Engineering Clinical Trials on a Chip for Dystrophin-Deficient Muscular Dystrophy

抗肌营养不良蛋白缺陷型肌营养不良症芯片的工程临床试验

基本信息

批准号：
10685462
负责人：
David Alan Kass
金额：
$ 78.99万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685462
关键词：
3-Dimensional Animal Model Architecture Becker Muscular Dystrophy Behavior Benchmarking Biological Assay Biological Availability Biological Markers Cardiac Cardiac Myocytes Cations Cell Communication Cell Shape Cells Child Clinical Clinical Engineering Clinical Trials Clinical Trials Design Clustered Regularly Interspaced Short Palindromic Repeats Data Data Set Development Disease Disease stratification Dose Duchenne muscular dystrophy Dystrophin Electrophysiology (science)Engineering Extracellular Matrix Functional disorder Gene Deletion Genes Genetic Diseases Genetic Heterogeneity Genotype Goals Heart failure Heterogeneity Histology Human Image In Vitro Ion Channel Link Magnetism Mechanics Methods Modeling Modification Molecular Mus Muscle Muscle function Muscular Dystrophies Mutation Myocardium Myopathy Normal Cell Optics Oral Outcome Output Patients Pharmaceutical Preparations Pharmacodynamics Phase Phenotype Physiological Play Population Positioning Attribute Proteins Protocols documentation Recovery Reporting Role Running Safety Severity of illness Silicones Skeletal Muscle Skeletal Myoblasts Stress Striated Muscles System TRP channel Techniques Testing Therapeutic Therapeutic Studies Time Tissue Engineering Tissue Model Tissues Toxic effect Treatment Efficacy Utrophin Validation antagonist base chromatin immunoprecipitation clinical phenotype clinical trial on a chip cost design disease heterogeneity disease phenotype drug testing dystrophic cardiomyopathy effectiveness evaluation efficacy evaluation efficacy testing flexibility high throughput analysis high throughput screening human tissue imaging capabilities improved in vivo in vivo Model induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inhibitor kidney fibrosis male mdx mouse medication safety microphysiology system molecular marker mortality mouse model muscle engineering mutant novel novel therapeutics patient population personalized medicine phase 1 study pre-clinical pressure receptor response safety testing screening sensor skeletal skeletal muscle weakness skeletal tissue

项目摘要

PROJECT SUMMARY Goal: We will develop and validate 3D engineered muscular tissues (EMTs) as an enabling “clinical trial-on-a- chip” platform to determine cardiac and skeletal muscle deficiencies in human Duchenne and Becker muscular dystrophy (DMD/BMD), and test the efficacy of novel therapeutics. We leverage state-of-art techniques developed by our team: (1) a method to differentiate and mature iPSC-derived cardiomyocytes and skeletal myoblasts. (2) phenotype-confirmed hiPSCs from DMD patients (3) 3D-tissue engineering technique using decellularized extracellular matrix (dECM) (4) Protocols to construct a multicellular architecture (5) non-invasive, high-throughput screening system allowing parallel electrophysiological and contractile assessment. (6) Novel antagonist of the cation channel – TRPC6 that displays in vivo potential in a severe mouse model of DMD. We integrate these techniques and methods into an assay that recapitulates the major hallmarks of DMD, enabling real-time assessment of treatment efficacy. To demonstrate the utility of our EMT assay as a “clinical trial-on-a- chip,” the new TRPC6 blocker is tested through Phase I safety/toxicity, Phase II dosing/ efficacy in EMT from a few DMD patients, and Phase III outcomes in EMTs from a larger heterogenous population of DMD/BMD patients. Focus/Aim: The UG3 phase establishes protocols to engineer optimized, hiPSC-derived cardiac and skeletal muscle tissues using our magnetic sensing platform and integrating this platform with our high- throughput imaging capabilities. The developed platform will be used to characterize the functional phenotypes of engineered muscle tissues generated from hiPSC-derived cardiomyocytes and skeletal myoblasts from dystrophic patients or healthy controls. This will verify that the ‘clinical trial-on-a-chip’ assay possesses sufficient sensitivity to recapitulate DMD phenotypes, stratify disease severity, and define contractility and electrophysiological outcomes that can be used to inform therapy efficacy testing in the UH3 phase. The UH3 phase will use the EMT assay to simulate protocols for running a 3-phase clinical trial. The therapeutic to be tested is BI 749327, a novel and promising selective and potent inhibitor of TRPC6 (Transient Receptor Potential- Canonical channel 6). The drug is the first orally bioavailable TRPC6 blocker, and we have already reported efficacy in pressure-load and renal fibrosis models in vivo. New data shows efficacy in DMD. In Aim 1, the toxicity profile and dose range of BI 749327 is determined in healthy EMTs. In Aim 2, mechanical and electrical effects of BI 749327 over a range of doses is applied to DMD-derived EMTs to identify an optimal dose and pharmacodynamic profile to move forward to broader testing. In Aim 3, we will use the prior information to perform a Phase 3-style study that will involve iPSC-derived EMTs from DMD patients with varying mutations causing total dystrophin deletion, and from BMD patients that express mutant dystrophin resulting in varying clinical phenotypes. The goal is to establish the clinical trial-on-a-chip to inform and support human DMD clinical trial design, optimizing dosing and personalizing therapy for patients.

