Therapeutic oligonucleotides in cardiovascular and metabolic diseases: insights for the internist

Domenico Girelli, Fabiana Busti, Giacomo Marchi, Nicola Martinelli, Oliviero Olivieri

The idea of using small RNA fragments (oligonucleotides) for therapeutic purposes dates back to the 1990s, following the landmark discoveries on the mechanisms of gene silencing and RNA-interference (RNA-i). However, the first applications in medicine were hampered by difficulties in chemical stabilization and efficient delivery to target tissues. Recent advances in chemical manipulation of oligonucleotides have, at least partially, bypassed such obstacles. In particular, conjugation with ligands for specific receptors allows the selective uptake of oligonucleotides by critical cells (e.g., hepatocytes), where they inhibit the synthesis of the target protein by binding the complementary mRNA and inducing its degradation. In parallel, next-generation sequencing (NGS) studies at population levels have identified a number of key molecular targets, mainly through the discovery of "human knock-outs," i.e., subjects lacking a given protein because of nonsense mutations in the corresponding gene. Such highly informative individuals are often healthy, or even protected from the development of certain diseases. Indeed, subjects with null mutations in certain genes controlling lipoprotein metabolism like PCSK9 or ANGPTL-3 have a lower risk of cardiovascular disease. Since the complete absence of such proteins does not appear to carry any negative health effect, the corresponding genes are ideal candidates for the silencing approach. Pilot clinical trials with long acting anti-PCSK9 or anti-ANGPTL-3 oligonucleotides have yielded very promising results, so that their use as "vaccines" against atherosclerosis has been suggested in the future. As therapeutic oligonucleotides can virtually target innumerable proteins, their increasing development is predicted to substantially expand the repertoire of the "biological drugs," in addition to, or even substituting, more consolidated approaches like monoclonal antibodies.