RNA: From the messenger to the medicine
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In the 1990s, my colleagues and I were gene hunters. In the years before the human genome was fully sequenced, we searched tirelessly for the genetic roots of disease. It was a decades-long endeavor to first define a syndrome, then locate the responsible gene, determine its sequence, study its mutations and manipulate it for therapeutic benefit.
At the time, RNA science wasn’t being seriously considered. DNA was our star, and RNA was a bit player.
It’s a different story today, now that mRNA vaccines that were developed in record time are protecting millions of people from a dangerous illness. There is a dawning awareness of the potential for RNA-based medicines. The CEO of the Bill & Melinda Gates Medical Research Institute, Penny Heaton, calls mRNA vaccines the beginning of “a new golden age of vaccinology.”
But she could have been even more optimistic. Because after decades of research into this nucleic acid that was once seen as a humble assistant to DNA, RNA science is offering new insights into intractable conditions whose causes were previously a mystery. It’s also unlocking powerful new treatments.
Genes tell the body what to do. But if their code is garbled or incomprehensible, disease will get the upper hand. RNA—present in every cell in the body—is the messenger of these important instructions. These messages (RNA transcripts) can be edited to achieve a substantial therapeutic effect, and this has implications in a wide range of degenerative diseases.
It’s hard to believe we ever viewed RNA as a poor relation to DNA. It’s not just a golden age for vaccines that we have entered, it’s the beginning of a whole new era for medical science.
Hundreds of diseases can be traced to dysfunctional proteins in the body. While DNA essentially instructs cells to create or regulate these proteins in a way that promotes health and survival, there are often misprints, typos, deletions and other errors in DNA’s instructions. Consequently, the body sometimes fails to produce necessary proteins, produces toxic proteins or fails to properly regulate protein production. This means disease.
It also means the potential for RNA-based medicines, which seek to correct these errors, is vast. And these treatments offer something that gene therapy or gene editing does not: the ability to make changes to cells that are reversible and will not last a lifetime.
Unlike gene therapies or gene editing, RNA can be made to function the way conventional drugs do. It can achieve a therapeutic result without making a permanent change to the patient’s cells. Gene therapies or gene editing risk creating off-target effects in neighboring cells and organs, which can become permanent changes. By contrast, the body can shed an RNA therapy the way it can shed the effects of a drug.
The ability of RNA to clarify DNA instructions to promote human health, without permanent alterations to a person’s cells, is why the potential for RNA-based medicines goes far beyond developing the next generation of vaccines. Biotech companies are exploring the many possibilities today.
One successful common approach involves “knocking down” dysfunctional proteins that can lead to disease, for example degenerative conditions like amyotrophic lateral sclerosis (ALS) or metabolic disorders. Biotech companies have been making inroads on these conditions by editing RNA instructions to eliminate a “gain-of-function” protein. In these cases, weakening the production of certain toxic proteins lessens the disease impact.
Other companies are aiming not to eliminate proteins but simply alter their production by splicing the pre-mRNA that provides their instruction guide and directions for regulation. This is the case at Sarepta, where I previously served as CEO and chief medical officer.
The company I lead now, Stoke Therapeutics, is pioneering a whole different RNA approach. Stoke is focused on haploinsufficiencies or diseases like Dravet syndrome (a severe and progressive genetic epilepsy) and autosomal dominant optic atrophy that are caused by “loss of function” mutations in one copy of a gene, which result in insufficient protein levels that are essential to human health. Rather than knocking down the dysfunctional gene, as other companies seek to do, Stoke is designing RNA-based medicines to increase expression of the properly functioning gene in the pair, “up-regulating” its protein production and thereby compensating for the non-functional copy of the gene. By selectively restoring, or “stoking”, the production of the naturally occurring protein, Stoke’s TANGO (Targeted Augmentation of Nuclear Gene Output) approach has the potential to address the underlying genetic cause of haploinsufficient diseases.
RNA science is even carving out a presence in diagnostics, with RNA analysis of liquid biopsy for cancer enabling earlier diagnosis.
Vaccines did not usher in a whole new era of RNA-based medicine. But they shined a light on this area, which has been developing steadily for two decades, and which is opening the door to a seemingly endless array of applications, disease states and treatment pathways that, once explored, will alter how we understand and treat genetic diseases.
Before I took the helm at biotechnology companies, I treated patients at the point of care. Most of my patients were children with rare diseases.
I have seen what genetic diseases can do, and I know the frustration that comes with talking to parents about idiopathic conditions that degrade their children’s quality of life – or worse. Idiopathic means we just can’t shed much light on the cause of disease, even when its effects are all too visible. For a doctor, the frustration that came with diagnosis and treatment of idiopathic conditions was too intense to describe.
One of the great things about this new era of genetic medicine we are living in is that we now know far more about the causes of disease. Many conditions are inherited.
But too often, understanding the cause has not led to a cure or even a lessening of the condition. Gene therapy and gene editing have shown initial promise, but we need additional strategies if we are to translate fully our increased understanding of disease into powerful treatments.
RNA is the next leg of this exciting journey. As DNA’s transcriber and messenger, its use in medicine brings us closer to stopping diseases of all kinds right at their source.