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 目前，治疗 I 型糖尿病的方法是进行终生全身免疫抑制以避免免疫。 尽管临床研究表明存在危及生命的不良反应，但仍拒绝移植。 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 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 NICHE，一个 创新的皮下血管化封装系统，局部洗脱免疫抑制剂以保护 NICHE 提供双重经皮可再填充储存器，用于移植细胞免受免疫排斥。 药物和细胞分别由纳米多孔膜隔开，局部免疫抑制剂的递送受到限制。 到发生免疫药物攻击的移植部位，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不良反应 NICHE 细胞库已完全血管化。 功能血管，重建有利于维持长期活力的理想生理环境 我们勇敢地说，NICHE 将提供一个血管化的环境。 局部免疫抑制剂的递送有利于成功的长期胰岛同种异体移植 恢复糖尿病非人灵长类动物 (NHP) 的血糖正常 在目标 1 中，我们将研究其功效和安全性。 局部免疫抑制剂组合以及通过体外研究表征它们从 NICHE 中的释放。 随后的目的是确定同种异体胰岛移植的最佳局部免疫抑制方案 在目标 3 中，我们将评估健康 NHP 中的药物药代动力学 (PK) 和生物分布。 NICHE 同种异体移植胰岛对糖尿病 NHP 恢复和维持血糖正常的疗效 拟议的研究基于我们团队在植入药物和细胞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，以及支持性初步数据和之前发表的工作，重要的是，NICHE 是。 设计时优先考虑有效性、安全性和用户可接受性的临床考虑。 药物再填充可以在需要时轻松补充药物，从而延长植入物的使用寿命 此外，NICHE 的尺寸较薄且紧凑，比封装更小。 正在进行临床研究的植入物，有利于用户接受建议的成功。 这项工作将提供一种广泛适用的封装系统，具有局部免疫抑制剂的递送功能，可用于长期 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副作用 这可能转化为在胰岛以外部署细胞疗法的药物临床突破，包括 干细胞衍生的β细胞，用于治疗糖尿病和其他疾病。