173 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 Therapy Strategy Target Executed study Positive outcome Disadvantages ref Mavacamten (MYK-461) selective cardiac myosin inhibitor Humanized PLNR14del mice Can decrease the contractility without affecting Ca2+ transients No improvement in the decreased contractile function was found in this study. 99 Anti-fibrotic strategies Eplerenone Antifibrotic agent PLN-R14del Mouse Reduced ventricular dilatation. No improvement in contractile dysfunction or survival rate. 223 Eplerenone Antifibrotic agent Clinical trial iPHORECAST with 42 presymptomatic PLN-R14del carriers. Study pre-emptive established antifibrotic effects, and reduce disease progression. No significant improvement in asymptomatic PLN p.Arg14del carriers. 102,224 ER stress modulation BiX Induces BiP expression PLN-R14del hiPSCCMs and EHTs. Enhanced contractility to and nearly complete force restoration. Biphasic, as a high concentration of BiX, leads to decreased contractility. 225 Metabolism modulation Bezafibrate PPARA agonist PLN-R14del hiPSCCMs and cardiac spheroids. re-activates mitochondrial FAO and improves Ca2+ transients. Hyperhomocysteinemia risk, No major long-term outcome trials with clear results are available. 95 PLN gene/protein regulation TALENs PLN-R14del PLN-R14del hiPSCCMs TALEN-correction ameliorates the PLNR14del phenotype in hiPSC-CMs and EHTs. Early stage of development and with ethical concerns, this technique is still far from clinical application. 226,227 rAAV2 PLN-R14del CRISPR-engineered PLN-R14del hiPSCCMs rAAV2-driven expression of PLN rescues arrhythmic Ca2+ transients and alleviates decreased Ca2+ transport. The CUPID 2 trial (AAV1/ SERCA2a) did not reduce terminal events in the overall study population. 228 AAV6 PLN Patient-specific PLN-R14del hiPSCCMs AAV-PLN overexpression reduced irregular calcium transients and hypertrophic factors. Safety concerns due to the use of delivery vectors. 229 ASOs (KD) PLN Homozygous PLNR14del mice KD of the PLN gene expression leads to decreased protein aggregation, fibrosis, and improved survival in PLN-R14del mice. Targeting both mutated and non-mutated PLN mRNA might induce lethal dilated cardiomyopathy.230 231 CRISPR/ Cas9 PLN-R14del Humanized PLNR14del mice Specific disruption of mutant PLN allele leads to reduced susceptibility to developing ventricular tachycardia. Safety concerns due to possible off-target effects and the use of delivery vectors. 232 Abbreviations: AMPK = adenosine monophosphate-activated protein kinase; ASOs = antisense oligonucleotides; EF = Ejection fraction; EHT = Engineered heart tissue; FAO = Fatty acid oxidation; hESC-CMs = human embryonic stem cell-derived cardiomyocytes; HF= Heart failure; hiPSC-CMs = Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes; HTx=heart transplantation; ICD= Implantable Cardioverter Defibrillator; KD = Knock-down, LV = Left Ventricle; LVAD= Left Ventricular Assist Device; modRNA = modified RNA; siRNA = small interfering RNA; shRNA = short hairpin RNA; TALENs = transcription activator-like effector nucleases; TF = Transcription Factor.
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