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.

摘要 对于那些1型糖尿病患者来说，等待细胞疗法来控制血糖，而不需要全身性的 免疫抑制长期以来一直令人失望。虽然最近的商业收购， 细胞疗法提供了希望，该领域最终正在取得进展，将需要许多选择， 就像新冠疫苗一样。Likarda拥有多项关于我们小说的专利 用于诱导多能干细胞分化为胰岛素产生细胞的微孔板，以及 围绕我们独特的封装技术，使我们能够使用生物相容性水凝胶， 可用于传统的微胶囊化方法。我们区分了临床上合适的 人多能细胞转化为胰岛素产生细胞（胰岛素产生诱导多能干细胞 - IPiPSC）使用我们的5步方案，与已发表的方案相比， 并可以逆转免疫受损小鼠的糖尿病。我们将胰岛包裹在 基于PEG的水凝胶和逆转糖尿病的免疫能力的大鼠在其寿命没有 免疫抑制剂或外源性胰岛素。然而，IPiPSC在PEG-100中没有很好地发挥作用。 基于水凝胶。初步数据表明，我们已经创建了一种新的水凝胶配方， 巯基化透明质酸（ThHA）是IPiPSC的更好匹配。该项目的目的是 通过在糖尿病犬中进行的初步试验，检查ThHA持久逆转大鼠糖尿病的能力。的 具体目的是：1）鉴定IPiPSC在包封和植入到细胞中后的遗传稳定性， 2）确定在糖尿病大鼠中植入ThHA包封的人IPiPSC是否能促进糖尿病大鼠的生长; 大鼠和比格犬阻止了糖尿病的临床症状; 3）识别可能的异物的生物标志物 糖尿病大鼠在移植后2周、3和9个月，糖尿病大鼠在移植后6个月， 糖尿病狗一旦我们确定了IPiPSC的最佳水凝胶配方，我们将加入 它们进入我们的带状装置，一个可回收的装置，保持大表面积和低扩散 微球的屏障特性，同时提供法规要求的可回收性。在 完成这项I期可行性研究后，我们将在自发性糖尿病患者中进行II期研究。 由于平行临床表现，犬是人类T1 D的最佳模型， 自身抗体、病理学和并发症。在自发性糖尿病患者中具有良好的长期结果 狗将为人类临床试验提供强有力的临床前数据。