368 Chapter 13 disease leads to multiple pathological phenotypes, gaining a better understanding of the Ca2+ signaling function, and how the delayed SERCA2a activation influences contractility, mitochondrial damage, UPR activation, and fibrosis, is an important challenge. As proposed in Chapter 12, multi-omics approaches such as RNA sequencing and proteomics with spheroids from different culture ages could identify the spatiotemporal processes to identify mechanistic insights in the ‘first to fail’ mechanism of the PLN-R14del cardiomyopathy. These outcomes will provide new insights into finding a therapeutic target that could delay or even better, prevent the disruption of phosphorylation-mediated calcium cycling abnormality in the PLN-R14del-associated cardiomyopathy. Towards the future - Therapeutic interventions for genetic cardiomyopathies Detailed signaling pathways that promote cardiac pathology have been unraveled, and we continue to discover important molecular targets that have important roles in the pathologic pathway regulation of cardiomyopathies. Many therapeutic interventions have been tested in both animal models and hiPSC-CMs to cure PLN-R14del cardiomyopathy. For example, two promising drugs targeting myosin (the sarcomeric motor protein); activator Omecamtiv Merabil (FDA approved) and inhibitor Mavacamptem (Clinincal Trial III) have been tested in humanized PLN-R14del mice. Myosin activation by Omecamtiv Merabil could improve contractile dysfunction in RV myocytes, while the myosin inhibitor Mavacamptem had no effects.101 Since Omecamtiv Merabil did not improve Ca2+ handling parameters and the continuous activation of resting myosin ATPase, could limit its clinical benefits in the current treatment options for the PLN-R14del cardiomyopathy. Another therapeutic intervention, the antifibrotic agent Epelerone, did not improve the contractile dysfunction or reduce disease progression in both PLN-R14del mice nor in a clinical trial with 42 presymptomatic PLN-R14del carriers.87,102 Taken together, unfortunately, targeting the contractile dysfunction or fibrosis did not improve the PLN-R14del phenotype. As previously described in this thesis, we explored the potential therapeutic strategies for activating the FAO metabolism (Chapter 8), modulating the UPR pathway (Chapter 9), and SERCA activity (Chapter 12) for curing the PLN-R14del cardiomyopathy. In Chapter 8, we showed for the first time, the potential of bezafibrate in re-activating mitochondrial FAO and improving Ca2+ transients, suggesting future therapeutic strategies for PLN-R14del patients by targeting FAO regulators (i.e. PPARA). In Chapter 9, we used a compound called BiX (binding immunoglobulin protein) inducer X), to modulate the UPR activation in PLN-R14del hiPSC-CMs. BiX showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional models without affecting the calcium homeostasis. However, the detrimental effect at high doses limits the application of BiX as a therapeutic strategy because it may activate the ER stress pathway, inducing apoptosis. In a recent study by Ouwerkerk et al., genomic, transcriptomic, proteomic, and clinical data from 1738 patients with heart failure identified pathways related to the progression of heart failure and early mortality.103 ERBB
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