RNAi: A Coming of Age Story

This year the first RNA interference therapy was approved, after 20 years in development. We asked some experts about the current state of the field and what we can expect to see in 2019 and beyond. 

After two decades of scientific effort, multiple devastating clinical trial setbacks, and billions of dollars of research and development, RNA interference therapies are finally here. This year, for the first time, patients in both the EU and the USA are receiving life-saving treatments based on RNAi for a rare neurological disease called hereditary transthyretin-mediated amyloidosis.

It has been a long road to get to this point, and there were times when it seemed RNAi therapies might be consigned to the dustbin of ideas that failed to make it from the academic’s blackboard to the clinician’s inventory.


Investigating RNAi

As every biology student learns early on, DNA makes RNA and RNA makes protein. This (simplified) rule, coined by the co-discoverer of the DNA double helix, Francis Crick, is known as the ‘central dogma’ of molecular biology.

Disruptions in this process, such as a mutant gene producing a faulty protein, can cause disease. The conventional method of treatment has been to target the faulty protein, and more recently to target the gene itself via gene therapy. It seems obvious that a third approach would be to target and degrade the RNA, the middleman of the process, but this proved easier said than done.

RNAi - Silence Therapeutics

In the late 1990s, early work on understanding the mechanism by which RNAi can silence the expression of a gene was carried out by American researchers Andrew Fire and Craig Mello. Their research opened the door to the real possibility that this newly uncovered mechanism of RNA interference could form the basis of new therapies. Their work earned them the 2006 Nobel Prize in Physiology or Medicine and RNAi was named ‘Breakthrough of the Year’ in 2002 by the journal Science. Despite the fanfare, however, the hard work was only just beginning.

Targeting translational challenges

The development process of RNAi treatments was fraught with difficulties. These included problems with achieving safe systemic delivery and serious side effects and patient deaths during a number of clinical trials.  Notably, Alnylam’s Phase III trial of revusiran, one of its most promising early candidates to treat hereditary transthyretin-mediated amyloidosis, was one of the most problematic trials and had to be halted when 18 patients died.

These challenges resulted in several pharmaceutical giants, including Roche, Pfizer, Abbott, and Merck, backing out of RNAi research and development entirely, even after spending billions of dollars chasing the first generation of blockbuster RNAi drugs.

However, Alnylam and a few other companies persisted and in August 2018, the US FDA granted approval for the first RNAi therapy, Alnylam’s Onpattro (patisiran) for patients with hereditary transthyretin-mediated amyloidosis. The European Commission followed shortly after, granting EU marketing approval for Onpattro later the same month.


Hereditary transthyretin-mediated amyloidosis is characterized by the build-up of abnormal, amyloidogenic variants of the transthyretin protein around the peripheral nervous system. By targeting and silencing specific messenger RNA, Onpattro blocks the production of transthyretin in the liver, reducing its ability to accumulate in the body’s tissues, thus potentially halting or reversing disease progression. Before the approval, the only treatment option for some patients was a liver transplant.

While other companies started to exit the field, we continued to believe in the life-changing benefits of RNAi, and that persistence has paid off,” Alnylam’s President Barry Greene told me.

“The approval of the first RNAi therapeutic was a major scientific milestone, not only for Alnylam, but for the entire field. RNAi represents an entirely new way to treat disease. It has the potential to bring hope to tens of thousands of patients around the world living with genetic and rare diseases that were once thought to be untreatable.”

Onpattro - RNAi - Alnylam Pharmaceuticals

New therapies in development

Buoyed by Onpattro’s approval, several European companies are working hard to bring their own RNAi therapies through the developmental pipeline to patients in the near future, one of them is London-based biotech Silence Therapeutics.

Historically, RNAi medicines had a brilliant childhood in terms of exciting, well-funded companies being started, but as often happens there was a difficult adolescence. Now, with the recent approvals, and with companies like ours maturing, the future post-adolescence looks very bright indeed,” said David Solomon, the recently appointed CEO of Silence Therapeutics.

With the recent approval of Onpattro, much like the rise of antibody medicines in the mid-90s, we’ve seen that RNAi medicines are here to stay. We’ve also experienced an enormous amount of interest since Onpattro was approved, not only from investors, but also from pharma companies wanting to do co-development and licensing deals.

Silence’s lead RNAi medicine in development aims to treat and reverse iron overload disorders – notoriously underdiagnosed and undertreated conditions – including beta thalassemia, myelodysplastic syndrome, and hemochromatosis.

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Hemocromatosis pic - RNAi feature

The company believes that by targeting mRNA from the TMPRSS6 gene, the drug candidate can reduce serum iron levels. The TMPRSS6 protein controls the levels of another protein called hepcidin, which is a key regulator of iron balance in the body.  Silence plans to launch a Phase Ib clinical trial in the second half of 2019 at centers across Europe.

Another key player in the EU RNAi landscape is Madrid-based Sylentis. The company develops RNAi therapies — administered as eye-drops – to combat eye diseases such as dry eye disease, glaucoma and retinal diseases, which cumulatively affect hundreds of millions of people across the globe.

So far, the goal of dry eye disease treatments has been to relieve its symptoms. Artificial tears are used to help lubricate the eye and need to be applied several times a day,” explained Ana Isabel Jiménez, COO and R&D Director of Sylentis.

That is why Sylentis is busy researching for ways to improve treatment and make it much more effective, using the mechanism of RNA interference which makes it possible to control and reduce the levels of abnormal proteins that would naturally improve eye hydration and thus reduce the pain and discomfort of dry eye.

Sylentis is pushing ahead with its R&D in the wake of Onpattro’s approval: the company has a dry eye disease treatment currently in Phase III, a glaucoma treatment in Phase II, and a promising retina disease candidate that they hope will enter clinical development next year.

Future directions

The post-Onpattro atmosphere of RNAi optimism has spurred on a new global wave of investment and licensing deals, totaling billions of dollars in October alone, with Alexion, Eli Lilly, and Janssen all announcing deals with companies developing RNAi therapies.

With any luck, RNAi’s ‘difficult adolescence’ truly is over. While there are still some issues to be overcome (such as the high price of first wave RNAi medicines hampering affordability), the technology looks to be finally living up to its potential as a truly revolutionary and disruptive new class of medicines.



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