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Is this the decade of RNA?

Stereo Chemistry explores why RNA is having kind of a moment in the drug discovery world

by Lisa M. Jarvis , Ryan Cross
January 15, 2019


Credit: C&EN

RNA should be a terrible drug target. It’s long, noodle-like structure lacks the nooks and crannies that small-molecule drugs use to grab onto proteins and thereby control them. But a decades-old disregard for RNA is starting to change. In August 2018, the US Food and Drug Administration approved the first-ever RNA interference (RNAi) drug, which uses a double-stranded RNA molecule to prevent the production of disease-related proteins. In the past two years, several startups have launched to show that some RNAs can, just like proteins, be drugged with small molecules. And a third group of companies recently emerged with plans to drug proteins that make modifications to RNA, part of the budding field of epitranscriptomics. In this episode, C&EN visits Alnylam Pharmaceuticals, Novartis, and Accent Therapeutics to discuss these three strategies, and to understand how RNA-modulating therapies will compete in the wider world of drug discovery.

Subscribe to Stereo Chemistry now on iTunes, Google Play, or TuneIn.

The following is the script for the podcast. We have edited the interviews within for length and clarity.

A computer-generated image of a methylated RNA duplex.
Credit: J. Am. Chem. Soc.

John Maraganore: I had the audacity in 2010 to get in front of the JP Morgan Healthcare conference and declare the decade of 2010 to 2020 as the RNA decade. And I wasn’t actually far off, to be honest. I mean, it really has been a remarkable decade for RNA, and I think that’s only going to continue for the next, you know, many decades from here.

Ryan Cross: You’re listening to Stereo Chemistry, and I’m Ryan Cross, a biotech reporter for C&EN. That audacious claim was brought to you by John Maraganore, the CEO of Alnylam Pharmaceuticals. His company develops drugs made from RNA. So he might be a little biased when giving RNA the win for the decade.

Lisa Jarvis: You think? This is Lisa Jarvis, and I’m C&EN’s pharmaceuticals editor. And even though we aren’t ready to call this past decade for RNA, Ryan and I both have noticed that in the last year or two, we were writing an awful lot about RNA.

Ryan: Yeah, I think it’s fair to say that RNA is kind of a having a moment in the drug discovery world. And in this episode, we’re going to talk to a bunch of people about why that is and what that means.

Lisa: We’ve written a lot of stories about the buckets of cash raised by biotech companies trying to modulate RNA in some form or fashion. And big pharma is getting in on the field by striking rather lucrative deals with these biotechs. So now seemed like a good time to explore why RNA was, like Ryan said, having a bit of a moment.

Ryan: Before we go any further, though, let’s talk about RNA. It’s a tremendously important biomolecule that gets nowhere near the love that DNA does. Right? Thanks to things like 23andMe, I think it’s safe to say that everyone is familiar with DNA. You might understand DNA as our genetic blueprint or the recipe for building proteins.

That’s mostly true, but it skips a step. First, the DNA is transcribed into an intermediate molecule, called messenger RNA, or mRNA for short. Then our cell’s machinery translates that mRNA code into instructions for making proteins.

Lisa: And proteins pretty much do everything for us. They give our bodies structure, help us move, carry messages. Basically, they’re responsible for nearly all the action in our cells. For decades now, drug hunters have been pretty focused on the protein. But in the last decade or so, scientists have said, wait a minute, what if we invent drugs that can control RNA? That approach would keep proteins from being made altogether—a tantalizing idea.

Ryan: As we mentioned earlier, people are now using so many different strategies to go after RNA. Remember John Maraganore from the beginning of the episode? His company Alnylam is using a technique called RNA interference. In this strategy, short stretches of double-stranded nucleotides, which you might hear called short interfering or “siRNA,” are used to shut down the activity of certain genes by binding to mRNA and preventing it from being used to make proteins.

Lisa: And even before that, there were antisense oligonucleotides. These rely on single-stranded stretches of nucleotides to shut down RNA.

Ryan: And don’t forget that many companies are trying to make therapies out of mRNA itself, which could be used to prompt the body to make proteins that are missing or could be used therapeutically.

Lisa: And then, there’s small molecules that directly bind RNA.

Ryan: And small molecules that change how chunks of RNA code are stitched—or as biologists like to call it, spliced—together.

Lisa: Oh, and small molecules that modulate the proteins and enzymes that control RNA. And...

Ryan: Maybe we should stop there.

Lisa: But there’s more!

