RNAi isn’t ready to be silenced

In this screengrab from a Nature video, a siRNA, cradled by an argonaute protein, binds to a messenger RNA. (Watch the full video at: https://www.youtube.com/watch?v=cK-OGB1_ELE)
An siRNA, cradled by an argonaute protein, binds to a messenger RNA. (More from Nature at www.youtube.com/watch?v=cK-OGB1_ELE)

RNA interference (RNAi) is a therapeutic technology that blocks gene expression with either small interfering RNAs (siRNA) or microRNAs (miRNA). RNAi’s discovery was considered transformative enough to earn the 2006 Nobel Prize for Physiology or Medicine, but from the start the challenge of delivering RNA-silencing therapeutics to the right tissues has hobbled efforts to use RNAi to treat patients.

Citing this challenge, the pharmaceutical giant Novartis is the latest major company to withdraw from RNAi research, following Merck and Roche. Forbes was prompted to write:

…for certain diseases where an RNAi therapeutant can be more readily introduced, such as the eye, or ‘privileged compartments’ such as the liver, RNAi still has potential. But given that these therapies would be expensive due to the high cost-of-goods involved in synthesizing these agents, they would have to be targeted to diseases where the cost of therapy would be justified by the beneficial medical effects. … to say that RNAi therapy will rival monoclonal antibodies in terms of revenue potential—well, that’s a bit of a stretch.

Barry Greene, COO of Alnylam Pharmaceuticals, a biotech that’s championed RNAi, countered in Fierce Drug Delivery: “Novartis pulling out is an exemplar of Big Pharma not being able to innovate, and historically they have never been able to innovate.”

Those are fighting words. To get some perspective, Vector consulted Ryan Dietz, JD, licensing manager in the Technology and Innovation Development Office at Boston Children’s Hospital. Dietz handles several RNAi intellectual properties including technology licensed to Alnylam.

Should we be writing RNAi’s obituary? 


No. There are scientific challenges, but I see the biopharmaceutical industry’s withdrawal from this space as more a signal of changing business models than a statement about RNAi. We should be writing RNAi’s resume: Its career is young, it has come from the best educational background, and it has proven itself as an invaluable research tool. Converting RNAi into drugs for humans does pose challenges, but the technology is advancing due to great science and very effective companies. I’m confident there will be important therapeutics in the coming years.

There seems to be a lot of industry maneuvering around RNAi. What’s going on?

Industry trends make it clear that biopharmaceutical companies are abandoning platforms and shifting their focus to areas where they have a core competency. This is mainly the result of changing risk tolerance and expected return on investment, not as a statement specific to RNAi. Increasingly, large biopharmaceutical companies don’t want to be the ones taking on the risk of basic research or building platforms in order to discover new drugs. They are increasingly licensing later-stage drugs from academics and smaller companies where risk has already been removed.

Why is RNAi targeting proving to be such a difficult problem to solve?

Most drugs don’t require a specific guiding component; the drug essentially guides itself to target tissues where it has the intended effect. In RNAi, the delivery molecule has to be optimized in addition to the drug itself. It needs to link effectively to the siRNA or miRNA drug, remain long enough in the circulation and manage multiple steps in the delivery process: everything from finding the specific cellular receptor to getting inside the cell and releasing its cargo in a specific compartment—namely, the nucleus—at the right levels.  And it needs to do all those things with no major side effects.

Delivery is also an important question for other drug platforms including gene therapy and modified RNA therapy.

What applications are looking most promising?

As with gene therapy, RNAi technology is most applicable to disorders where there’s a known protein involved in the pathology that can be knocked down to have a positive therapeutic effect.

To date, RNAi is having the most impact in treating disorders affecting tissues and organs where the molecules naturally end up locating in the body. This includes the liver, where RNAi has shown to be effective in animal models and in ongoing clinical trials. Delivery has worked well in the liver because it basically acts as a blood filter—it is naturally a place where RNAi will land. Blood-related conditions are being targeted for similar reasons. Alnylam, for example, recently published results of a Phase I clinical trial using RNAi to target a liver protein in hypercholesterolemia, in partnership with Genzyme, and recently started a Phase I trial in hemophilia.

What would it take to turn the corner and prove RNAi technology?

I feel targeted delivery is a key driver of RNAi’s long-term value as a therapeutic platform. My original hope was that we could develop a broad platform that could be optimized to target any specific tissue. But it’s turning out to be more complicated. We will need significant basic and translational research, and the near-term beneficiaries will be specific patient populations with high unmet needs.

A lot of targeting technologies have been explored in the past seven to eight years, including antibodies, peptides and nanoparticles.

At Boston Children’s, Judy Lieberman, MD, PhD, has had success with a dual approach in targeting breast cancer cells, packaging siRNAs in a peptide that protects them from being broken down in the bloodstream and attaching an antibody fragment that homes to HER2-positive cells—the specific cells of therapeutic interest. Once there, the siRNA turns off a gene called PLK1, stopping tumor growth and suppressing metastasis.

Where do you see RNAi heading?

I think we will find that there are a lot of diseases that simply can’t be treated any other way, and RNAi will be transformative for those patients. Currently, because of the risk, RNAi therapeutics are most often considered for conditions that lack an existing treatment, such as rare diseases. As the technology matures, I think it will become applicable to disorders with much larger patient populations.

Industry representatives interested in RNAi technologies at Boston Children’s can read more here and here, or email Ryan.Dietz@childrens.harvard.edu.