Personalized therapy for AATD-associated liver disease via IPS modeling

通过 IPS 建模对 AATD 相关肝病进行个性化治疗

基本信息

批准号：
8888673
负责人：
ANDREW A WILSON
金额：
$ 50.38万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888673
关键词：
Adult Affect Alleles Autophagocytosis Base Pairing Biological Biological Models Blinded Carbamazepine Cell physiology Cells Child Clinical Clinical Treatment Clinical Trials Clinical Trials Design Clustered Regularly Interspaced Short Palindromic Repeats Data Daughter Disease Drug toxicity Effectiveness Endoplasmic Reticulum Enrollment Evaluation Future Gene Expression Gene Expression Profile Genetic Genetic Variation Goals Hepatocyte Hepatotoxicity Hereditary Disease Human In Vitro Individual Libraries Liver Fibrosis Liver diseases Lung diseases Measures Mediating Modeling Molecular Mutation Noise Other Genetics Outcome Participant Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase II Clinical Trials Phenotype Point Mutation Polymers Population Production Proteins Randomized Clinical Trials Relative (related person)Reporting Research Research Personnel Seminal Stem cells System Testing Tissues Toxic effect Transgenic Mice alpha 1-Antitrypsin Deficiency base blind cell type disease phenotype drug efficacy drug testing efficacy testing experience gene correction genome editing human CASP4 protein in vivo induced pluripotent stem cell innovation liver injury multicatalytic endopeptidase complex mutant novel personalized medicine protein aggregate protein folding protein misfolding public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Human clinical drug trials test the efficacy and toxicity of drugs in groups of patients affected with a given disease and in doing so provide an estimate of a drug's effects across a population. However, they often do not give clinicians the ability to predict which specific patients are likely either to benefit or to experience serious toxic effects from the drug being tested. The discovery of induced pluripotent stem cells (iPSCs) has now made it possible to model genetic diseases in vitro using the differentiated progeny of iPSCs created from patients. For example, PiZZ iPS-- derived hepatocytes have been shown to recapitulate key features of alpha-- 1 antitrypsin deficiency (AATD) associated liver disease, demonstrating the potential of disease-- specific iPS-- derived cells to model this and other genetic diseases. The studies outlined in this application test a novel, personalized approach to clinical drug trials, using an iPS-- based model system to test the effectiveness of the drug carbamazepine in ameliorating an AATD-- associated liver disease phenotype. Carbamazepine will be tested in iPS-- derived hepatocytes created from subjects enrolled in the ongoing clinical trial NCT01379469 (Carbamazepine in Severe Liver Disease Due to Alpha-- 1 Antitrypsin Deficiency) to perform a "clinical trial in a dish". The investigators will be blinded to the resuls of the in vivo clinical trial to create a "triple-- blinded" study in which the iPS study results willbe used to predict outcomes of the in vivo study. The accuracy of these predictions will then be assessed upon completion of the two studies to determine how well this iPS modeling approach recapitulates response to treatments in actual patients. The overall goal of the research is to determine whether patient-- specific, iPS-- derived cell types serve as faithful surrogates for analogous in vivo cell types in the patient from whom they were created. A second goal of the research is to determine whether carbamazepine ameliorates the affects of AATD-- associated liver disease. To achieve these goals three specific aims are proposed. First, a library of iPSCs will be created from subjects enrolled in clinical trial NCT01379469. Second, a subset of these iPSCs will undergo genome editing to correct the single base pair mutation responsible for the PiZZ AATD phenotype. Parental, diseased (PiZZ) iPSCs and gene-- corrected, daughter (PiMM) iPSCs will then be differentiated in parallel to iPS-- hepatocytes to create a signature of disease that results specifically from aberrant AAT protein production. Finally, iPSCs created in aim 1 will be differentiated to iPS-- hepatocytes and treated with carbamazepine to recapitulate clinical trial NCT01379469 in vitro. The results between the two studies will be correlated to determine whether iPS-- based in vitro studies faithfully recapitulate in vivo clinical trial results and thu could serve as the basis for personalized medicine approaches as well as provide an alternative future approach to clinical trial design.

描述（由适用提供）：人类临床药物试验测试患有给定疾病的患者组中药物的有效性和毒性，并在此过程中估计了药物在人群中的影响。但是，他们通常不会使临床医生能够预测哪些特定患者可能受益或经历严重的有毒作用从正在测试的药物中。现在发现诱导多能干细胞（IPSC）的发现已使使用患者产生的IPSC的差异进展在体外对遗传疾病进行建模。例如，披萨IP-衍生的肝细胞已被证明可以概括α-1抗抗蛋白酶缺乏症（AATD）相关的肝病的关键特征，证明了疾病的潜力 - 特定的IPS-衍生细胞来模拟该遗传疾病和其他遗传疾病。在此申请中概述的研究测试了一种新型的个性化临床药物试验方法，使用基于IPS的模型系统来测试药物卡马西平在改善AATD的有效性 - 相关的肝病表型。卡马西平将在IPS中进行测试 - IPS衍生的肝细胞由正在进行的临床试验NCT01379469的受试者（由于α-1抗抗胰蛋白酶缺乏症引起的严重肝病中的卡amazepine）而产生的肝细胞，以在菜肴中进行临床试验”。研究人员将对体内临床试验的结果视而不见，以创建一项“三重 - 盲”研究，其中IPS研究结果将用于预测体内研究的结果。然后，将在两项研究完成后评估这些预测的准确性，以确定这种IPS建模方法如何概括实际患者对治疗的反应。该研究的总体目标是确定患者 - 特定的IPS - 衍生细胞类型是否可以作为忠实的替代体的替代体的体内细胞类型的替代物，并将其从中产生。该研究的第二个目标是确定卡马西平是否可以改善AATD - 相关肝病的影响。为了实现这些目标，提出了三个具体目标。首先，将根据临床试验NCT01379469的受试者创建IPSC库。其次，这些IPSC的子集将进行基因组编辑，以纠正负责披萨AATD表型的单基对突变。父母，剥离（披萨）IPSC和基因 - 纠正的女儿（PIMM）IPSC将与IPS平行区分 - 肝细胞，以创建疾病的标志这特别是由异常的AAT蛋白产生产生的。最后，在AIM 1中创建的IPSC将与IPS区分开 - 肝细胞并用卡马西平治疗以概括临床试验NCT01379469体外。这两项研究之间的结果将是相关的，以确定基于IPS的体外研究是否忠实地概括了体内临床试验结果，而THU可以作为个性化医学方法的基础，并为将来的临床试验设计提供了另一种方法。