Ryan: Let’s just stick to where we’re seeing all the money going for now.

Lisa: Ok. So you might be wondering why don’t drug developers just keep knocking down proteins like they used to? Why shift the focus to RNA? Let’s hear from John again.

John Maraganore: You know, there’s also this world of undruggable targets where you can’t really approach them with small molecules or antibodies as they stand right now. You have to target the RNA to get to the end result.

Lisa: Avid Stereo Chemistry listeners might recall an earlier episode that was all about undruggable targets. It turns out that something like 85% of the proteins our body makes can’t be wrangled by conventional small molecules and antibodies. That out-of-bounds group includes a whole swath of proteins that we know cause disease.

Ryan: So how do you go about targeting RNA? Let’s start by talking with Alnylam, since they’ve sort of been the star of this past year. FDA approved their drug, Onpattro, back in August. It is the first drug that acts by RNA interference that has made it to market. That’s a remarkable development.

Lisa: What makes it so remarkable is that RNA interference, or RNAi as the cool kids like to call it, was discovered only two decades ago. To back up, scientists had long known that our cells use some mechanism—or mechanisms—to turn off gene expression—but what was it? That part was a mystery. Then in 1998, Craig Mello and Andrew Fire reported that they could turn off specific genes in worms by using short, double-stranded RNA molecules running 20 to 25 nucleotides long. Suddenly, by mimicking our cell’s own process, scientists had an amazingly simple, but still extremely powerful method for exploring the function of different genes. It was a pretty big deal.

Ryan: Super big deal. They won the Nobel Prize in Medicine for that work. After Mello and Fire’s discovery, lots of researchers started to tinker with RNAi in the lab. In 2000, one of those researchers, Phillip Sharp, came into Millennium Pharmaceuticals, where John worked at the time, to talk about what they’d learned.

John Maraganore: Phil reached out to me as an executive at Millennium and said, look you know this is a really interesting finding of RNA interference. And most people think it’s only a biological process that occurs in lower organisms like plants and the worm. But we have identified that this is a pathway that is operative in mammalian cells. And that wasn’t published at the time.

Ryan: That crew of RNA experts went on to form Alnylam to try to translate their finding into medicines. In 2002, John joined as CEO, and as he’ll readily admit, it was a pretty risky move. Both his kids and his boss suggested it was a bad idea. You see, the concept of turning RNAi into a drug had a lot of promise, but very little data, particularly in live animals, or as we call it in the science world, in vivo.

John Maraganore: We actually had to teach the Alnylam founders that a cell experiment result is not in vivo. They used to think I mean, I kid you not, they would think, “Oh, we have in vivo data, we have cell data.” Well that’s not in vivo, guys. That’s a petri dish. And so it took time. We knew it was early. We knew it was very early.

Ryan: Even when Alnylam filed the paperwork to go public in 2004, they had yet to demonstrate gene silencing in an animal. Knocking down RNA in humans? That would take many more years and a lot of trial and error.

The problem boiled down to sneaking these molecules into cells, where they could work their magic. You see, even though these are short strands of RNA, they’re still way bigger than a small molecule. And there are other problems, too. We’ll let John explain.

John Maraganore: These molecules are 14,000 Daltons, right? So they’re pretty big. Biophysically, they’re like a rod. They’re incredibly charged on the outside, they’ve got you know just phosphate backbones like with negative charges all over the place. So they are the most deplorably unfit type of molecules to cross the cell membrane.


So we had to get from the outside of the cell into the inside of the cell and then on top of it to add to our challenge, right, we know that these molecules in the body can be degraded very rapidly. If you don’t chemically modify them, they’re degraded within minutes. So anything you’d inject would get you instantly destroyed.

Ryan: To make matters worse, John says, when RNA is in the bloodstream, or outside of cells, the body thinks it is under attack from a virus, which triggers an immune response. And the list goes on.

John Maraganore: And then on top of that I should mention, how do you make these things specific, right? How do you make sure that you’re only going after the target gene of interest and not like, you know 100 other target genes. So there were a lot of things that had to get done to make them a viable pharmaceutical molecule.

Ryan: Figuring out how to solve all of those problems took years. It turns out that researchers had the right idea early on. It just took a long time to get it to work well.

That right idea was a lipid nanoparticle, a Trojan horse of sorts, that could sneak siRNA inside cells. Imagine a spherical shell made up of a collection of different lipids, each meant to do a different job, like interacting with cellular membranes, keeping the drug in the bloodstream longer, or even just giving the particle some structure. The hollow core of the lipid nanoparticle can h old a payload of siRNA that, assuming everything works out as it should, doesn’t get released until the nanoparticle is in just the right place in the body.

