LeDucq-funded programme: from pathomechanisms to personalized therapy of cardio-laminopathy

Cardiac laminopathies are a group of inherited disorders caused by disease-associated variants in the LMNA gene, which encodes the nuclear envelope proteins lamin A and C. One of the most significant cardiac manifestations of LMNA-related disease is non-ischaemic dilated cardiomyopathy (DCM), characterized by ventricular dilation, loss of normal systolic function, cardiac conduction disease, and arrhythmias.1 While DCM is genetically and phenotypically diverse, pathogenic variants in the LMNA gene are a common cause, accounting for 5%–10% of cases in both children and adults, and represent the first gene associated with conduction disease and arrhythmias in DCM.2 These variants can lead to various morbidities, including heart failure (HF), atrioventricular block, conduction disease, and life-threatening arrhythmias, all contributing to significant mortality. LMNA-related DCM is highly penetrant and can present early in life, increasing the occurrence of HF and requiring a ventricular assist device, heart transplant, or resulting in sudden death. Beyond cardiac manifestations, laminopathies can also affect other organ systems, such as adipose tissue, presenting as partial lipodystrophies, as well as skeletal muscle, where myopathies may develop before or after cardiac involvement. The phenotypic presentation of skeletal myopathies is highly variable, ranging from early severe congenital muscular dystrophies and Emery–Dreifuss muscular dystrophy to limb-girdle muscular dystrophy; yet, all are associated with the development of life-threatening cardiac disease.3 Despite this morbidity and mortality, there are no precision therapies for laminopathies, and current therapies are largely adapted from treatments for more common conditions, such as ischemic heart disease. These therapies are often inadequate for managing the disease. LMNA-related DCM arises from pathogenic variants in the LMNA gene, which disrupt the ability of lamin A and C to maintain the structural integrity of the nuclear envelope, and which can also affect the interaction of lamins with its binding partners. This leads to nuclear destabilization, increased nuclear envelope rupture, DNA damage, and perturbed activation of cardiomyopathic signalling pathways. Disease-associated variants are often single nucleotide variants that are inherited in an autosomal dominant fashion or can arise de novo. The variants are generally classified into missense and loss-of-function variants resulting in early truncation of the protein and loss of the allele. Less commonly, small insertion/deletions in-frame or out-of-frame, mRNA splice-alternating variants, and gain-of-function variants can also lead to disease. While founder mutations in LMNA have been reported, over 500 disease-associated variants vary widely and can occur across the gene’s coding region. This diversity of genetic variants causes a myriad of potential functional effects on lamin A and C, thus there is, at present, no unifying pattern by which a LMNA variant causes disease through a single mechanism. Further, recent evidence has highlighted the role of genetic variants across the genome in modifying how disease presents and progresses, particularly in genetic cardiomyopathies. This has several implications. First, disease onset, presentation, and progression remain unpredictable. For example, the same LMNA variant in different individuals, and even within the same family, can show variable disease penetrance and an unpredictable course. Second, while early stage clinical trials have been launched for other forms of genetic cardiomyopathies,4 the genetic heterogeneity of LMNA-related DCM has slowed the advancement of pre-clinical discovery to clinical trials. Among many factors, the lack of a singular genetic mechanism, particularly one amenable to genetic ‘replacement,’ has highlighted the need for a more mechanistic understanding of the genetic influences on disease expression and novel approaches to genetic therapies. Finally, the mechanistic gaps in our understanding of disease pathogenesis and the apparent lack of a unifying ‘common’ pathway for cellular dysfunction in LMNA-related DCM have slowed the development of individualized precision therapies. Novel precision medicine-based therapies are critically needed. For instance, implantable cardioverter-defibrillators (ICDs) improve prognosis in high-risk LMNA-positive individuals, and LMNA-related DCM was the first condition for which prophylactic ICD placement was recommended.5 However, despite this intervention, the myopathic component of the disease remains progressive, and the burden of HF is substantial, with up to 30% of ICD recipients experiencing severe complications within five years.6 Recent attempts to develop new therapies have met with challenges. For example, the REALM-DCM trial, a Phase 3, randomized, placebo-controlled trial of ARRY-371797, which enrolled patients with LMNA-related DCM and symptoms of HF, was terminated due to futility.7 An interim analysis found no significant differences between the 6-minute walk test distance, Kansas City Cardiomyopathy Questionnaire (KCCQ)-physical limitation score, KCCQ-total score, and NT-proBNP levels in those who received ARRY-371797 vs placebo. Furthermore, there was no difference in the composite outcome of HF or all-cause mortality or overall survival between the groups. Ultimately, the genetic heterogeneity and lack of mechanistic understanding must be addressed if novel therapeutic approaches are to be discovered and successfully implemented