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.

细胞封装技术有望提高传统胰岛移植的效率

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.

具有局部免疫抑制的植入式生态裂市场，用于同种异体移植的胰岛，可实现大鼠的1型糖尿病逆转。

• 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