An Ultrasensitive, High-Throughput, and Low-Cost Autoimmunity Panel for the Early Diagnosis and Improved Treatment of Type 1 Diabetes

用于 1 型糖尿病早期诊断和改进治疗的超灵敏、高通量和低成本自身免疫组合

• 批准号: 9559575
• 负责人: David Seftel
• 金额: $ 74.98万
• 依托单位: ENABLE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9559575
• 关键词: Acceleration; Affect; Agglutination; Agreement; American; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmunity; Automation; Beta Cell; Biological Assay; Biological Sciences; CLIA certified; Cessation of life; Chemistry; Child; Clinical; Color; Comorbidity; Companions; Consumption; DNA; DNA Probes; DNA Sequence; Data; Decentralization; Detection; Development; Devices; Diabetes Mellitus; Diabetes autoantibodies; Diabetic Ketoacidosis; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; FDA approved; Funding; General Population; Gold; Hemoglobin; Immunoassay; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Laboratories; Life; Lipids; Liquid substance; Manuals; Methods; Monoclonal Antibodies; Output; Patients; Pediatric Hospitals; Phase; Population; Preventive; Procedures; Process; Production; Quality Control; Radioactive; Radioimmunoassay; Reagent; Reproducibility; Research; Resources; Risk; Risk Assessment; Robotics; Sampling; Sensitivity and Specificity; Serum; Services; Site; Source; System; Technology; Test Result; Testing; Therapeutic; Time; Validation; Variant; Work; base; biobank; clinical diagnostics; cohort; commercialization; cost; design; diabetes control; emergency settings; fluorophore; improved; islet cell antibody; manufacturing process; medical schools; member; novel; pre-clinical; predictive marker; prevent; prototype; quality assurance; screening; screening panel; skills; software development; tertiary care

Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys islet-cell insulin production. Millions of Americans, especially children, are affected and must rely on lifelong insulin administration and struggle with life-threatening co-morbidities. Most new cases of T1D are diagnosed in emergency settings with presentation in potentially deadly diabetic ketoacidosis (DKA). Current pre-clinical diagnostic tests that can permit preventive action for T1D are slow and not readily available outside of tertiary care centers. In this proposal Enable Biosciences will further develop and validate a novel low-cost and high-throughput immunoassay to rapidly and sensitively screen for the four cardinal autoantibody markers that predict risk for type 1 diabetes. Such a test could supplant the current expensive, slow radioactive method. By reducing costs while retaining sensitivity and specificity with a robust very low-sample volume assay, Enable Biosciences' product will permit increased testing to reveal incipient T1D in the general population at the optimal time for intervention. During the Phase I funding period, Enable prototyped a 3-member T1D autoantibody panel using their core Antibody Detection by Agglutination-PCR (ADAP) technology and demonstrated substantial equivalence with the gold-standard assay while removing reliance on radioactive reagents. In this Phase 2 proposal, Enable presents a comprehensive plan to enhance this panel via automation using a dedicated robotic liquid handling system, greatly increasing assay throughput and reliability while further reducing costs. We will also adapt our assay chemistry to be able to use Taqman probes. This will result in further throughput acceleration and cost reductions. Building upon promising preliminary results from Phase 1 work, we will incorporate the fourth and final T1D autoantibody (ZnT8) to create the world's first ever “4-in-1” screening panel, creating a product that provides the highest level of risk assessment for T1D screening and diagnosis. These optimized and automated panels will then be rigorously validated with thousands of clinical samples provided by our wide network of enthusiastic academic and institutional partners that include the Joslin Diabetes Center, Stanford School of Medicine, the T1D Exchange and Tufts Children's Hospital. This data will be used to plan and direct commercialization efforts that will include a phased approach from delivering a CLIA-certified laboratory service to FDA-approved reagent kits with companion integrated sample-to-answer hardware devices for easy, low-skill use and deployment across research and clinical laboratories and screening sites worldwide.

1 型糖尿病 (T1D) 是一种破坏性自身免疫性疾病，会破坏胰岛细胞的胰岛素分泌，数以百万计的美国人（尤其是儿童）受到影响，必须终生依赖胰岛素​​注射，并与危及生命的合并症作斗争。在紧急情况下被诊断出可能致命的糖尿病酮症酸中毒 (DKA)，目前可以采取预防 T1D 行动的临床前诊断测试进展缓慢，并且在三级护理中心之外不易获得。在这项提案中，Enable Biosciences 将进一步开发和验证一种新型低成本、高通量免疫测定法，以快速、灵敏地筛选预测 1 型糖尿病风险的四种主要自身抗体标记物，这种测试可以取代目前昂贵的、缓慢的放射性测试。通过降低成本，同时通过强大的极低样本量检测保持灵敏度和特异性，Enable Biosciences 的产品将允许在干预的最佳时间增加检测，以揭示一般人群中的早期 T1D。在第一阶段资助期间，Enable 使用其核心凝集 PCR 抗体检测 (ADAP) 技术制作了一个由 3 名成员组成的 T1D 自身抗体小组原型，并证明了与金标准检测的实质等效性，同时消除了对放射性试剂的依赖。 Enable 提出了一项全面的计划，通过使用专用机器人液体处理系统的自动化来增强该面板，从而大大提高检测通量和可靠性，同时进一步降低成本。这将导致通量进一步加速并降低成本，基于第一阶段工作的有希望的初步结果，我们将整合第四种也是最后一种 T1D 自身抗体 (ZnT8)，以创建世界上第一个“四合一”筛选组合，从而创建该产品可为 T1D 筛查和诊断提供最高水平的风险评估，然后将使用我们广泛的热心学术和机构合作伙伴网络（包括 Joslin Diabetes）提供的数千个临床样本对这些优化的自动化面板进行严格验证。该数据将用于规划和指导商业化工作，其中包括从提供 CLIA 认证的实验室服务到 FDA 批准的带有配套集成样本的试剂盒的分阶段方法。应答硬件设备，可在全​​球研究和临床实验室以及筛查场所轻松、低技能地使用和部署。