SA-FasL-engineered human islets as a novel product for the treatment of type 1 diabetes

SA-FasL 工程化人类胰岛作为治疗 1 型糖尿病的新产品

• 批准号: 9347611
• 负责人: ESMA S YOLCU
• 金额: $ 22.45万
• 依托单位: FASCURE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347611
• 关键词: Acute; Adverse effects; Affect; Alloantigen; Allogenic; Allografting; Antigens; Apoptosis; Apoptotic; Autoantigens; Autoimmune Diseases; Autoimmunity; Binding; Biologic Development; Biotin; CD95 Antigens; Cell surface; Cells; Chronic; Cleaved cell; Clinic; Clinical; Clinical Trials; Contracts; Data; Development; Diabetes Mellitus; Engineering; Ensure; Eragrostis; Extracellular Domain; FOXP3 gene; Failure; Generations; Goals; Graft Rejection; Graft Survival; Home environment; Homeostasis; Human; Human Engineering; Hyperglycemia; Hypoglycemia; IL2RA gene; Immune; Immune Targeting; Immunomodulators; Immunosuppression; Insulin; Insulin-Dependent Diabetes Mellitus; Investigational New Drug Application; Islets of Langerhans; Islets of Langerhans Transplantation; Lead; Lesion; Ligands; Manufacturer Name; Matrix Metalloproteinases; Mediating; Membrane; Membrane Proteins; Memory; Metabolic Control; Metalloproteases; Modeling; Mutation; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Physiological; Play; Population; Prevention; Proteins; Quality of life; Recurrence; Regulatory T-Lymphocyte; Rights; Rodent; Role; Site; Small Business Technology Transfer Research; Solid; Streptavidin; Surface; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Translations; Transplantation; Tumor Necrosis Factor Ligand Superfamily Member 6; base; cGMP production; chimeric gene; chronic autoimmune disease; clinical application; clinical translation; design; efficacy testing; gene therapy; graft function; humanized mouse; immunoregulation; immunosuppressed; improved; insulin secretion; interest; islet; islet allograft; mouse model; negative affect; novel; novel strategies; prevent; product development; response; scale up; stability testing; standard care; standard of care; technological innovation

PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide. Exogenous insulin treatment is the standard of care for T1D, but often negatively affects the quality of life and is ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show that human islet allografts can restore long-term normoglycemia and insulin independence, protect from severe hypoglycemia, and slow progression of microvascular lesions in immunosuppressed T1D patients. However, immune rejection and continuous use of immunosuppression to control rejection are two major limitations of clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and also has significant adverse effects on the graft and graft recipients. Therefore, the development of novel approaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. FasCure Therapeutics is focused on the development of biologics with desired immune modulatory activities for targeted indications. The Company has exclusive rights to a portfolio of proprietary novel immune inhibitory ligands as components of an immunomodulatory platform for prevention and treatment of autoimmune diseases and graft rejection. The Company’s lead therapeutic platform includes islets engineered with a novel form of Fas ligand immunomodulatory protein, SA-FasL. T cells are the main culprits of T1D as well as allogeneic islet graft rejection. T cells upregulate Fas receptor on their surface following antigen activation, and become sensitive to Fas/FasL-mediated apoptosis. Importantly, FasL-induced apoptosis plays an important role in T cell homeostasis and tolerance to self-antigens. As such, SA-FasL has significant potential for the induction of tolerance to auto and alloantigens. Consistent with this notion, the transient display of SA-FasL protein on pancreatic islets have shown robust efficacy in overcoming immune rejection in various allogeneic and xenogeneic rodent transplantation models. The major goals of this phase I STTR application is to: i) assesses the feasibility of engineering human islets with SA-FasL protein without negatively impacting their function, and ii) test the efficacy of SA-FasL-engineered islets in overcoming rejection in a humanized mouse model in the absence of continuous immunosuppression. If feasibility and efficacy are shown in the humanized mouse model, the SA-FasL-engineered human islets will be further developed as a novel product in a Phase II STRR application for translation into clinic.

项目摘要 1型糖尿病（T1D）是一种慢性自身免疫性疾病，影响了全球约1％的人口。外源 胰岛素治疗是T1D的护理标准，但通常会对生活质量产生负面影响，并且无效 防止复发性高血糖发作和慢性并发症。最近的研究表明人类 胰岛同种异体移植可以恢复长期正常血糖和胰岛素独立性，免受严重保护 免疫抑制的T1D患者的低血糖和微血管病变的缓慢进展。然而， 免疫排斥和连续使用免疫抑制来控制排斥反应是两个主要局限性 临床胰岛移植。标准免疫抑制无效地实现长期移植物存活率 并且对移植者和移植者也有重大的不利影响。因此，新颖的发展 防止在没有慢性免疫抑制的情况下拒绝胰岛移植物的方法是一个重要目标。 Fascure Therapeutics的重点是具有所需免疫调节的生物制剂的发展 有针对性指示的活动。该公司拥有专有小说免疫投资组合的专有权 抑制配体作为预防和治疗的免疫调节平台的组成部分 自身免疫性疾病和移植抑制。该公司的铅疗法平台包括工程设计的胰岛 带有新型FAS配体免疫调节蛋白的形式，SA-FASL。 T细胞是T1D的主要罪魁祸首 以及同种异体胰岛移植的排斥。 T细胞在抗原后将FAS受体上调在其表面上 激活，并对FAS/FASL介导的细胞凋亡敏感。重要的是，FASL诱导的凋亡作用 在T细胞稳态和对自我抗原的耐受性中的重要作用。因此，SA-FASL具有重要意义 诱导汽车和同种抗原的耐受性的潜力。与这个概念一致 在胰岛上显示SA-FASL蛋白在克服免疫排斥中表现出强大的效率 各种同种异体和异种啮齿动物移植模型。我sttr的主要目标 应用是：i）评估没有SA-FASL蛋白的工程人胰岛的可行性 对其功能产生负面影响，ii）测试SA-FASL工程胰岛的效率 在没有连续免疫抑制的情况下，人性化小鼠模型的排斥。如果可行的话 在人源化小鼠模型中显示了有效的人，SA-FASL工程的人类胰岛将进一步 在II期STRR应用中以新型产品的转化为临床。