From Traditional Pharmacological Towards Nucleic Acid-based Therapies for Cardiovascular Diseases

Ulf Landmesser; Wolfgang Poller; Sotirios Tsimikas; Patrick Most; Francesco Paneni; Thomas F. Lüscher


Eur Heart J. 2020;41(40):3884-3899. 

In This Article

Summary and Outlook

There is increasing interest in novel molecular therapeutic tools for cardiovascular medicine capable to address hitherto inaccessible targets, or significantly facilitating treatment regimens compared to existing modalities. Thus, RNA-targeted nucleic acid-based suppression of apo(a), apoCIII, PCSK9, or TTR has achieved very high efficacy after drug injection. Beyond this important progress towards large-scale clinical studies, the exploration of the non-coding human genome as well as the human epigenome has expanded the spectrum of therapeutic targets of interest.

Of note, there is growing evidence that multiple regions of the human epi/genome are not single-function units comparable to classical protein-coding genes, but highly integrated RNA processing systems steering complex biological programmes, e.g. cell proliferation and migration at the cellular level. Beyond that, they may co-ordinate systems level biological processes, e.g. the immune response control of which is lost in multiple CVDs. The challenge to survive has certainly put strong evolutionary selection pressure in favour of any such 'master regulators', and recent research does suggest their existence at the epigenome and non-coding genome level. They may prove useful as truly novel therapeutic targets and should be within reach of advanced pharmaceutical tools.

Despite the remaining technological challenges standing in the way of clinical translation for some of the novel nucleic acid-based therapies, it is most encouraging that first successful clinical trials have already illustrated that cardiovascular RNA-targeting drugs need not to address the heart or vasculature directly. On the contrary, liver-targeted RNA-based drugs are currently a highly interesting and successful development in the cardiovascular field. In addition, the advent of cardiac-specific rAAVs may corroborate our efforts to render the diseased heart amenable to the next-generation of rAAV-based GTMPs for which the desired level of myocardial transduction comes as a 'natural' consequence.

Beyond advanced pharmaceutical technology, stringent patient selection remains a key factor for successful translational science. Precise definition of trial patient cohorts in whom one single pathomechanism is a dominant cause of disease development and progression, as well as suitable clinical outcome parameters need to be highly considered.

Anticipation of clinical scenarios in which there will be room for the new approaches is appealing, but clinical application may be entirely dependent on methodological breakthrough discoveries which cannot be reliably foreseen. Nevertheless, room for the novel approaches will be quite generally exist or emerge for CVD patient subpopulations displaying rapidly progressing disease despite optimal standard therapy (drugs + devices) and state-of-the art risk factor reduction. If there is no alternative pharmacotherapy, e.g. for Lp(a) reduction, and clinical efficacy and safety is demonstrated, nucleic-based drugs may likely become standard of care. Moreover, if pharmacokinetics is favourable for this type of drugs (e.g. for PCSK9 siRNA), these may develop into a treatment of choice for respective large target populations. Finally, Figure 9 illustrates potential long-term perspectives for the evolution of molecular cardiovascular therapies over the next decades.

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.