in the clinic. The Cardio-Laminopathy: From pathomechanisms to personalized therapy (PRIORITY) collaborative network is a Leducq Foundation-funded international network of excellence with the overall goal of establishing the genetic, cellular, and clinical understanding of cardiac laminopathies to accelerate the development of personalized therapies to treat LMNA-related DCM. PRIORITY aims to determine the genetic modifiers of disease development and progress, uncover the underlying pathophysiological mechanisms of LMNA-related DCM, and develop innovative, mechanism-based therapies. To pursue this goal, an international team of experts in HF, arrhythmias, advanced cardiac imaging, gene therapy, high-throughput screening, genetics/genomics, mechanobiology, and cryo-electron tomography has been assembled. As customary for the Leducq Foundation-funded consortium,8 the PRIORITY team consists of investigators from Europe and the United States. The Principal Investigator and European Coordinator is Gisèle Bonne (Sorbonne Université—Inserm, Paris, France). The co-Principal Investigator and United States (US) Coordinator is Andrew Landstrom (Duke University School of Medicine, Durham, North Carolina, US). The network members include Jan Lammerding and Haiyuan Yu (Cornell University, Ithaca, New York, US), Karim Wahbi (Paris-Cité University—Imagine Institute, Paris, France), Ioannis Karakikes and Mark Mercola (Stanford University, California, US), Yigal Pinto (University of Amsterdam, Amsterdam, The Netherlands), Leon Schurgers and Rogier Veltrop (Maastricht University, Maastricht, The Netherlands), and Ohad Medalia (University of Zurich, Switzerland). The Network Administrative Office is based at the Netherlands Heart Institute in Utrecht, The Netherlands. Importantly, PRIORITY has formed a partnership with the patient association LMNAcardiac (LMNAcardiac.org) to encourage outreach to, and participation of, the LMNA patient community. The team has established robust cellular and animal models, leverages a multi-disciplinary suite of technologies, including cryo-electron tomography, gene editing, biophysical assays to probe nuclear structure and integrity, and multi-omics. Additionally, the team has created a comprehensive LMNA patient registry and biorepository. The PRIORITY network is structured around three key aims: Aim 1 focuses on defining genotype–phenotype relationships through in-depth cardiovascular phenotyping and genetic analysis to stratify patient risk and guide personalized therapies. Aim 2 investigates disease mechanisms using stem cell-based and animal models to understand the impact of LMNA mutations on nuclear stability, chromatin organization, and cellular function. Aim 3 translates these insights towards clinical care by developing gene therapies and pharmacological treatments targeting LMNA-related DCM pathology. The aims of PRIORITY are summarized in Figure 1. To accomplish its goals, PRIORITY will prioritize training early career researchers, fostering international collaborations, and sharing novel technologies to accelerate scientific progress. By integrating multi-disciplinary approaches, PRIORITY seeks to advance the understanding of LMNA-DCM and pave the way for effective, personalized treatments. Schematic summarizing the objectives and aims of the Cardio-Laminopathy: From Pathomechanisms to Personalized Therapy (PRIORITY) collaborative network. The goal of PRIORITY is to utilize advanced cellular and animal models, integrating cryo-electron tomography, biophysical measurements, gene editing, and multi-omics, along with a comprehensive LMNA patient registry and biorepository to (1) define genotype–phenotype relationships through in-depth cardiovascular phenotyping and genetic analysis, enabling patient risk stratification and personalized therapy development; (2) determine the impact of disease on nuclear stability, chromatin organization, and cellular function using stem cell-based and animal models; and (3) translate these findings into clinical care through the development of gene therapies and pharmacological treatments targeting LMNA-related dilated cardiomyopathy. Figure created using BioRender. The success of PRIORITY can be defined by several key deliverables, including: (i) establishing a trans-Atlantic clinical and genetic registry and biobank; (ii) understanding the natural history of LMNA-DCM and how genetic variants influence risk and disease progression; (iii) deciphering the pathomechanisms of LMNA variants, thereby uncovering the undeciphered structure and function of lamins A and C; (iv) conducting proof-of-concept studies demonstrating that pharmacologic and gene-therapy strategies can be leveraged to correct the underlying cellular mechanisms of the disease; (v) developing a roadmap for early phase clinical trials guided by both natural history studies, genetic risk evaluation of participants, and therapeutic targets; and (vi) fostering a collaborative group of early career investigators and trainees to advance this work. In this way, PRIORITY opens the door to the development of novel therapeutics to treat LMNA-related DCM, allowing individuals with this rare disease to live healthy and happy lives. We gratefully acknowledge the Leducq Foundation for supporting the PRIORITY collaborative through Grant Agreement 24CVD03. We gratefully acknowledge the research participants who have informed, and will continue to inform, this collaborative work. We gratefully acknowledge Edina Lee for creation of Figure 1. All authors declare no conflicts of interest. Leducq Foundation supported this work through Grant Agreement 24CVD03.