Almost all drugs target proteins. This makes intuitive and logical sense; proteins are the drivers of practically all cellular processes. They form receptors for signals, they are signals, they convey signals, break down other molecules and control replication and transcription of DNA. Defective or overactive proteins cause both familial illness and acquired maladies ranging from cancer, dementia and diabetes. Indeed, all the tremendous advances in medicine up to now have come by targeting proteins either to potentiate or block their activity. Shifts in the pharmaceutical industry towards cell and gene therapies are underway, perhaps more slowly than anticipated, and these shifts are being rewarded with GSK’s Strimvelis approved in 2016 to treat a rare genetic immunodeficiency and Novartis’ 2017 approval for a CART-T cell therapy to treat a form of white blood cell cancer (B-cell precursor acute lymphoblastic leukaemia).
The century-long focus on proteins has left ribonucleic acid (RNA) underappreciated. Messenger mRNA acts as a middle man carrying information from DNA in the nucleus to protein producing factories in the cytoplasm called ribosomes. Some antibiotics – aminoglycosides like gentamycin and streptomycin which you may have heard of – target ribosomal RNA (RNA molecules inside ribosomes that catalyse protein synthesis) to kill bacteria and treat infections. Drugs that target messenger RNA have often been discovered in huge, high throughput screens where researchers test thousands of molecules to see if any can reverse the disease phenotype in model organisms which I’ve waxed lyrical about before. These screens are carried out before the researchers look more deeply at what the effective molecules are doing. Drugs emerging from these screens that target RNA were initially viewed as chemical quirks that would be difficult to translate to the clinic. Now however, they can be viewed as examples of a new class of potential therapies which could help hit the estimated 75% of ‘undruggable’ proteins before they become proteins by shooting the messenger.
RNA is single stranded unlike the famous double helix of DNA and bends back upon itself to form irregular 3D structures. Recent studies by Novartis and researchers at the University of North Carolina have shown, with a mountain of data from E. coli, that ‘druggable’ structures are abundant in the RNA molecules found inside cells. These 3D structures are diverse – which is crucial as drugs need to be able to target only the RNA carrying the code for a deleterious protein rather than obliterating all the RNA in a cell.
It would be easy to assume that RNA targeting drugs are years away from the clinic as other RNA therapeutics, such as RNA interference, have been beset by failures and taken the best part of 20 years to get close to the clinic. Yet, somewhat surprisingly, a clinical trial testing a small molecule that targets RNA is already underway. Novartis are testing branaplam for the treatment of spinal muscular atrophy, the most common genetic cause of child mortality where motor neurons are lost in the spinal cord and muscles become progressively weaker due to mutations in SMN1 gene. Branaplam binds to SMN2 RNA (a gene that acts as a back-up for SMN1) while it is still in the nucleus and changes how it is processed by the cell’s splicing machinery so that levels of SMN2 protein increase and rescue the motor neurons. Many eyes will be fixed on the results of the Phase II clinical trial late next year.
Where does the field go from here? A number of new biotech firms have sprung up with missions to find small molecules that can target disease-causing RNAs and one in particular, Arrakis Therapeutics, has gobbled up millions in investment for its lead programme targeting the expanded mRNA for HTT, the Huntingdon’s causing protein. That big pharma players such as Merck and Biogen are also jumping into the fray with their RNA targeting programmes currently shrouded in secrecy must mean RNA as a drug target is here to stay.