Abstract P2105: Precision Medicine In Pediatric Calmodulinopathy
| Autor: | K. Ashley Fetterman, Malorie Blancard, Mariam Jouni, Franck Potet, Gregory G Webster, Alfred L George, Paul W Burridge |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Circulation Research. 131 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.131.suppl_1.p2105 |
| Popis: | Calmodulinopathy is a life-threatening cardiac arrhythmia syndrome resulting from a single heterozygous mutation in any of the three calmodulin (CaM) genes. Most (68%) persons with a pathogenic CaM variant will experience a major arrhythmic event such as aborted cardiac arrest or sudden cardiac death by the age of five years. Calmodulinopathies result in heterogenous clinical features with one of the predominant clinical phenotypes being long QT syndrome (CaM-LQTS). Despite current treatments, 56% of calmodulinopathy patients experience breakthrough cardiac events, underscoring the need for improved therapeutics. A current barrier to effective treatment is our incomplete understanding of how calmodulin genetic variants contribute to pathological phenotypes. Human induced pluripotent stem cells (hiPSCs) can be differentiated into cardiomyocytes (hiPSC-CMs) while maintaining the patient’s genetic background. Application of hiPSC-CMs in the context of this disease allows us to better understand patient-specific heterogeneity at the cellular level. We have established a CaM-LQTS hiPSC-CM model using hiPSCs generated from five persons with a pathogenic CaM variant who present with CaM-LQTS. We hypothesize that we can model a CaM-LQTS phenotype using patient-specific hiPSC-CMs, identify clinically appropriate drugs that correct it, and determine underlying mechanisms that drive this phenotype. We have determined the cellular CaM-LQTS phenotype of each patient line using blinded electrophysiological, contractility, and calcium imaging studies and have identified FDA-approved drugs that alleviate these phenotypes. We are also performing experiments, with a focus on calcium cycling dysregulation, to identify underlying mechanisms that drive the cellular CaM-LQTS phenotype. In conclusion, these studies will provide a patient-specific methodology to identify necessary clinical treatments for CaM-LQTS and elucidate the drivers of this rare and severe disease. |
| Databáze: | OpenAIRE |
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