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

Abstract

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.

Bioconjugated Oligonucleotides: Recent Developments and Therapeutic Applications

“…After binding to ASGPR, the complex is quickly internalized to form early endosomes via a clathrin dependent mechanism. 68 As a result, ASGPR targeting conjugates are readily delivered to the liver through intraveneous injection.…”

“…Importantly, this success laid the foundation for a number of oligonucleotides being ushered into commercial development and the reader is referred to several reviews on this topic. 68,143–146…”

“…Importantly, this success laid the foundation for a number of oligonucleotides being ushered into commercial development and the reader is referred to several reviews on this topic. 68,[143][144][145][146] As discussed in the introduction of this Review, the design of oligonucleotides for use in the clinic requires specific design considerations and optimizations other than improved delivery. 147 For enhanced in vivo efficacy, oligonucleotides containing chemical modifications such as 2'-O-MOE, 2'OMe, LNA and PMO are used to protect against degradation and increase target binding affinity.…”

“…These lectin type C receptors are highly expressed on the plasma membrane of hepatocytes and both galactose and GalNAc are the preferred ligands for these receptors. After binding to ASGPR, the complex is quickly internalized to form early endosomes via a clathrin dependent mechanism . As a result, ASGPR targeting conjugates are readily delivered to the liver through intraveneous injection.…”

“…Vitravene is still authorized in Switzerland and can be administered in the European Union upon specific request. Importantly, this success laid the foundation for a number of oligonucleotides being ushered into commercial development and the reader is referred to several reviews on this topic. ,− …”