RNA-based drugs are here to revolutionize the way we know pharmacology. Covid vaccines were just the tip of the iceberg, but much more awaits in the wings.
A small interfering ribonucleic acid (siRNA)-based drug to treat hypercholesterolemia has been on the front pages these past weeks. The Spanish Ministry of Health will finance it for cardiovascular patients who do not manage to reduce their low-density lipoprotein cholesterol (LDL-C) (“bad” cholesterol) despite using statins and following healthy guidelines.
How does this siRNA-based drug work?
Inclisiran, also known as Leqvio by its commercial name, is a cholesterol-lowering, double-stranded siRNA conjugated on the sense strand with a complex carbohydrate (GalNAc) to facilitate the uptake by the liver by binding to the asialoglycoprotein receptor of hepatocytes.
In hepatocytes, Inclisiran utilizes the RNA interference mechanism and directs the catalytic breakdown of mRNA for proprotein convertase subtilisin kexin type 9 (PCSK9). This increases LDL-C receptor recycling and, in turn, the expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation. Three main clinical studies involving 3,660 patients found Leqvio dropped LDL-cholesterol levels by over 50% in patients treated with the drug compared with those receiving a placebo.
Leqvio is administered by injection under the skin. After the first injection, the next dose is given after 3 months, followed by a 6-month administration regime. This administration regime represents a substantial advantage over monoclonal antibodies (mABs) already approved for inhibiting PCSK9 (Alirocumab and evolocumab), which are also administered subcutaneously but every 2 to 4 weeks. In addition, the improved cost-effective ratio of RNA-based medicines makes them a great competitor over recombinant proteins such as mABs.
Targeted delivery is crucial to transforming molecules into therapeutic agents
The presence of GalNAc in this drug is not trivial. It guides the siRNA to the cholesterol regulator PCSK9 gene in the hepatocyte, assuring a targeted delivery to the liver, where cholesterol metabolism occurs. The siRNA then neutralizes the gene at the mRNA level. As Inclisiran only acts in the liver, the drug concentration can be reduced.
Targeted delivery ensures enhanced efficacy and reduces side effects, improving patient quality of life.
Other approaches based on nanotechnology have recently emerged to facilitate targeted delivery to different organs besides the liver. For example, modifying the lipid composition and variation of the surface charge and composition modulate accumulation in the liver, spleen, and lungs [1]. Surface decoration with targeting ligands also modulates biodistribution [2]. Lipid nanoparticles offer an excellent alternative to encapsulate and deliver RNA therapeutics. Nanotechnology not only plays a role in directing RNA toward the site of interest, but it is also crucial to decrease immunogenicity.
At DIVERSA, our R&D efforts are focused on developing highly adaptable lipid nanoemulsions designed to precisely deliver peptides, proteins, nucleic acids, and small molecules. Additionally, DIVERSA’s technology allows for precise modulation by optimizing lipid composition and decoration with proteins and ligands for targeting purposes. We are committed to bridging the gap between the bench and the bedside.
Our labor aims to provide delivery solutions by designing new and safe lipid-based vehicles to facilitate the release of biomolecules and drugs, mainly when their target is found at the intracellular level and access is limited.
We can be your partner to turn your molecules into therapeutic agents. We have the expertise, the will, and the resources to make it happen.
We can tailor our technology to your requirements. If you need help with your research project, don’t hesitate to contact us!