Lisa: Getting these particles to work was no easy feat. In the early days, it took a huge dose of lipid nanoparticles to see the siRNA payload have any sort of impact on shutting down gene expression. When they tested those high doses in mice, they saw some pretty serious side effects, like inflammation and even death. But over the years, chemists and chemical engineers tinkered with the lipid composition to get to something that could work as a drug.

Ryan: That drug is Onpattro, which treats a rare genetic disease called hereditary transthyretin-related amyloidosis, or hATTR. In the disease, a mutation in a protein called transthyretin causes the protein to misfold into structures called amyloid fibrils. Transthyretin is primarily made in the liver, but the amyloid fibrils form toxic clumps in the nerves, heart, and other tissues. The siRNA tucked away inside Onpattro’s lipid shell blocks the production of the transthyretin, preventing further buildup of those dangerous amyloid deposits.

The FDA gave itself a deadline of August 10, 2018, to make a decision on the drug, and it really let it go down to the wire. John can tell us about that day.

John Maraganore: It turns out—and this is just so crazy—I happened to be in front of our sales force. We were over at the Logan Airport Hilton and we had all of our reps you know they are all our entire field force there. I was literally on the stage. It was about noon and somebody from our field force said, “John, when will we know when we get the approval”? And I’m like, well you know we’ll probably get an e-mail or fax and then we’ll find out. And literally at that moment Barry Greene our president jumped up and said, “John, we just got approved!” Literally at the moment. I think it’s been memorialized on social media because people were you know taking videos that we tweeted out and it was an amazing moment.

Ryan: Beyond that memorialization from Alnylam itself, social media that day was chock full of congratulatory messages from researchers and executives far and wide. People were just plain excited to see an RNAi finally cross the threshold from Nobel-winning idea to a marketed drug. It was a rare moment of unity and excitement in the biotech community—and reminiscent of a similar moment at the end of 2017 when the FDA approved the first gene therapy in the US. Gene therapies, which we’ll hear a bit more about later, use viral shells to shuttle DNA into the body, and scientists have been trying to make them safe and effective for decades.

Lisa: So Ryan, I get the excitement. But just to be clear, we aren’t all going to be trading in our pills for injectable RNAi therapeutics or DNA-stuffed viruses anytime soon.

Ryan: That’s right. Although Alnylam has a whole pipeline of medicines in the works—in fact, it plans to soon ask FDA to approve a second drug that uses a newer delivery system—RNAi still faces some challenges. And they aren’t trivial. The lipid nanoparticles are taken up by a receptor that’s in liver cells, meaning the technology is most appropriate for diseases that manifest in the liver. Alnylam is making some progress in using a method of injecting the drug into the spinal cord to treat neurological disorders, but you’d really only want to take that route that for a very serious, life-threatening disease.

Lisa: Ah, yes, so getting back to all those undruggable targets we talked about earlier—this technology can address some, but definitely not all of them.

Ryan: And during the 16 years that Alnylam was working towards getting Onpattro onto the market, other companies have made a lot of progress in using various flavors of RNA as a drug. Antisense oligonucleotides, which had been around even before RNA interference drugs, finally have started to get traction, especially in neurological disorders. Just to remind you: These are kind of like siRNA, but they’re short segments of single-stranded RNA rather than double-stranded RNA.

For nearly a decade, billions of dollars have also gone into turning mRNA itself into a drug, and some of those efforts are now being tested in humans. Both antisense oligos and mRNA have their own delivery problems, which, again, means they can’t tackle every disease. And, by the way, all of these things are breathtakingly expensive. Onpattro? That drug carries a price tag of $450,000 per year.

Lisa: So RNA is a potentially great target, but using it as a drug might have its limits.

Ryan: Exactly. And in the last three years, something kind of interesting has happened that could change how we think about drugging RNA. An explosion of research and money has gone into another way to block, modify, or generally wrangle RNA.

Lisa: We’re talking about small molecules!

Ryan: Amazingly, yes. Instead of using expensive, tough-to-deliver nucleic acid-based therapies, researchers have been trying to figure out if they can control RNA with good old-fashioned small molecules. If they are successful, it could open up a wide expanse of targets that, at least with current delivery technologies, are impossible for siRNA and antisense oligonucleotides to reach.

Lisa: We’ll tell you how as soon as we get back from a short break.

