Abstract and Introduction
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.
We are currently witnessing a rapid development of novel nucleic acid-based cardiovascular therapies, because important progress in their efficacy and safety has been achieved, at least for some therapeutics, and treatment targets can now be addressed that are not optimally amendable to small molecule or antibody-based treatment approaches. Moreover, recent genetic and epigenetic studies have identified several novel potentially causal therapeutic targets for prevention and management of cardiovascular diseases (CVDs). Here, we discuss key nucleic acid-based therapeutic strategies and their current clinical translational status and future perspectives.
Prominent examples of actual practical interest are clinical studies on RNA-targeted nucleic acid-based therapeutics [antisense oligonucleotides (ASOs), siRNAs] to lower transthyretin (TTR),[1–3] PCSK9,[4,5] apolipoprotein (a) [apo(a)],[6–9] or apoCIII,[8,10–12] in patients with amyloidosis or advanced atherosclerotic CVD, respectively. Only after extensive research and meeting demands of biopharmaceutical/industrial development, these technologies could be developed to a level of safety and efficacy allowing large-scale clinical endpoint trials.
The next sections will cover in more depth key principles and current state of clinical development for different nucleic acid-based treatment strategies for CVDs, in particular for (i) RNA-targeted ASO drugs, (ii) RNA-targeted RNA interference (siRNA) molecules, (iii) microRNA (miR)-modulating drugs (anti-miRs, miR mimics), (iv) epigenetic therapies (e.g. BET inhibition), (v) gene therapies for protein augmentation or short hairpin RNA (shRNA)-mediated protein depletion, and finally (vi) gene editing (DNA level, e.g. CRISPR-based). Whereas ASO and siRNA therapeutics are designed to silence single genes, e.g. apo(a) or PCSK9, microRNA-modulating or epigenetic treatment strategies target transcriptional networks. In Figure 1, these different nucleic acid-based therapeutic strategies for CVD are illustrated, i.e. principles, therapeutic tools and molecular targets as well as the current clinical development status, ranging from experimental proof of concept studies to phase II and III clinical trials (Figure 1 and Table 1).
Translational status of novel therapeutic strategies in cardiovascular diseases. Overview of the clinical translational status and practical impact of several novel nucleic acid-based therapeutic principles and tools for cardiovascular medicine.
Remarkably, two new therapeutic strategies of great potential impact were derived on the basis of recently discovered biological cell-based systems [RNA interference (RNAi), CRISPR-associated protein 9 (Cas9) gene editing] 'developed' by evolution. Moreover, important novel target types are emerging from recent human genome and epigenome research. In the future, some of these may possibly enable targeting of highly integrated processes (e.g. control and regulation of the innate and adaptive immune response, or cell differentiation).
Despite interesting long-term perspectives and already remarkable clinical translational progress with RNA-targeted therapies (ASO and siRNA therapeutics), there remain important challenges—in particular for the above more recent technological developments—regarding clinical safety and efficacy which need to be addressed and discussed. Furthermore, genome editing in humans raises also ethical concerns that need to be evaluated.
Key common determinants of clinical efficacy and safety, by which all these novel technologies need to be ultimately judged are summarized in Figure 2, i.e. by: (i) freedom from relevant side effects, (ii) high specificity of the drug to its molecular target, (iii) efficient delivery to the targeting organ, and (iv) appropriate stability for a given clinical purpose. Mechanistic details for two types of nucleic acid-based drugs (ASOs and siRNAs) according to their mode of production and delivery, principles of action, and key features are also illustrated in Figure 2. Such approaches will enable a new strategy for 'undrugable' targets (e.g. apolipoprotein(a)) but will likely also have a relevant clinical impact by providing significantly facilitated treatment regimens compared to existing therapies (e.g. RNAi-based suppression of PCSK9 over several months after a single subcutaneous drug injection).
Clinical efficacy determinants of ASO and siRNA therapeutics. Despite diversity of the new therapeutic principles and tools, they share key common determinants of clinical efficacy which are critical for possible translational success and need to be closely monitored in any clinical trial.
Eur Heart J. 2020;41(40):3884-3899. © 2020 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.