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Pharmacological analyzes in iPSC-derived cardiomyocytes of patients with Fabry Disease

Grant number: 19/13637-3
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2020
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:João Bosco Pesquero
Grantee:Lauro Thiago Turaça
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:14/27198-8 - Establishment of a center of genetic and molecular research for clinical challenges, AP.TEM
Associated scholarship(s):20/02588-9 - The impact of the FOXG1 gene during human neurodevelopment, BE.EP.PD


Fabry Disease (DF) is an X-linked disease caused by mutations in the ±-galactosidase A (GLA) gene. These mutations result in an altered enzyme and consequently cause the accumulation of glycosphingolipids, mainly globotriaosilceramide (Gb3). The accumulation of glycosphingolipids induces pathogenic alterations in several organs, including the heart, and Fabry's cardiomyopathy is the most frequent cause of death in patients with this disease. Existing therapies for the treatment of FD have limited efficacy, variable actions according to the genomic variants of the patients and are extremely expensive, which leads us to seek new therapeutic approaches for a better prognosis. The great difficulty in carrying out studies with the specific cells affected by the disease, such as the cardiac cells, is in its obtaining, since its collection is impracticable and the culture is fundamental in the tests in vitro. Thus, we intend to develop a platform for generation of induced Pluripotent Stem Cells (iPSCs) from human blood cells. IPSC cells are able to differentiate into cardiomyocytes (CM-iPSCs) and can be used as cellular models carrying different genetic mutations for drug testing. Currently there are only 3 drugs used to treat DF (Agalsidase, Migalastase and Eliglustat), however, the variability in the results obtained in these treatments is not well understood. It is believed that this variability correlates with the type of mutation present in the patient and the mechanism of action of these drugs on the cells, as for example in cardiomyocytes in the cardiac variant. Thus, this study intends to verify the molecular and phenotypic effects caused by the different drugs on CM-iPSCs of patients with FD. The implementation of this platform in cells carrying different mutations will open the way for testing new drugs and a better pharmacogenetic understanding between these variants and the most appropriate treatment for each patient. (AU)

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