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.

Public Health Relevance

This proposal tests the ability of patient-- derived stem cells and their differentiated progeny to predict real world patient responses to drug therapy. It aims to determine the potential for utilizing these patient-- derived stem cells, known as induced pluripotent stem cells (iPSCs), for personalized medicine applications and as a new adjunct approach to performing clinical trials. It also utilizes a new iPS-- based model to explore and understand better the pathogenesis of liver disease resulting from the genetic disease alpha-- 1 antitrypsin deficiency, a major cause of liver disease in children and adults.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZDK1)
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Doo, Edward
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Reeves, Emer P; O'Dwyer, Ciara A; Dunlea, Danielle M et al. (2018) Ataluren, a New Therapeutic for Alpha-1 Antitrypsin-Deficient Individuals with Nonsense Mutations. Am J Respir Crit Care Med 198:1099-1102
Kaserman, Joseph E; Wilson, Andrew A (2017) Protocol for Directed Differentiation of Human Induced Pluripotent Stem Cells (iPSCs) to a Hepatic Lineage. Methods Mol Biol 1639:151-160