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：
10038171
负责人：
David Alan Kass
金额：
$ 79.33万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10038171
关键词：
3-Dimensional Animal Model Architecture Becker Muscular Dystrophy Behavior Benchmarking Bioavailable Biological Assay 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 Dose Duchenne muscular dystrophy Dystrophin Effectiveness 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 Phase III Clinical Trials Phenotype Physiological Play Population Positioning Attribute Proteins Protocols documentation Recovery Reporting Role Running Safety Severity of illness Signal Transduction Silicones Skeletal Muscle Skeletal Myoblasts Stress Striated Muscles System Techniques Testing Therapeutic Therapeutic Studies Time Tissue Engineering Tissue Model Tissues Toxic effect Treatment Efficacy Utrophin Validation base chromatin immunoprecipitation clinical phenotype cost design disease heterogeneity disease phenotype drug testing dystrophic cardiomyopathy efficacy testing flexibility high throughput analysis high throughput screening human tissue imaging capabilities improved in vivo in vivo Model induced pluripotent stem cell inhibitor/antagonist kidney fibrosis male mdx mouse medication safety 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.

项目概要目标：我们将开发并验证 3D 工程肌肉组织 (EMT)，作为一种可行的“临床试验” 芯片”平台可确定人类杜兴肌和贝克肌的心肌和骨骼肌缺陷营养不良（DMD/BMD），并测试治疗小说的功效我们利用最先进的技术。我们团队开发的：（1）一种分化和成熟 iPSC 来源的心肌细胞和骨骼细胞的方法 (2) 来自 DMD 患者的表型确认的 hiPSC (3) 使用 3D 组织工程技术脱细胞细胞外基质 (dECM) (4) 构建多细胞架构的方案 (5) 非侵入性、 (6) 小说阳离子通道拮抗剂——TRPC6，在严重 DMD 小鼠模型中显示出体内潜力。将这些技术和方法集成到概括 DMD 主要特征的测定中，从而使实时评估治疗效果，以证明我们的 EMT 检测作为“临床试验”的实用性。芯片”，新的 TRPC6 阻断剂通过了 I 期安全性/毒性、EMT 中的 II 期剂量/功效测试。少数 DMD 患者，以及来自较大异质 DMD/BMD 群体的 EMT 的 III 期结果焦点/目标：UG3 阶段建立了设计优化的 hiPSC 衍生的心脏和疾病的方案。骨骼肌组织使用我们的磁传感平台并将该平台与我们的高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肌细胞产生的工程化肌肉组织这将验证“临床芯片试验”检测是否具有足够的能力。概括 DMD 表型、对疾病严重程度进行分层以及定义收缩性和电生理结果可用于指导 UH3 阶段的治疗效果测试。阶段将使用 EMT 测定来模拟运行三阶段临床试验的方案。测试的是 BI 749327，一种新型、有前途的选择性和有效的 TRPC6（瞬时受体电位- Canonical 通道 6）。该药物是第一个口服生物可利用的 TRPC6 阻滞剂，我们已经报道过。在体内压力负荷和肾纤维化模型中的功效新数据显示了在 DMD 中的功效。 BI 749327 的毒性特征和剂量范围是在健康 EMT 中确定的，目标 2：机械和电气。将 BI 749327 在一定剂量范围内的效果应用于 DMD 衍生的 EMT，以确定最佳剂量和在目标 3 中，我们将使用先前的信息来进行更广泛的测试。进行一项 3 期研究，该研究将涉及来自具有不同突变的 DMD 患者的 iPSC 衍生 EMT 导致肌营养不良蛋白完全缺失，以及表达突变肌营养不良蛋白的 BMD 患者，导致不同的肌营养不良蛋白目标是建立芯片临床试验，为人类 DMD 临床提供信息和支持。试验设计、优化剂量和为患者提供个性化治疗。