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.

项目摘要/摘要 糖尿病是全球越来越重要的健康问题。尽管最近的糖尿病护理进展， 包括长效胰岛素配方，胰岛素泵和连续的葡萄糖监测器，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有效恢复血糖 控制，由于原始材料有限和对终身的要求，此类程序仍然很少 免疫抑制。为了避免这些障碍中的第一个，再生医学解决方案（RMS）具有 开发了一种专有协议，用于转换诱导的多能干细胞（IPSC），几乎是无限的细胞 来源，进入包括产生胰岛素的β样细胞的细胞的胰岛样簇（ILC）。消除需求 对于免疫抑制，Itolerance，Inc已推进了由FAS配体共轭组成的产品 微粒（ITOL-100）与啮齿动物或灵长类小岛共转移时，会产生局部免疫 耐受性并长期保护糖尿病动物模型中的同种异体移植排斥。在此提议中 项目，RMS将与迈阿密大学的糖尿病研究所合作测试合并产品 由ITOL-100混合的ILC组成，作为候选细胞基于细胞的糖尿病治疗，可以减轻需求 终身免疫抑制。为了确定这种合并产品的可行性，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 合并产品的治疗功效将在免疫功能低下的小鼠模型中得到验证 糖尿病。最后，合并产品延迟免疫中异种移植反应反应的能力 将确定有能力的糖尿病小鼠。这些研究将为II期项目奠定基础 其中将测试合并产品的能力，以逃避与与 人类免疫系统，以及其他可以实现临床翻译的基本研究。可用性 不需要慢性免疫抑制药物的丰富β细胞替代疗法 长期的同种异体耐受性将使这种形式的治疗范围扩大到不断增长的数字 可能会从中受益的患者。