In August 2018, patisiran, a first-in-class therapy was approved in the US and EU to treat the polyneuropathy associated with a genetic disease 002D hereditary transthyretin-mediated amyloidosis. The therapy uses small pieces of ribonucleic acid (RNA) to effectively ‘silence’ a faulty gene, without changing the deoxy ribonucleic acid (DNA) of the patient. This is significant!
The Dogma of Molecular Biology has been overturned
Watson and Crick demonstrated the double-helical structure of DNA in 1953 and Dr. Severo Ochoa discovered the RNA in 1959. From thereon, the biggest puzzle was how the information in DNA was transferred to generate the encoded protein. Till about 25 years ago, the statement: “DNA makes RNA makes protein” was the prevailing model. As RNA biology advanced, this model of RNA as a passive carrier of genetic information from DNA to protein has been overturned. Beyond the three types of protein synthesizing RNAs such as Messenger (mRNA), Ribosomal (rRNA) and Transfer (tRNA), the alphabet soup is rapidly evolving with new RNA sub-types e.g. Non-Coding RNA (ncRNA), Small Nuclear (snRNA), Small Nucleolar (snoRNA), Short Interfering (siRNA), micro (miRNA), Ribozymes (RNAase-X), XISTRNA (xisRNA), Double-Stranded (dsRNA) and RNA Secondary Structures are just an illustrative list of subtypes under the rapidly growing RNA Family.
Why bother with RNA at all?
For most of 20th century, therapeutic strategy has centered around proteins — find an active site or pocket on a problematic protein, stuff in a small molecule to interfere with that protein’s function, and hopefully, ameliorate the disease caused by that malfunctioning protein. Virtually all marketed drugs act on proteins as receptor blockers, receptor agonists, enzyme inhibitors, and signalling-molecule inhibitors The problem – only 15-30% of proteins have an active site/pocket leading the rest to be termed as undruggable! This chasm has led the drug developers to target RNA specifically with small molecules (for safety reasons) that could bind to the misbehaving RNAs and prevent their translation into problematic proteins or, if they are noncoding, block their disease-promoting function within the cell.
Are there any approved RNA targeting drugs?
In the recent past, several RNA-based drugs have shown clinical benefits for treating previously intractable diseases. Several compounds that block protein translation of specific mRNAs have been on the market for a while e.g. tetracylines, macrolides, and aminoglycosides, as well as synthetic oxazolidinones, act by disrupting the function of bacterial ribosomes—the sites of mRNA’s translation into protein. More recently, Novartis’ branaplam approved for Spinal Muscular Atrophy (SMA) and Roche-PTC’s risdiplam in development, work by targeting the faulty RNA transcripts of the SMN2 gene. In 2016, two drugs, nusinersen (Spinraza) and eteplirsen (Exondys 51) – both antisense oligonucleotide (ASO) drugs that alter mRNA splicing of genes implicated in spinal muscular atrophy and Duchenne’s muscular dystrophy, respectively, were approved. Several companies e.g. MSD, AZ, Pfizer, Alnylam are either directly working on RNA targeting therapies or working closely with smaller companies e.g. Arbutus, Arcturus, Ribometrix, Arrakis among many others.
What are the pros and cons of RNA directed drugs?
Let’s have a look…
|Active on ‘undruggable’ targets – that’s the whole point of going after the biology preceding that of the malfunctioning protein
|Intracellular delivery across cell and endosomal membranes
|Easy and rapid design due to predictable conserved secondary and tertiary RNA structures
|Poor pharmacokinetic properties, partly due to urinary excretion and ubiquitous RNases
|Chemical synthesis without the variability of biologics
|Activation of innate immune nucleic acid sensors
|No neeed for cold chain (mostly)
|Potential Off-Target Effects: Suppression of unintended homologous targets Activation of DNA repair pathways Translocations or imprecise gene editing
|Stable, unfluctuating suppression of target protein for up to 6 months
|Easy to combine into drug cocktails
The path forward
With the explosion of new RNA classes, we are on the verge of unlocking a new therapeutic strategy: mimic or inhibit the function of malfunctioning RNAs. However, the sailing won’t be smooth: RNA biology is relatively new versus traditional targets in several diseases. It is difficult to predict which small molecules will have the desired effect in living organisms i.e. the path from bench to market will still be long and risky! The good news- there are plenty of druggable targets to choose from and the count is increasing rapidly. Here are only some of the most advanced therapeutic targets in research
So, RNA seems to offer more targets than proteins. So What?
Discoveries in RNA biology will result in more druggable targets which in turn will expand the pharmaceutical pipeline. Even if we assume a high bench-to-market failure rate among the RNA targeted molecules, we can aniticipate a steady shift of standard of care in many diseases driven by improved and sustained efficacy of RNA targeting drugs. Patients and Physicians can look forward to a steady stream of medicines that are likely to be more effective and potentially safer. For the financially inclined, there’s an enormous amount of private money being ploughed in RNA research. Many of today’s RNA startups will become $100 M+ companies within the coming five years as the licensing frenzy continues.