Von Kräutern zu Pillen, Biologics und Nukleinsäuren

Pharmacotherapy has made massive advances: what began with herbs and fungi led to synthetic pills that interfered ever more precisely with receptors and metabolic pathways. Finally, antibodies against specific proteins became part of our therapeutic armamentarium. But none of these measures get to the heart of the matter: the latest revolutionary chapter in pharmacotherapy uses organ-specific nucleotides, short RNA sequences that intervene in pathogenic metabolic pathways even before proteins are formed and sometimes exert a very targeted effect over surprisingly long periods of time. In cardiovascular medicine, this pharmacotherapy of the future is mainly used in the treatment of lipometabolic disorders. RNA interference technology involving the modified small interfering RNA therapeutic inclisiran against the messenger RNA of proprotein convertase subtilisin/kexin type 9 (PCSK9) couples the therapeutic RNA with N-acetylgalactosamine in order to achieve liver-specific silencing of the protein formation of PCSK9 by binding to the asialoglycoprotein receptors on the surface of hepatocytes. Thus, a marked and consistent reduction of PCSK9 and LDL cholesterol levels in plasma can be achieved over more than 6 months. Other developments use antisense oligonucleotides (ASOs) against angiopoietin-like protein 3 (ANGPTL3) or apolipoprotein C-III (apoC-III) to specifically lower triglyceride levels, and the ISIS-APO(a) Rx ASO, massively reduces (>70%) the formation of lipoprotein (a). These new RNA-targeted therapeutics have key advantages, such as a long duration of action, which relates to patient compliance, the specificity of their action in certain cells or organs and metabolic pathways, and they allow for the first time an effective treatment of hypertriglyceridaemia and the mostly genetically determined elevated levels of lipoprotein (a). Large randomised clinical trials testing the effect of these new nucleic acids on cardiovascular events such as myocardial infarction and death are currently underway, including in Switzerland, and will further determine the efficacy and safety of these new drugs. This will certainly herald a new era in the treatment of various cardiovascular diseases.