August 1st was World RNA Day! A World Without RNA would be pretty lifeless, so I think it’s worthwhile to give you all a primer on this topic. (The people who got that joke probably don’t need to read this, ironically).
We all remember the Central Dogma of DNA to RNA to protein, and if you think real hard, you can probably remember the Initiation, Elongation, and Termination phases of DNA transcription, also known as RNA synthesis. And the ultimate goal of RNA synthesis is protein synthesis, which requires various types of RNA, including messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), and a bunch of non-coding RNAs as well.
But since Lipid Land is a place of whimsy rather than controversy, we aren’t going to spend today discussing mRNA. (Depending on your point of view, the term “Kill the Messenger” has taken on an entirely new meaning since 2020).
Instead, we will discuss Small Interfering RNA, or siRNA, which is often mistakenly confused with mRNA. Many novel Lipid-Modifying therapeutics utilize this rather elegant technique, so let’s dive in!
Remember, the ultimate goal of all the RNA guys is to create a mature protein, so the goal of an siRNA is to INTERFERE with the process of protein production, particularly if that protein is felonious (like Lp(a) or mischievous (like PCSK9 or ApoC3). The aforementioned proteins are produced either entirely or primarily by the liver, so siRNA attempts to target the drug delivery specifically to the liver, thus theoretically avoiding off-target side effects.
SiRNA technologies typically use an access card called n-acetylgalactosamine, or GalNAc, to enter the liver. This GalNAc can only be recognized by the asialoglycoprotein receptor (ASGPR), and since the ASGPR is only located in the liver, it’s a clever way to ensure the drug isn’t getting into the wrong places.
Once the siRNA therapeutic has flashed its GalNAc access card, the siRNA utilizes the hepatocytes’ own intracellular machinery to prevent the mature protein (such as Lp(a) or PCSK9) from being translated. There are various characters involved, including argonaute enzymes and an RNA silencing complex called the RISC, that help create an anti-sense nonsensical union rather than a complementary, “happily married” pair. (And if you want to take on the RISC of complete befuddlement, you can read THIS ARTICLE that goes into immense detail on the topic).
But basically, these siRNA approaches create a disastrous “Unhappy Couple” that you know will never last. Think of Britney Spears and Kevin Federline…certainly not destined for long-term success! And so the siRNA “annuls” the marriage and the mature protein is not produced.
Some of the siRNAs that are either currently available or in development include Plozasiran, Olpasiran, and Inclisiran (the suffix -iran gives it away as an siRNA, and despite having the same name as a historically conflicted Middle Eastern country, -iran rolls off the tongue a little better than -irna). Feel free to further investigate the marriages that those medications are halting at the altar😊
Happy RNA Day!
–A note about ASOs:
*Anti-sense oligonucleotides (ASOs) also often use the GalNAc access card and work similarly to siRNAs in inhibiting protein translation. However, these ASOs utilize single stranded RNAs (vs the double stranded approach of siRNA) and the intracellular machinery utilized by ASO therapy is RNase H1, which can be present in both cytoplasm and nucleus. SiRNA does its work in the cytoplasm*
