研究是基于我们团队在植入性药物和细胞移植方面的广泛专业知识。 输送系统，组织工程，研究和临床移植，移植免疫学，1型 糖尿病，以及支持性的初步数据和先前发表的工作。重要的是，NICHE 设计优先考虑有效性、安全性和用户可接受性的临床考虑。经皮细胞和 药物再填充允许在需要时容易地进行药物补充，从而潜在地延长植入物寿命， 患者的一生。此外，NICHE的薄且紧凑的尺寸，其小于封装， 临床研究中的植入物有利于用户可接受性。圆满完成拟议的 工作将提供一种广泛适用的包封系统，其具有局部免疫抑制剂递送， 长期保护移植的胰岛，以及最大限度地减少与免疫抑制相关的副作用 毒品这可能转化为胰岛以外细胞疗法部署的临床突破，包括 干细胞衍生的β细胞，用于治疗糖尿病以及其他疾病。