Evaluation of a beta cell replacement therapy combined product that avoids the need for immunosuppression via localized induction of immune tolerance

评估通过局部诱导免疫耐受而无需免疫抑制的 β 细胞替代疗法组合产品

• 批准号: 10603016
• 负责人: DENA E COHEN
• 金额: $ 27.5万
• 依托单位: REGENERATIVE MEDICAL SOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603016
• 关键词: Allogenic; Allograft Tolerance; Animal Model; Antidiabetic Drugs; Appearance; Beta Cell; Biological Assay; Blood; Blood Glucose; C-Peptide; Cadaver; Caring; Cell Survival; Cell Transplantation; Cells; Chronic; Coculture Techniques; Data; Diabetes Mellitus; Diabetic mouse; Dose; Ensure; Eragrostis; Ethics; Evaluation; Flow Cytometry; Formulation; Future; Glucose; Graft Rejection; Health; Homologous Transplantation; Human; Immune Tolerance; Immune system; Immunocompetent; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; In Vitro; Insulin; Insulin Infusion Systems; Investigation; Investigational New Drug Application; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Legal patent; Life; Long-Acting Insulin; Malignant Neoplasms; Measures; Medical; Metabolic; Monitor; Mus; Organ Donor; Pancreas; Pancreas Transplantation; Patients; Pharmaceutical Preparations; Phase; Primates; Procedures; Protocols documentation; Regulatory T-Lymphocyte; Reproducibility; Research Institute; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Sampling; Serum; Source; T-Lymphocyte; Testing; Therapeutic; Tissues; Transplantation; Treatment Efficacy; Tumor Necrosis Factor Ligand Superfamily Member 6; Universities; Work; Xenograft procedure; allograft rejection; base; beta cell replacement; blood glucose regulation; capsule; cell replacement therapy; clinical translation; cost; curative treatments; diabetic patient; differentiation protocol; effector T cell; experimental study; glucose monitor; glycemic control; graft function; humanized mouse; in vitro Assay; in vivo; in vivo evaluation; indexing; induced pluripotent stem cell; infection risk; innovative technologies; insulin secretion; islet; mouse model; pre-clinical; prevent; reconstitution; regenerative; response; restoration; second transplant; side effect; stem cells; virtual

Project Summary/Abstract Diabetes is an increasingly important health problem worldwide. Despite recent advances in diabetes care, including long-acting insulin formulations, insulin pumps, and continuous glucose monitors, a majority of diabetic patients cannot achieve currently recommended targets for blood glucose control. Although transplantation of diabetic patients with donor-derived pancreatic islets or intact pancreas effectively restores blood glucose control, such procedures remain rare due to limited source material and the requirement for life-long immunosuppression. To circumvent the first of these obstacles, Regenerative Medical Solutions (RMS) has developed a proprietary protocol for converting induced pluripotent stem cells (iPSC), a virtually unlimited cell source, into islet-like clusters (ILC) of cells that include insulin-producing beta-like cells. To eliminate the need for immunosuppression, iTolerance, Inc, has advanced a product consisting of Fas ligand conjugated microparticles (iTOL-100) that, when co-transplanted with rodent or primate islets, create localized immune tolerance and provide long-term protection from allograft rejection in animal models of diabetes. In this proposed project, RMS will work with the Diabetes Research Institute at the University of Miami to test a combined product consisting of ILC mixed with iTOL-100 as a candidate cell-based diabetes therapeutic that will alleviate the need for life-long immunosuppression. To establish the feasibility of such a combined product, we will first demonstrate in vitro cytocompatibility of the two products (ILC and iTOL-100). Next, the in vivo cytocompatibility and therapeutic efficacy of the combined product will be verified in an immunocompromised mouse model of diabetes. Finally, the ability of the combined product to delay the xenograft rejection response in immune competent diabetic mice will be determined. Together, these studies will lay the groundwork for a Phase II project in which the combined product will be tested for its ability to evade allograft rejection in mice reconstituted with a human immune system, along with other essential studies that will enable clinical translation. The availability of an abundant beta cell-replacement therapy that does not require chronic immunosuppressive medication for long-term allograft tolerance will extend the reach of this form of treatment to the ever-growing numbers of patients who may benefit from it.

项目概要/摘要 糖尿病是全世界日益重要的健康问题。尽管糖尿病护理最近取得了进展， 包括长效胰岛素制剂、胰岛素泵和连续血糖监测仪，大多数糖尿病患者 患者无法达到目前推荐的血糖控制目标。虽然移植 具有供体胰岛或完整胰腺的糖尿病患者可有效恢复血糖 由于原材料有限且需要终身使用，此类程序仍然很少见 免疫抑制。为了规避第一个障碍，再生医疗解决方案 (RMS) 开发了一种用于转化诱导多能干细胞 (iPSC) 的专有协议，这是一种几乎无限的细胞 来源，进入胰岛样细胞簇（ILC），其中包括产生胰岛素的β样细胞。为了消除需要 对于免疫抑制，iTolerance, Inc 推出了一种由 Fas 配体缀合的产品 微粒 (iTOL-100)，当与啮齿动物或灵长类动物胰岛共同移植时，可产生局部免疫 耐受性并为糖尿病动物模型提供长期保护，防止同种异体移植排斥。在这个提议中 项目中，RMS 将与迈阿密大学糖尿病研究所合作测试组合产品 由 ILC 与 iTOL-100 混合组成，作为候选的基于细胞的糖尿病治疗药物，将缓解这一需求 用于终生免疫抑制。为了确定这种组合产品的可行性，我们将首先证明 两种产品（ILC 和 iTOL-100）的体外细胞相容性。接下来，体内细胞相容性和 组合产品的治疗效果将在免疫功能低下的小鼠模型中得到验证 糖尿病。最后，组合产品延迟免疫中异种移植排斥反应的能力 将确定有能力的糖尿病小鼠。这些研究将为第二阶段项目奠定基础 其中将测试组合产品在重组小鼠中避免同种异体移植排斥的能力 人类免疫系统，以及其他有助于临床转化的重要研究。可用性 一种丰富的 β 细胞替代疗法，不需要长期服用免疫抑制药物 长期的同种异体移植耐受性将使这种治疗形式的范围扩大到越来越多的患者 可能从中受益的患者。