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

Challenges in Clinical Translation of Novel Nucleic Acid-based Therapies

Clinical translation of the above discussed fascinating and far-reaching options faces challenges ranging from molecular drug design and delivery to clinical safety and regulatory issues. Whereas animal studies are most valuable and indispensable for proof-of-principle, most of these studies use young otherwise healthy animals and thus rarely reflect clinical reality. On the solid foundation of extensive animal studies, several pioneering clinical trials were successful in demonstrating technical and clinical feasibility of nucleic acid therapeutic approaches. However, each new drug and therapeutic target may raise specific and previously unexpected issues—the most critical are regarding safety (immune activation, off-target effects at the cellular level, systemic mis-targeting and accumulation, delayed-onset safe effects).

Delivery of Nucleic Acid Drugs in Human Cardiovascular Diseases

For many cell types and tissues, there is currently no clinically feasible targeting technology. Thus, selective targeting of cardiomyocytes or cardiac fibroblasts which are key players in multiple cardiac pathologies,[105,287–293] is currently not possible. Several experimental studies have targeted monocytes-macrophages,[294–302] but none of these approaches has successfully entered the clinical arena, yet. Myocardial targeting by use of recombinant AAV vectors with high affinity for cardiomyocytes was achieved in animal models with therapeutic success regarding improved cardiac function,[190–197] but clinical trials employing this type of vector systems could so far not provide evidence of clinical efficacy.[159,162,201]

Requirement for High Pharmacovigilance

It should be emphasized that each individual, e.g. siRNA or ASO drug formulation may have a specific side-effect, or particularly high efficacy, which is not 'group-specific' i.e. not common to the siRNA or ASO class of drugs in general. Seemingly minute molecular details of a siRNA, ASO, or gene therapy drug may determine whether e.g. immune reactions or thrombopenia will be triggered by this individual compound. High vigilance therefore needs to be focused upon each individual drug from the field of novel nucleic acid-based and epigenetic therapies.