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: 10656255
• 负责人: Alessandro Grattoni
• 金额: $ 69.85万
• 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/10656255
• 关键词: Address; Adoption; 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; Cutaneous; Data; Diabetes Mellitus; Disease; Drug Delivery Systems; Drug Implants; Drug Kinetics; Encapsulated; Engraftment; Environment; Event; Exposure to; Future; Goals; Graft Rejection; Homing; Hormone secretion; 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; Osmosis; 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; clinical development; clinical investigation; clinical translation; conditioning; design; diabetic; diabetic rat; efficacy evaluation; engineered stem cells; euglycemia; flexibility; immunoregulation; immunosuppressed; improved; innovation; islet; islet allograft; manufacture; minimally invasive; neovascularization; pharmacokinetic model; post-transplant; prototype; scaffold; stem cells; subcutaneous; technology platform; 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。 通过局部免疫抑制剂输送成功实现长期胰岛移植以恢复正常血糖 在目标 1 中，我们将研究间充质干细胞在糖尿病宿主体内诱导血管形成的能力。 NICHE并调节NICHE免疫微环境有利于胰岛移植 在糖尿病大鼠中，目标 2 随后将进行局部洗脱的免疫抑制剂的生物分布分析。 NICHE 以及糖尿病大鼠免疫调节和药代动力学的评估 在目标 3 中， NICHE 为成功的胰岛移植提供合适的环境以恢复正常血糖的功效 将在一年内对糖尿病大鼠进行评估，同时对 NICHE 微环境进行纵向研究 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。

项目成果

Emerging immunomodulatory strategies for cell therapeutics.

• DOI: 10.1016/j.tibtech.2022.11.008
• 发表时间: 2022-12
• 期刊: Trends in biotechnology
• 影响因子: 17.3
• 作者: C. Y. Chua;A. Jiang;Tatiane Eufrásio-da-Silva;A. Dolatshahi-Pirouz;R. Langer;G. Orive;A. Grattoni

Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats.

• DOI: 10.1038/s41467-022-35629-z
• 发表时间: 2022-12-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Paez-Mayorga, Jesus;Campa-Carranza, Jocelyn Nikita;Capuani, Simone;Hernandez, Nathanael;Liu, Hsuan-Chen;Chua, Corrine Ying Xuan;Pons-Faudoa, Fernanda Paola;Malgir, Gulsah;Alvarez, Bella;Niles, Jean A.;Argueta, Lissenya B.;Shelton, Kathryn A.;Kezar, Sarah;Nehete, Pramod N.;Berman, Dora M.;Willman, Melissa A.;Li, Xian C.;Ricordi, Camillo;Nichols, Joan E.;Gaber, A. Osama;Kenyon, Norma S.;Grattoni, Alessandro
• 通讯作者: Grattoni, Alessandro