The evolution of the RNA therapeutics landscape 

RNA vaccine

Bruce Sullenger, PhD Founder and Scientific Advisor of Basking Biosciences, and Joseph W And Dorothy W Beard Distinguished Professor of Experimental Surgery and the Founding Director of the Translational Research Institute at Duke University, explores the rise of RNA therapeutics.  

For decades, the life sciences community held the belief that RNA was merely the intermediary messenger (mRNA) between DNA and protein, a dogma that has been the foundation of biology. However, the RNA landscape has drastically changed in recent years and we now know that the molecule is more than just a transient, linear carrier of information. With high-throughput RNA sequencing, it is evident the majority of RNAs in human cells are not actually messengers. Instead, most RNAs are non-coding RNAs that significantly affect many cellular processes including gene expression, providing valuable insights into human health and disease.  

Since discovering the complexities of RNA, academia, biopharma, and life science investors are pouring considerable amounts of time, energy and funding into unlocking the power of RNA for therapeutic purposes. While mRNA vaccines and RNA interference therapies have garnered much attention, a new class of RNA therapeutics known as aptamers is gaining momentum, particularly to address acute diseases. 

RNA vaccines: encoding linear information 

The first category of RNA therapeutics is probably the most well recognised in medicine – mRNA vaccines. This RNA system is based upon the one-dimensional, linear structure of RNA and utilises a singular sequence of information, prompting the creation of viral protein and triggering an immune response to them. This revolutionary discovery helped the world create a novel therapeutic modality quickly and effectively to battle the Covid-19 pandemic.  

Given this intervention is transient and the virus is continually evolving, boosters are needed to help keep the immune system ready for the next infectious threat. 

RNA interference: silencing gene expression 

The second category of RNA therapeutics is a class that has also yielded marketable drugs in recent years. These drugs, known as RNA interference (RNAi)-based therapeutics use Watson-Crick base-pairing to form an RNA helix, short duplexes of double-stranded RNA molecules. The most developed RNAi is small interfering ribonucleic acid (siRNA)-based therapies. Upon delivery to the body and uptake in the cell, the siRNA is split into single strands by a protein, and this complex binds to the target mRNA by base-pairing, and degrades it thereby preventing the mRNA from being translated into protein.  

In a significant milestone in 2018, the US Food and Drug Administration (FDA) approved the first siRNA agent, known as patisiran. Patisiran is indicated for adults with polyneuropathy caused by hereditary transthyretin amyloidosis (hATTR), a rare genetic disease that can pathologically affect multiple systems, including the cardiovascular and central nervous systems. By silencing transthyretin (TTR) mRNA, patisiran decreases the production of TTR protein, the molecule responsible for causing the disease. Since then, the FDA has approved five other siRNA drugs – givosiran, lumasiran, inclisiran, nedosiran and vutisiran – for various other diseases. 

The 3D RNA: a new wave of therapeutics 

There have been significant strides in understanding the complex structure of RNA. It is clear the molecule is not simply a linear string of information or just capable of forming simple duplexes to target RNA, but rather it can form highly folded structures that can interact and bind with proteins. These findings have significant implications for understanding disease biology and its progression.  

With the knowledge that RNA can adopt a diverse range of structural shapes, we can now develop therapeutics using RNAs 3D structure, similar to creating antibody therapies or small molecules that can target surfaces on proteins. More specifically, one approach gaining momentum is the use of RNA aptamers, single-stranded RNA that directly bind and inhibit proteins through three-dimensional conformational folding. Two such FDA-approved RNA aptamers are pegaptanib and avacincaptad pegol, indicated for the treatment of macular degeneration. 

RNA aptamers have several advantages in that they lack immunogenicity, unlike antibody or protein-based drugs, and have controllable pharmacodynamics and pharmacokinetics, enabling the development of highly selective therapies that can be rapidly effective. These are critical attributes for acute care applications. 

Scientists at Basking Biosciences are developing a novel RNA aptamer targeting vWF (von Willebrand Factor), a structural component that helps stabilise blood clots and a driver of the clotting process. In ischemic stroke, high levels of vWF protein can lead to total vessel occlusion and blood flow restriction. Large animal studies demonstrate that this anti-vWF RNA aptamer inhibits vWF, facilitating rapid recanalisation of the occluded artery. Initial clinical studies have shown that it is safe in healthy humans. 

Importantly, a key benefit to this RNA aptamer approach is the ability to rapidly reverse the process through an oligonucleotide agent that selectively binds the aptamer, essentially having a failsafe system to thwart excess bleeding. In cardiovascular disease, a balance between resolving a blockage and hemorrhaging has always been a major challenge for other modalities, such as antibodies and small molecules. RNA aptamers have the potential to overcome this challenge through the use of a reversal agent to quickly and effectively stabilise patients. 

The tipping point of RNA therapeutics 

The RNA therapeutics landscape is continually evolving, offering diverse ways we can harness the power of RNA. While RNA-based vaccines have been leveraged for preventative measures and siRNA have been instrumental for genetic manipulation, a third, three-dimensional wave of RNA-based medicines is emerging with promising applications in short-term acute care – RNA aptamers. Now that the scientific community is more aware than ever before of RNA’s structural complexity, we are at a tipping point where continued innovation will help us translate the wealth of new found RNA information into safe and effective medicines. Thus, the world of RNA therapeutics is no longer flat. 


Professor Sullenger is the Joseph W. And Dorothy W. Beard Distinguished Professor of Experimental Surgery and the Founding Director of the Translational Research Institute at Duke University. Professor Sullenger is a globally recognised expert in RNA biology. Over the last 20 years, his research has been focused on the generation and clinical translation of RNA aptamers that block proteins involved in cardiovascular diseases and immune modulation. Professor Sullenger has over 25 issued U.S. patents related to RNA therapeutics.  

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