项目摘要目标：我们将开发和验证3D工程肌肉组织（EMT）作为“临床试验” 芯片”平台，以确定人类和贝克尔肌肉的心脏和骨骼肌缺陷营养不良（DMD/BMD），并测试新疗法的效率。我们利用最先进的技术由我们的团队开发：（1）一种分化和成熟IPSC衍生的心肌细胞和骨骼的方法成肌细胞。（2）使用DMD患者的表型确认的HIPSC（3）3D组织工程技术使用脱细胞外基质（DECM）（4）构建多细胞体系结构（5）非侵入性的协议，高通量筛选系统允许平行电生理和收缩评估。（6）小说阳离子通道 - TRPC6的拮抗剂在DMD的严重小鼠模型中显示体内电位。我们将这些技术和方法整合到概括DMD的主要标志的测定中实时评估治疗效率。为了证明我们的EMT分析的实用性，作为“临床试验” 芯片，“新的TRPC6阻滞剂通过I期安全/毒性测试 DMD患者很少，来自较大的异源DMD/BMD的EMT中的III期结果患者。焦点/目标：UG3阶段为工程师优化，HIPSC衍生的心脏和使用我们的磁性传感器平台的骨骼肌肉时间安排，并将该平台与我们的高吞吐量成像功能。开发的平台将用于表征功能表型由HIPSC衍生的心肌细胞和骨骼成肌细胞产生的工程肌肉组织营养不良患者或健康对照。这将验证“临床试验”测定法具有足够的敏感性概括DMD表型，分层疾病的严重程度，并定义收缩力和可用于在UH3阶段为治疗效率测试提供信息的电生理结果。 UH3 阶段将使用EMT测定法来模拟进行3阶段临床试验的方案。治疗经过测试的是BI 749327，这是一种新颖且承诺的选择性和潜在的抑制剂（瞬态受体电位 - 规范频道6）。该药物是第一个口头生物利用的TRPC6阻滞剂，我们已经报告了体内压力负荷和肾纤维化模型的功效。新数据显示了DMD的效率。在AIM 1中 BI 749327的毒性特征和剂量范围在健康的EMT中确定。在AIM 2中，机械和电气 BI 749327对一系列剂量的影响应用于DMD衍生的EMT，以识别最佳剂量和最佳剂量药学特征，以进行更广泛的测试。在AIM 3中，我们将使用先前的信息来进行三阶段研究的研究，该研究将涉及来自不同突变的DMD患者的IPSC衍生的EMT 引起总肌营养不良蛋白缺失，以及来自表达突变型肌营养不良蛋白的BMD患者，导致变化临床表型。目的是建立临床试验，以告知和支持人DMD临床试验设计，优化患者的剂量和个性化疗法。