369 General Discussion - hiPSC-CMs Disease Modelling and Future Perspectives 13 receptors and their downstream effects on the PI3K and MAPK pathways were identified as the strongest pathways for cardioprotective effects. Interestingly, Neuregulin, an ERBB receptor ligand, is currently in the early phase of clinical development in patients with HFrEF.104 Both metabolic and cell stress interventions are important for the modulation of downstream pathways that are affected by the PLN-R14del mutation. As PLNs main function is the regulation of calcium by the modulation of SERCA, multiple therapeutic strategies have been tested to modulate calcium handling. The CaMKII inhibitor KN93 reversed the proarrhythmic phenotype in myocytes of PLN-R14del mice, consequently suggesting its anti-arrhythmic application and especially potentially preventing SCD.105 On the contrary, Metoprolol (β-blocker) significantly decreased the heart rate and showed no increase in the survival rate of PLN-R14del mice.87 Given the molecular effects of β-blocker are not based on a modulation of CaMKII, it seems the community is open and motivated for new pharmacologic drugs for CaMKII inhibition. Ca2+‐binding proteins GCaMP6f and parvalbumin mainly reduced the UPR expression and led to dynamic alterations within the ER-mitochondrial compartment.84 Interestingly, GCaPM6f was associated with significantly improved force development in PLN-R14del EHTs, but not parvalbumin. Recently, in homozygous PLN-R14del mice, reduced calcium handling, PLN aggregation, and fibrosis were all observed within 5 weeks of age. The overexpression of Dwarf open reading frame (DWORF) counteracts the PLN regulatory calcium handling function in the sarco/endoplasmic reticulum (S/ER) and reveals delayed PLN aggregates and prolonged the life span in PLN-R14del Cardiomyopathy Mice.85 Both therapeutic strategies targeting Ca2+‐binding and regulation revealed mainly the cardioprotective effect in ER/UPR alternations, rather than a direct effect on improved calcium regulation or contractility. If the PLN-R14del results in enhanced calcium reuptake, rather than the previously described super-inhibition, increasing calcium S/ER reuptake could be ineffective in PLN-R14del cardiomyopathy and need to be further evaluated before more therapeutic testing. Therapeutic therapies targeting intracellular gene expression hold great promise for the modification of deranged intracellular signaling that is often difficult to target in cardiomyopathies with traditional drug therapies. For genetic cardiomyopathies, we have the opportunity to target or restore the genetic abnormality affected by the genetic mutation, rather than improving only the affected downstream pathways. Therapeutic genes can be delivered either by using genetic material or by non-viral or viral carriers containing the DNA or RNA of interest. Viral vector transgene delivery vehicles such as lentiviruses, adenoviruses, and adeno-associated viruses (AAV), are more efficient than naked or non-viral vector delivery in crossing the cardiomyocyte membrane. AAVs contain single-stranded DNA, producing long-term expression, with a low immune response. All of the viral vectors provide safe gene delivery but their gene-transduction efficacy in the human heart remains suboptimal. To overcome this limitation, AAVs have the possibility to design tissue tropism from 13 serotypes and the ability to transduce both dividing and non-dividing cells, making this viral
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