Leducq Transatlantic Network of Excellence to Cure Phospholamban-Induced Cardiomyopathy (CURE-PLaN).

The deletion of Arginine 14 of the phosholamban gene (PLN p.R14del) is associated with the pathogenesis of an inherited form of cardiomyopathy with prominent arrhythmias. Patients carrying the PLN R14del mutation are at risk of developing dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Although the genetic etiology is well defined, the molecular mechanism underlying the pathogenesis of PLN R14del-cardiomyopathy is unknown. Our CURE PLaN network, funded by the Foundation Leducq, will bring together leading scientists, clinicians, and patients to elucidate the genotype-phenotype relationships in R14del cardiomyopathy with the ultimate goal of developing innovative disease-specific therapeutic modalities. With the generous support of the Leducq Foundation, our Transatlantic Network of Excellence consortium to cure Phospholamban (PLN)-induced cardiomyopathy (CURE-PLaN) unites 6 leading centers to address the current challenges associated with arrhythmogenic right ventricular cardiomyopathy/dilated cardiomyopathy (DCM) with an initial focus on PLN and development of effective treatments. The Network is led by Evangelia (Litsa) Kranias (University of Cincinnati) in the United States and Pieter A. Doevendans (Netherlands Heart Institute/UMC Utrecht NL) in Europe. The other US project leaders are Kevin Costa (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York) and Mark Mercola and Ioannis Karakikes (Stanford University), who are focusing on induced pluripotent stem cell (iPSC)-based disease models, tissue engineering, gene therapy, and drug discovery. On the European side, the project leaders are Despina Sanoudou (Biomedical Research Foundation of the Academy of Athens) analyzing the PLN interactome and Stephan Lehnart (University of Gottingen) addressing the subcellular and disrupted protein interactions affected in PLN-mutant cardiomyocytes. Other key members within the Netherlands Heart Institute are Peter van Tintelen on PLN genetics, Folkert Asselbergs on epigenetics and Rudolf de Boer on clinical trials. We are also privileged to get support from Arthur Wilde (University of Amsterdam), Sakthivel Sadayappan (University of Cincinnati), and Roger Hajjar (Phospholamban Foundation), who have had a long-standing interest in cardiac physiology and pathophysiology with emphasis on underlying pathways and potential therapeutic targets. The consortium is also fortunate to embrace a patient advocate, Pieter Glijnis, incorporating the voice of the patients to research in every step. Our goal is to build and share a platform of patient data coupled with in vitro and in vivo models to promote scientific discovery and advance novel treatments. Phospholamban is a small phosphoprotein in the cardiac sarcoplasmic reticulum, and it is the major regulator of SERCA2a activity and calcium (Ca)-cycling. Chronic inhibition of SERCA2a by PLN has been implicated in the aberrant Ca-cycling of failing hearts. Studies in HF models have shown that decreasing PLN activity may rescue cardiac remodeling and dysfunction. Several human PLN mutations, leading to inhibition of Ca-uptake into the sarcoplasmic reticulum, are linked to inherited DCM.

Phospholamban R14del disease: The past, the present and the future.

Arrhythmogenic cardiomyopathy affects significant number of patients worldwide and is characterized by life-threatening ventricular arrhythmias and sudden cardiac death. Mutations in multiple genes with diverse functions have been reported to date including phospholamban (PLN), a key regulator of sarcoplasmic reticulum (SR) Ca2+ homeostasis and cardiac contractility. The PLN-R14del variant in specific is recognized as the cause in an increasing number of patients worldwide, and extensive investigations have enabled rapid advances towards the delineation of PLN-R14del disease pathogenesis and discovery of an effective treatment. We provide a critical overview of current knowledge on PLN-R14del disease pathophysiology, including clinical, animal model, cellular and biochemical studies, as well as diverse therapeutic approaches that are being pursued. The milestones achieved in <20 years, since the discovery of the PLN R14del mutation (2006), serve as a paradigm of international scientific collaboration and patient involvement towards finding a cure.