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.

细胞封装技术被中毒以改善常规胰岛移植到更有效的 管理I型糖尿病。目前，终身进行全身免疫抑制以避免免疫 尽管威胁生命的不良反应，但对移植的拒绝。临床研究表明 移植物最终由于缺乏对营养和氧气供应和宿主免疫的血管支持而失败 拒绝。为了满足所有这些关键需求并得到初步研究的支持，我们提出了利基市场 具有免疫抑制剂的局部洗脱以保护的创新皮下血管化封装系统 免疫排斥的移植细胞。利基市场呈现双重可再填充的储层，用于 药物和细胞分别由纳米孔膜分离。局部免疫抑制剂递送 吸毒到发生免疫攻击的移植部位，最大程度地减少对身体其余部分的接触，从而避免 全身免疫抑制和相关的不良反应。利基细胞储层已完全血管化 功能血管，重新创建理想的物理环境，以保持长期生存能力 和移植细胞的功能。我们假设利基市场将提供一个血管化的环境 随着局部免疫抑制剂的递送，可以成功地植入长期胰岛，以恢复尤利西亚 在糖尿病宿主中。在AIM 1中，我们将研究间充质干细胞诱导血管化的能力 利基和调节利基免疫微环境是为导电的胰岛移植 在糖尿病大鼠中。通过对本地洗脱的免疫抑制剂的生物分布分析，将随后在AIM 2中 在AIM 3中，评估糖尿病大鼠的免疫调节和药代动力学。 利基效率为成功的胰岛植入提供了合适的环境，以恢复在 糖尿病大鼠将在1年内进行评估，并与利基微环境进行纵向研究 重塑。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 糖尿病以及支持性的初步数据和先前发表的工作。重要的是，利基是 设计优先考虑效率，安全性和用户可接受性的临床考虑。经细胞和 药物补充允许在需要时易于补充，因此可能会延长植入物的寿命 患者的寿命。此外，小众的薄而紧凑的尺寸，该属性小于封装 在临床调查下的植入物有利于用户可接受性。成功完成拟议的 工作将提供广泛适用的封装系统，并提供局部免疫抑制剂输送 移植胰岛的术语保护，并最大程度地减少与免疫抑制相关的不良反应 毒品。这可以转化为部署胰岛以外的细胞疗法的临床突破，包括 干细胞衍生的β细胞，以治疗糖尿病以及其他疾病。

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