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Toxicogenetic of statins using induced pluripotent stem cells from patients with Familial Hypercholesterolemia

Grant number: 17/21055-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2018
Effective date (End): May 31, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Mario Hiroyuki Hirata
Grantee:Raul Hernandes Bortolin
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Statins is the therapeutic pillar of hypercholesterolemia. Although statins present a good safety profile, several reports of therapeutic intolerance attributed to statins, particularly myopathy, represent an obstacle in its clinical prescription. Moreover, the exact mechanism of this intolerance is not well established. Therefore, the present study proposes to carry out an unprecedented experimental approach evaluating the association of genetic variability with mRNA expression profile of pharmacokinetics- and pharmacodynamics-related genes of statins, as well as regulatory profile via microRNA (miR) in rhabdomyolysis induced by statin using an in vitro model of induced pluripotent stem cells (hiPSC) from familial hypercholesterolemia (HF) that will be reprogramed into three cell types: hepatocytes, cardiomyocytes and skeletal muscle. HF patients, phenotypically characterized, will be invited to participate of the research. Whole blood will be collected to obtain hiPSC, with further differentiation into cardiomyocytes (hiPSC-CM), hepatocytes (hiPSC-HP) and skeletal myocytes (hiPSC-ME). The reprogramed cells will be incubated with different doses of simvastatin, rosuvastatin and atorvastatin, and then total RNA will be extracted for gene expression study through pre-configured panels of cholesterol metabolism, membrane transporters and metabolism of statins, as well as myogenesis/myopathy and apoptosis. In silico tools will be used for integrative analyses of miR-mRNA and the predicted miRs will also be evaluated by their expression in hiPSC-CM, hiPSC-HP and hiPSC-ME incubated with statins. The results will provide important data for the understanding of genotypic influence and its association with miR expression profile, improving the description of the genetic and epigenetic mechanisms in pharmacokinetics and pharmacodynamics and the possible relation with statins adverse effects prescribed in clinical practice. This study, to the best our knowledge, is pioneer in this approach that proposes a methodology for pharmacogenetic and epigenetic in vitro studies, using peripheral blood cells, without need of invasive procedures and with relevance in the individualized therapy. Another unpublished purpose of this project will be the creation of a cell bank transformed with well characterized genotypes of HF that will be available to the scientific community.