From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases Ulf Landmesser 1,2,3,*†,Wolfgang Poller 1,2,*†, Sotirios Tsimikas 4, Patrick Most 5,6,7, Francesco Paneni 8,9,10, and Thomas F. Lüscher 8,11 1 Department of Cardiology, Campus Benjamin Franklin, CC11 (Cardiovascular Medicine), Charite—Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; 2 German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; 3 Berlin Institute of Health, Anna-Louisa-Karsch-Strasse 2, 10178 Berlin, Germany; 4 Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, 9500 Gilman Drive, BSB 1080, La Jolla, CA 92093-0682, USA; 5 German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany; 6 Center for Translational Medicine, Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107, USA; 7 Molecular and Translational Cardiology, Department of Medicine III, Heidelberg University Hospital, Im Neuenheimer Feld 669, 69120 Heidelberg, Germany; 8 Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, 8952 Schlieren, Switzerland; 9 Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland; 10 Department of Research and Education, University Hospital Zurich, Rämistrasse 100, MOU2, 8091 Zurich, Switzerland; 11 Research, Education and Development, Royal Brompton and Harefield Hospital Trust and Imperial College London, National Heart and Lung Institute, Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK Ulf Landmesser and Wolfgang Poller contributed equally to the study. Corresponding authors. Tel: +49-30-450-513702, Email: [email protected] (U.L.); Tel: +49-30-450-513765, Email: [email protected] (W.P.) Nucleic acid-based therapeutics are currently developed at large scale for prevention and management of cardiovascular diseases (CVDs), since: (i) genetic studies have highlighted novel therapeutic targets suggested to be causal for CVD; (ii) there is a substantial recent progress in delivery, efficacy, and safety of nucleic acid-based therapies; (iii) they enable effective modulation of therapeutic targets that cannot be sufficiently or optimally addressed using traditional small molecule drugs or antibodies. Nucleic acid-based therapeutics include (i) RNA-targeted therapeutics for gene silencing; (ii) microRNA-modulating and epigenetic therapies; (iii) gene therapies; and (iv) genome-editing approaches (e.g. CRISPR-Cas-based): (i) RNA-targeted therapeutics: several large-scale clinical development programmes, using antisense oligonucleotides (ASO) or short interfering RNA (siRNA) therapeutics for prevention and management of CVD have been initiated. These include ASO and/or siRNA molecules to lower apolipoprotein (a) [apo(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoCIII, ANGPTL3, or transthyretin (TTR) for prevention and treatment of patients with atherosclerotic CVD or TTR amyloidosis. (ii) MicroRNA-modulating and epigenetic therapies: novel potential therapeutic targets are continually arising from human non-coding genome and epigenetic research. First microRNA-based therapeutics or therapies targeting epigenetic regulatory pathways are in clinical studies. (iii) Gene therapies: EMA/FDA have approved gene therapies for non-cardiac monogenic diseases and LDL receptor gene therapy is currently being examined in patients with homozygous hypercholesterolaemia. In experimental studies, gene therapy has significantly improved cardiac function in heart failure animal models. (iv) Genome editing approaches: these technologies, such as using CRISPR-Cas, have proven powerful in stem cells, however, important challenges are remaining, e.g. low rates of homology-directed repair in somatic cells such as cardiomyocytes. In summary, RNA-targeted therapies (e.g. apo(a)-ASO and PCSK9-siRNA) are now in large-scale clinical outcome trials and will most likely become a novel effective and safe therapeutic option for CVD in the near future. MicroRNA-modulating, epigenetic, and gene therapies are tested in early clinical studies for CVD. CRISPR-Cas-mediated genome editing is highly effective in stem cells, but major challenges are remaining in somatic cells, however, this field is rapidly advancing. Cardiovascular diseases • Nucleic acid therapeutics • Non-coding genome • Epigenome • RNA interference • Antisense • CRISPR Figure 9 Perspectives for the evolution of molecular cardiovascular therapies. System integration in engineering is the process of bringing together the component sub-systems into one system (an aggregation of subsystems cooperating so that the system is able to deliver the overarching functionality) and ensuring that the subsystems function together as a whole. System integration in information technology means the process of linking together different computing systems and software applications physically or functionally, to act as a co-ordinated whole. System integration in human molecular biology accordingly means the linking together of the component sub-systems of the human genome into one system able to deliver the overarching functionality at the cellular level which already is a huge challenge. However, beyond the complexity of non-biological systems in engineering and information technology, overall ‘healthy’ system integration in humans requires critical further levels of co-ordination since multiple types of cells with entirely different tasks and internal regulation need to work together to maintain proper structure and function of the entire organism. The ultimate challenge is to ensure this under ‘normal’ baseline conditions and also under conditions of pathogenic stress. One may safely assume that the challenge to survive put critical evolutionary selection pressure for any ‘genomic integrator’ capable to improve integration of the sub-systems of higher organisms. Recent basic and clinical research suggests the existence of hitherto unrecognized ‘master regulators’ at the epigenome and non-coding genome level, and these targets may prove useful as a new type of therapeutic targets.