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RNA interference rebirth

Despite several recent setbacks, companies working in this sector are optimistic it will reap rewards in the next few years

RNA interference rebirthInitial enthusiasm for therapeutics based on RNA interference (RNAi), commonly referred to as gene silencing, faced some setbacks in 2010 after some late-stage trial failures and the withdrawal of Roche from the field.

Far from being despondent, however, companies involved in developing RNA-targeting medicines are extremely upbeat about the prospects for the technology, with more than 20 compounds in clinical development and the first product approvals expected within three to four years.

Roche's announcement, in November 2010, that it was making a wholesale exit from RNAi as part of a restructuring of its entire R&D portfolio, was taken in some quarters as evidence that the sector's popularity was waning, even though the firm had always maintained the decision not to press on with RNAi was about realigning research priorities and not a verdict on RNAi as a therapeutic modality.

Nevertheless, the negative perception was probably boosted by the fact that the announcement came shortly after Novartis decided not to take a $100m licence with RNAi specialist Alnylam Pharmaceuticals. To put that in perspective, the two companies had already generated over 30 different targets for drug development, with Alnylam standing to receive milestones and royalties on successful projects. However, add to those events a handful of development setbacks for compounds in mid- to late-stage trials (see table) and the sense of pessimism is perhaps understandable, if not justified.

"The drug industry works in long cycles, and it would be unrealistic to expect a brand new development platform to emerge and be validated with late-stage programmes in a decade or so," stated Akshay Vaishnaw, senior vice president for clinical research at Alnylam.

"The cycle will go back on the upside as clinical data emerge from the programmes that are in the global RNAi pipeline."

The rationale for targeting RNA is compelling. It is estimated that existing small-molecule and biologic drugs can only address around a fifth of the genes in the human genome, but focusing on RNA renders practically all gene products drug candidates.

Two-dimensional drug design
"The beauty of RNA interference is that it is really two-dimensional drug design: you have a target, which you know the sequence of and can easily generate a trigger to activate the cellular machinery to down-regulate gene expression," said John Rossi of the City of Hope Graduate School of Biological Sciences in California, US, and co-founder of RNAi company Dicerna.

The premise behind RNAi is simple, even though the cellular mechanisms are complex. All gene products made in the body are formed via a process in which messenger RNA (mRNA) carries sequence information to the ribosome, where the cellular machinery produces the proteins. By blocking mRNA this process is interrupted, no protein is made and the gene is effectively 'silenced'.

The early generations of RNA-targeting therapies in the 1990s, such as antisense oligonucleotides and ribozymes, suffered from being relatively unstable in the body and requiring relatively large numbers of oligonucleotides to enter the cell in order to exert an effect. Many of these early obstacles have now been overcome and antisense too could be on the cusp of fulfilling its potential, albeit more than 20 years after the approach was first postulated.

"Stability was a real problem in the early days of antisense, but chemical modifications of the oligonucleotides means that the latest drug candidates get into cells quite efficiently and are fairly long-lived," noted Rossi.

Meanwhile, in recent years, leaders in the antisense field such as Isis Therapeutics have learned from early clinical disappointments and started selecting drug candidates in indications that would show a result in the clinic more quickly, rather than the early projects in more difficult indications such as cancer. Isis' lead antisense product is now mipomersen, a drug for elevated cholesterol which has been licensed to Genzyme and looks set to be filed for approval in the first half of 2011.

However, proponents of RNAi argue that in comparison to antisense the technology offers a faster speed of onset, provides effects at lower doses and longer duration of effect, as well as generally higher potency.

The primary reason for this is that RNAi is based on double-stranded RNA, which, while being larger than single-strand antisense and therefore harder to get into cells, once there activates the cellular machinery to exert a long-term impact on gene regulation.

Most companies active in the RNAi field, such as Alnylam, Dicerna, RXi and big pharma players like Novartis and Merck, have elected to develop double-stranded, small interfering RNA (siRNA) oligonucleotides targeting mRNA. An emerging group of companies, notably Regulus and miRagen Therapeutics, are targeting microRNA, another family of RNA that is thought to exert a regulatory effect on mRNA. Finally another company, Santaris, is using both a traditional single-stranded antisense approach and a double-stranded RNAi approach in its drug development activities to target microRNA.

"Hope and expectations greatly outpaced knowledge in RNAi in the early years," said Rossi. "But as our knowledge of the pitfalls grows, the prospects and the opportunity become greater."

Delivery has often been cited as a primary obstacle to the development of RNAi drugs, but there have been dozens of different delivery systems, both targeted and non-targeted, used in animal models and human trials with some success, according to Rossi. Where the obstacles remain is not so much in the feasibility of delivery, but rather in intellectual property issues, which can make securing access to platforms costly, particularly at commercial scale.

Selectivity and toxicity are other oft-cited challenges, but latterly researchers have identified a number of chemical modifications that can be performed on the RNAi molecules, which block their ability to activate unwanted cellular pathways. For example, double-stranded RNA is known to interact with certain toll-like receptors on cells that can in turn trigger inflammatory pathways, but this can largely be overcome by placing side groups on the RNAi molecule.

"A lot of the issues with RNAi in the early days centred on not designing sufficiently potent and sufficiently immunosilent molecules," according to Vaishnaw. "Delivery was an issue from day one, but there has been a lot of progress and our own work on liposomal nanoparticles has yielded very promising results."

Alnylam itself expects to have five RNAi compounds in late-stage development by 2015 that others in the field will also be nearing commercialisation with therapeutic candidates.

Many liken the situation with RNAi to the early days of antibody development. Heralded as 'magic bullets' in the 1980s, it took a decade to realise that the immunogenicity and other issues related to the early mouse-derived antibodies were a major burden for the platform. Once these obstacles were understood and overcome, the field went from strength to strength.

There are also similarities in that most big pharma companies stayed out of biologics, with one or two exceptions, during the early days. But those early adopters, such as Roche, which became involved with antibodies in the 1990s, eventually reaped huge benefits.

"There will be a lot more people in the RNAi game in 2015 than were involved with antibodies at the equivalent phase of development," said Vaishnaw. "R&D productivity is going down in the pharmaceutical industry and we need new platforms to generate drug candidates. We think that RNA could be the next major platform after small molecules and proteins."

Drug development status






PF-655 (RTP801i)



wet age-related macular degeneration


diabetic macular oedema





 respiratory syncytial virus infection


miravirsen (SPC3649)

Santaris Pharma


hepatitis C virus infection


QPI-1002 (I5NP)



acute kidney injury


decreased graft function



Sylentis (Zeltia)

ß-2 adrenergic receptor




Calando Pharma


solid tumours




Keratin 6a

pachyonychia congenita





solid tumours




Caspase 2

ischaemic optic neuropathy





pancreatic adenocarcinoma





liver cancers





TTR-mediated amyloidosis








Opko Health


wet age-related macular degeneration


diabetic macular oedema





wet age-related macular degeneration





advanced solid tumours



Santaris Pharma





Santaris Pharma


solid tumours


The Author
Phil Taylor
is a freelance journalist specialising in the pharmaceutical industry

To comment on this article, email  

6th June 2011


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