Matt Davenport: Hey everyone. This is C&EN reporter and Stereo Chemistry producer Matt Davenport. There’s a good chance you already know what I’m about to tell you, but it’s so important I don’t want to make any assumptions. In addition to hosting fantastic podcasts, Ryan and Lisa also write fantastic news stories for the C&EN magazine and website.

Take this as a for instance. I’m recording this on January 2, 2019, and like three hours ago C&EN posted an awesome story by Lisa about the record number of drugs approved by FDA last year. On top of that, our art and web designers put together this amazing interactive graphic that lets you see what these drugs are and learn more about them.

And, look, I know you’re busy. Heck, if you’re like me, you probably listen to podcasts while you’re doing something else—driving, cooking, working hard to look casual yet actively avoid eye contact with anyone on public transit. So we know you’re not going to have time to read every article we publish or interact with every sweet, sweet graphic that we make.

That’s why we’ve got a newsletter that will send a collection of our best, most important stories directly to your inbox every week. And to get it, all you have to do is sign up at

Again, that link is

Subscribe now and kick off your new year with the peace of mind that you’ll always be current with the biggest news in chemistry. And, speaking of which, let’s get back to Ryan and Lisa.

Ryan: When I reported a story last year about the growing number of biotech firms trying to develop RNA-targeting small molecule drugs, the concept seemed ... pretty wacky. People in the field are quick to say that on the face of it, RNA is a terrible drug target.

Lisa: For our listeners who aren’t RNA experts like you, Ryan, want to explain why it’s such an awful target?

Ryan: Well, it has to do with the shape of a protein compared to the shape of RNA. Proteins—at least the ones we’ve developed drugs against—have a compact shape that includes nice, well-defined pockets with lots of dangling amino acid residues for a small molecule to interact with. RNA, on the other hand, just lacks obvious toeholds for small molecules. It’s kind of like a strand of wet spaghetti—long and floppy.

Natalie Dales: With RNA, because it has a very flexible very dynamic structure and only a few pockets that aren’t very well defined and that are kind of moving and shaking quite a bit, it’s hard to get that specific interaction.

Ryan: That was Natalie Dales, and she knows a thing or two about coaxing small molecules into modulating the activity of RNA. As director of global discovery chemistry at Novartis, Natalie led a project to develop a compound called branaplam that everyone points to as the best evidence that small molecules can modulate RNA. It’s currently in clinical studies to treat spinal muscular atrophy. People with the disease are born with a mutation that prevents the production of a spinal motor neuron protein that is vital to the survival of nerve cells. Without treatment, babies born with the most severe form of the disease don’t usually live past two years old.

Lisa: So Natalie and her colleagues set out to develop a small molecule that could prompt cells to make that missing protein. And she will be the first to tell you that when her team began working on this in 2008, they weren’t planning on designing a small molecule that could specifically target RNA.

Ryan: They were running what’s called a phenotypic assay. So they weren’t looking for small molecules that bind to any particular target, they were looking for small molecules that could induce some sort of change in nerve cells. In this case, the change they were looking for was the production of that spinal motor neuron protein. This screening led them to branaplam, but it took them quite a long time to figure out how the molecule actually worked.

Natalie Dales: We designed this really beautiful screen. We identified molecules that came from that screen. We spent a lot of time on medicinal chemistry of those molecules to kind of advance the potency, these types of things. In the meantime, alongside that, we’re also elucidating the mechanism and that’s where a lot of work went in to really show that at the molecular level we could understand what compounds like LMI070, also called branaplam, are doing.

Ryan: Branaplam’s mechanism was even wonkier than they could have expected. Basically, it works by controlling splicing, or the process of stitching chunks of RNA together into a code that is ready to be translated into a protein. Splicing itself is controlled by a complex protein machine called the spliceosome.

Natalie Dales: The small molecule isn’t only interacting with that RNA, it’s actually acting with the protein and the RNA.

Ryan: What Natalie and her team found was that branaplam holds the RNA code for the spinal motor neuron protein alongside the spliceosome long enough to change the way the RNA is stitched together. That new pattern allows the missing protein to be synthesized.

Although the Novartis team didn’t set out to find a molecule that interacted with RNA, their program showed that it was possible and revealed a drug candidate that’s now in clinical trials. People working to develop small molecules targeting RNA often point to a 2015 publication from Novartis showing how branaplam works as a key turning point for the field.

Lisa: Moveover, in the ten years since Natalie and her colleagues began working on spinal muscular atrophy, researchers have developed new technologies that they think will allow drug developers to design these small molecules that interact with RNA on purpose.

