Vascularized NICHE with local immunosuppression for cell replacement for Type 1 diabetes

带有局部免疫抑制的血管化 NICHE 用于细胞替代治疗 1 型糖尿病

• 批准号: 10511952
• 负责人: Alessandro Grattoni
• 金额: $ 79.81万
• 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: 2022-09-12 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10511952
• 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; Dose; 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; In Vitro; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Islets of Langerhans Transplantation; Life; Longevity; Membrane; Mesenchymal Stem Cells; Microspheres; Nanoporous; Nutrient; Organ; Oxygen; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Polymers; Positioning Attribute; Procedures; Publishing; Pump; Quality of life; Regimen; Research; Rest; Safety; Site; Stem cell transplant; Supporting Cell; System; Technology; Testing; Therapeutic; Thinness; Tissue Engineering; Toxic effect; Translating; Transplantation; Transplantation Immunology; Transplantation Surgery; Vascularization; Work; allotransplant; base; clinical development; clinical investigation; clinical translation; clinically translatable; conditioning; design; diabetic; efficacy evaluation; efficacy study; euglycemia; flexibility; immunoregulation; immunosuppressed; improved; innovation; islet; minimally invasive; neovascularization; nonhuman primate; pharmacokinetic model; post-transplant; pre-clinical; prototype; stem cells; subcutaneous

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 conducive for successful long-term islet allotransplantation to restore euglycemia in diabetic nonhuman primates (NHP). In aim 1, we will study the efficacy and safety of local immunosuppressant combinations as well as characterize their release from the NICHE via in vitro studies. This will be followed in aim to define the optimal local immunosuppression regimen for islet allotransplantation in NICHE and establish drug pharmacokinetics (PK) and biodistribution in healthy NHP. In aim 3, we will evaluate the curative efficacy of NICHE with allotransplanted islets to restore and maintain euglycemia in diabetic NHPs for one year. 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.

细胞封装技术有望改进传统的胰岛移植，以更有效地 管理I型糖尿病。目前，终生全身免疫抑制是为了避免免疫 排斥移植，尽管有相关的危及生命的不良反应。临床研究显示， 由于缺乏营养、氧气供应和宿主免疫的血管支持，移植最终失败 拒绝。为了解决所有这些关键需求，并得到初步研究的支持，我们提出了利基市场，以及 创新的皮下血管包裹系统，局部洗脱免疫抑制剂以保护 来自免疫排斥反应的移植细胞。这个壁龛提供了两个经皮肤可再灌装的储液罐， 药物和细胞分别由纳米孔膜隔开。局部免疫抑制剂的给药限制 药物到发生免疫攻击的移植物部位，最大限度地减少对身体其他部位的接触，从而避免 全身性免疫抑制及相关不良反应。壁龛细胞储存库被充分的血管化为 功能血管，重塑有利于维持长期生存的理想生理环境 和移植细胞的功能。我们假设这个壁龛将提供一个有血管的环境 局部给予免疫抑制剂有利于同种异体胰岛移植的成功 恢复糖尿病非人类灵长类动物(NHP)的正常血糖。在目标1中，我们将研究阿司匹林的疗效和安全性 局部免疫抑制剂组合，并通过体外研究表征其从利基中的释放。 接下来将确定胰岛同种异体移植的最佳局部免疫抑制方案。 并建立药物在健康NHP体内的药代动力学和生物分布。在目标3中，我们将评估 同种异体胰岛移植壁龛恢复和维持正常血糖的疗效观察 一年的时间。建议的研究是基于我们团队在植入性药物和细胞方面的广泛专业知识 递送系统、组织工程学、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以前发表的工作。重要的是，利基市场是 设计优先考虑疗效、安全性和用户可接受性的临床因素。经皮细胞和 药物补充允许在需要时容易地进行药物补充，从而延长植入物的寿命 病人的生命周期。此外，壁龛的薄而紧凑的大小，比封装要小 植入物在临床研究中，有利于使用者的接受性。圆满完成拟议中的 工作将提供一种广泛适用的具有局部免疫抑制剂长时间给药的胶囊系统。 移植胰岛的长期保护，以及最大限度地减少与免疫抑制相关的不良反应 毒品。这可能转化为在胰岛以外部署细胞疗法的临床突破，包括 干细胞来源的β细胞，用于治疗糖尿病和其他疾病。