“Gene silencing” drugs hit the market and transform lives

The title for this blog was inspired by an analogy presented during an excellent BBC World Service podcast (“The Silence of the Genes”) describing a revolution in medicine that is taking place as a new class of drugs is added to the physician’s arsenal.

As we all hopefully know from elementary biology, the DNA (deoxyribonucleic acid) contained in every cell in our bodies is made up of many genes. The sequence of each of those genes can be thought of as a set of instructions for the manufacture of a specific protein which will then go on to perform its function in the body.

Normally, we want this process to carry on without interruption but what if, as in some rare diseases, the protein that is produced is actually harmful to the body? One example of such a disease is hereditary transthyretin-mediated amyloidosis (sometimes abbreviated to hATTR). In this case, a “rogue” gene causes the liver to produce a toxic protein called transthyretin which attacks nerves and organs and can ultimately lead to death in as little as three years.

It is for such diseases that gene silencing drugs can offer hope. To understand how they work, we need to be introduced to the third partner in the protein production chain. Liaising between the DNA and the protein is a less well-known intermediary called RNA (ribonucleic acid). The RNA Society helpfully explains the role of RNA as follows:

“When the cell needs to produce a certain protein, it activates the protein’s gene – the portion of DNA that codes for that protein – and produces multiple copies of that piece of DNA in the form of messenger RNA, or mRNA. The multiple copies of mRNA are then used to translate the genetic code into protein through the action of the cell’s protein manufacturing machinery, the ribosomes. Thus, RNA expands the quantity of a given protein that can be made at one time from one given gene, and it provides an important control point for regulating when and how much protein gets made.”

Here, we see the introduction of the term “messenger” and the clue to the title of this blog. What if we could knock out the intermediary between DNA and protein – “shoot the messenger” as it were – and thus prevent the production of the harmful protein?

This is precisely the mode of action of the most advanced class of gene silencing drugs, which act by a mechanism known as RNA interference (RNAi). In RNAi, small RNA molecules – either microRNA (miRNA) or small interfering RNA (siRNA) – bind to the messenger RNA and prevent it from producing the protein. This ability to silence the action of a specific gene gives RNAi the potential to treat many genetic disorders including hATTR. In fact, a siRNA drug called Onpattro (patisiran) designed to treat hATTR was the first RNA-targeting drug to be approved by the FDA and a whole parade of other potential treatments are in or near the clinic.

The “Silence of the Genes” may just be “music to the ears” of patients and their families waiting for treatments for a range of debilitating diseases, among them Cristina, a nurse and active mom of three, who was profiled previously on Eureka for living with amyloidosis. She and her family can now have hope that the progress of the disease can be slowed and that they can continue to live the active lives they enjoy currently.

(In April, a second RNAi drug was approved by the FDA and the European Union, in this case for acute hepatic porphyria. The drug marks the first treatment for AHP, a rare and life-threatening genetic condition in which patients lack the enzymes needed to produce heme.)