Clinical grade insulin-producing iPSCs encapsulated with durable hyaluronic acid for long-term treatment of type 1 diabetes

临床级产生胰岛素的 iPSC 封装有耐用的透明质酸，用于长期治疗 1 型糖尿病

• 批准号: 10322774
• 负责人: Lisa A. Stehno-Bittel
• 金额: $ 25.63万
• 依托单位: LIKARDA, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2022-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322774
• 关键词: 3-Dimensional; Alginates; Animals; Area; Autoantibodies; Beta Cell; Biological Markers; Blood Chemical Analysis; Blood Glucose; Canis familiaris; Cartoons; Cell Therapy; Cells; Characteristics; Chemistry; Clinical; Clinical Trials; Collagen; Cosmetics; Data; Devices; Diabetes Mellitus; Diffusion; Encapsulated; Feasibility Studies; Fibrosis; Filler; Foreign Bodies; Foreign-Body Reaction; Formulation; Future; Gel; Genetic; Glucose tolerance test; Glycocalyx; Goals; Grant; Growth Factor; Hematology; Human; Human Cell Line; Hyaluronic Acid; Hydrogels; Hyperglycemia; Immune; Immune system; Immunocompetent; Immunohistochemistry; Immunosuppression; Implant; In Vitro; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Joints; Kidney; Laboratories; Legal patent; Longevity; Lubricants; Methods; Microencapsulations; Microspheres; Modeling; Monitor; Mus; Omentum; Pathology; Phase; Pilot Projects; Process; Protocols documentation; Publishing; Quantitative Reverse Transcriptase PCR; Rattus; Research; Rodent; Rodent Model; Small Business Innovation Research Grant; Source; Stains; Stem Cell Research; Surface; Technology; Testing; Tissues; Transplantation; Urinalysis; Vaccines; Vertebral column; Work; base; biomaterial compatibility; capsule; coronavirus disease; diabetic; diabetic rat; differentiation protocol; human data; implantation; improved; in vivo; induced pluripotent stem cell; islet; macrophage; neutrophil; novel; phase 2 study; pilot trial; pluripotency; post-transplant; pre-clinical; response; stem cells

Abstract For those with type 1 diabetes, the wait for a cell therapy to control blood glucose without systemic immunosuppression has been long and disappointing. While recent commercial acquisitions for such cell therapies offer hope that the field is finally advancing, there will be a need for numerous options, much like the approach to the COVID vaccine. Likarda holds multiple patents surrounding our novel microplates used for differentiation of induced pluripotent stem cells into insulin-producing cells and around our unique encapsulation technology that allows us to use biocompatible hydrogels that are not available to traditional microencapsulation approaches. We have differentiated clinically-appropriate human pluripotent cells into insulin-producing cells (Insulin-Producing induced Pluripotent Stem Cells – IPiPSCs) using our 5-step protocol that incorporates few growth factors compared to published protocols and can reverse diabetes in immune-compromised mice. We have encapsulated islets in a PEG-based hydrogel and reversed diabetes in immune-competent rats for their lifespan without immunosuppression or exogenous insulin. However, the IPiPSCs did not function well in the PEG- based hydrogel. Preliminary data indicates that a new hydrogel formulation we have created based on thiolated hyaluronic acid (ThHA) is a better match for the IPiPSCs. The purpose of this project is to examine the ability of ThHA to durably reverse diabetes in rats with a pilot trial in diabetic dogs. The specific aims are: 1) Identify genetic stability of the IPiPSCs after encapsulation and implantation into diabetic rats; 2) Determine whether implantation of ThHA-encapsulated human IPiPSCs in diabetic rats and beagles arrests the clinical signs of diabetes; 3) Identify biomarkers of a possible foreign body reaction in the surrounding tissue at 2 wks, 3 and 9 mos post-transplant int diabetic rats and 6 mos in diabetic dogs. Once we confirm the optimal hydrogel formulation for the IPiPSCs, we will incorporate them into our ribbon device, a retrievable device that maintains the large surface area and low diffusion barrier characteristics of microspheres while delivering retrievability for regulatory requirements. At the completion of this Phase I feasibility study, we will undergo Phase II studies in spontaneously diabetic dogs, which are an optimal model for human T1D due to parallel clinical presentation, similar autoantibodies, pathology and complications. Promising long-term results in spontaneously-diabetic dogs would offer strong preclinical data for human clinical trials.

抽象的 对于 1 型糖尿病患者来说，需要等待细胞疗法来控制血糖，而无需全身治疗 免疫抑制的发展历史悠久且令人失望。 细胞疗法带来了希望，即该领域最终取得进展，将需要多种选择， 就像新冠疫苗的方法一样，Likarda 拥有围绕我们的小说的多项专利。 用于诱导多能干细胞分化为胰岛素产生细胞的微孔板 围绕我们独特的封装技术，该技术使我们能够使用非生物相容性水凝胶 我们已经针对临床适用的情况进行了区分。 将人类多能细胞转化为胰岛素产生细胞（Insulin-Producinginduced Pluripotency Stem Cells – IPiPSC）使用我们的 5 步协议，与已发布的相比，该协议包含很少的生长因子 我们将胰岛封装在一个胰岛细胞中，并可以逆转免疫受损小鼠的糖尿病。 基于 PEG 的水凝胶可在免疫功能正常的大鼠中逆转糖尿病，使其终生不受影响 然而，IPiPSC 在 PEG- 中不能很好地发挥作用。 初步数据表明，我们基于水凝胶创建了一种新的水凝胶配方。 硫醇化透明质酸 (ThHA) 与 IPiPSC 更匹配。该项目的目的是 通过在糖尿病狗身上进行的试点试验，检查 ThHA 持久逆转大鼠糖尿病的能力。 具体目标是： 1) 确定 IPiPSC 封装并植入后的遗传稳定性 2) 确定ThHA封装的人IPiPSCs是否植入糖尿病大鼠体内 大鼠和比格犬阻止糖尿病的临床症状；3) 识别可能的异物的生物标志物 糖尿病大鼠移植后 2 周、3 和 9 个月以及移植后 6 个月周围组织的反应 一旦我们确定了 IPiPSC 的最佳水凝胶配方，我们就会将其纳入其中。 将它们放入我们的带状装置中，这是一种可回收的装置，可保持大表面积和低扩散 微球的阻隔特性，同时提供满足监管要求的可回收性。 完成第一阶段可行性研究后，我们将进行自发性糖尿病的第二阶段研究 狗，由于平行的临床表现，是人类 T1D 的最佳模型，类似 自身抗体、病理学和并发症对自发性糖尿病有希望的长期结果。 狗将为人类临床试验提供强有力的临床前数据。