175 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 hiPSC-CMs.244 Even within animal models, such as the PLN-R14del mouse and humanized mouse model, variations in the phenotypes occur (Table 1). Patient-specific iPSC-derived cardiomyocytes generated from both symptomatic and asymptomatic individual carriers could represent valuable human-based models to study PLN-R14del pathophysiology. However, the maturation status of the cells and the expression level of phospholamban should be carefully considered and controlled, as these factors could influence the cellular response to PLN-R14del mutation. Additionally, other factors such as genetic background and environmental factors could influence disease development and progression, so it is important to carefully consider these variables when using these human-based models to study disease mechanisms. The primary objective in understanding the pathogenesis of PLN-R14del cardiomyopathy is to pave the way for innovative, disease-specific treatments. These goals have been pursued through the significant efforts of organizations such as the PLN Foundation and collaborative research initiatives like the Leducq Transatlantic Network of Excellence consortium, known as CURE-PLaN.60 In both of these contexts, the final aim is to develop effective therapeutic approaches, which encompass two primary approaches: corrective gene therapy and the identification of pharmacological agents that can deplete or neutralize the pathological PLN protein. Furthermore, there are ongoing grants and research initiatives aimed at advancing our understanding and developing innovative therapies for PLN-R14del disease. These encompass heart vector-mediated gene therapy245, prime editing gene therapy246, as well as the exploration of oligonucleotide chemistries, gene editing, and gene modulation247. Currently, whether all PLN-R14del carriers should be offered preventive treatment due to the 50% lifetime risk of developing severe disease and if these therapeutic steps are ready is under debate within the scientific community.104,105 Here, we have systematically summarized the therapies that have been explored for their effectiveness in addressing PLN-R14del cardiomyopathy (Table 2). The discovery of an existing pharmacological agent would represent the most rapid and straightforward approach to treating patients. For example, a lower UPR activity or induced stress in life might explain the accelerated manifestation of symptoms observed in some patients and could potentially lead to the more severely affected PLN-R14del patients due to an elevated vulnerability to proteotoxicity. Modulating the UPR activity might subsequently normalize the disease phenotype.248 Moreover, as described above, the PLN-R14del mutation might not only directly regulate SERCA2a and Ca2+ re-entry, but also regulate other binding partners249, and could cause impairment of inter-organelle communication between ER and mitochondria. Ca2+‐binding proteins GCaMP6f and parvalbumin mainly reduced the UPR expression and led to dynamic
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