Natalie Dales: I think that’s exactly what we and others in the field are trying to do now. So using the learnings from our story and other stories, how do we now prospectively design? Now we understand a little bit more about RNA structure. One of the other things that we learned in this process was it’s very important to understand the sequence.

Ryan: On the technology front, Natalie says one of the big breakthroughs has been a tool called “RNA-seq,” which is a way of sequencing all of the RNA molecules in a cell. That tool lets scientists understand in minute detail how a compound affects the abundance and activity of RNA.

Natalie Dales: So with RNA-seq experiments, which can canvass the whole genome and can see with all of the different RNA changes that are happening due to compound, due to different concentrations of compound , time, all these things. Great advancements in that field have allowed those experiments to run much more quickly. So I think that’s going to be really key. So now you can study a series of compounds, across a series of time points, across a series of cell lines, and really see at the RNA level what are the different things that are happening.

Ryan: Success stories like the one from Novartis are contributing to a swell of interest in using small molecules to modulate RNA. In the past two years, a bunch of biotech companies—many well funded, like Arrakis, Expansion Therapeutics, and Ribometrix—have all launched to directly bind RNA with small molecules. Others, such as Skyhawk Therapeutics, are focused on controlling RNA splicing, like Novartis.

Lisa: That perception that RNA is a terrible target? It’s fair to say that it’s definitely shifting, but as Natalie reminds us, the field has a lot to learn. And it’s worth pointing out that, so far, Novartis is the only one of these companies with a drug in a clinical study.

Natalie Dales: I don’t know if this is a blip moment or a sustained moment. I think everyone’s kind of coming into the area with a lot of force and a lot of enthusiasm. But it isn’t like so trivial that you can take these learnings from this project and just say OK it’s going to open all these doors because it’s not so trivial. That’s kind of our dream as scientists in this field that we make it seem trivial, right, or make it seem regular like this. In five years we say, “Oh yeah, RNA you know that’s easy.”

Lisa: So, beyond spinal muscular atrophy, what are some of the drug targets or diseases that Novartis is going after with these RNA-targeting small molecules?

Ryan: They aren’t saying, but they did publish a big study back in May showing that potentially druggable mRNAs are much more common than anyone imagined. And we do know that other, smaller biotech companies pursuing this approach are working on some pretty interesting stuff.

For example, people are interested in drugging an mRNA involved in a neurodegenerative disease called Huntington’s. I’m sure we’ll be hearing more about that program and others in the coming years.

Lisa: So I think it’s important to mention a big caveat here: all of this is still in really early stages of research. None of these biotech startups have begun testing their RNA-targeting compounds in humans yet.

Okay, to recap, we’ve looked at companies using RNA as a drug, and we just talked about drugging RNA with small molecules. Wasn’t there a third, totally different approach that you wanted to discuss?

Ryan: There is, and I’ve saved this one for the finale. It’s all about making chemical modifications to RNA. And to learn about this, we spoke to Robert Copeland, president and chief scientific officer at the startup Accent Therapeutics.

Robert Copeland: For a long time RNA was considered to be a relatively passive molecule and that RNA was kind of a bystander. At Accent, we are focused on targeting enzymes that are involved in RNA modification. And the fact that RNA is modified has been known for something like 60 or 70 years, but until very recently it was sort of a laboratory curiosity. No one really understood what those modifications were all about.

Ryan: That’s really started to change recently. In fact, there is an entire new field of biology that is devoted to understanding the enzymes and proteins that modify RNA called epitranscriptomics.

Lisa: Which is kind of like the RNA version of epigenetics.

Ryan: Right! So epigenetics is the study of how chemical modifications on DNA are involved in turning genes on and off. Epitranscriptomics is similar, but is the study of how chemical modifications regulate the transcriptome, i.e., all of the RNA in a cell.

Three classes of proteins are responsible for chemically-modifying RNA. First, there are the “writers,”

Robert Copeland: These are enzymes and proteins that place specific modifications at specific locations within RNA ...

Ryan: Then you have enzymes that are the “erasers.”

Robert Copeland:... or remove those modifications ...

Ryan: And finally, the “readers.”

Robert Copeland: ... or proteins that bind to the modified form of the RNA.We call them RNA-modifying proteins or RMPs for short. We are not targeting RNA per se. We’re targeting the proteins and enzymes that modify RNA.

Ryan: Bob’s company, Accent Therapeutics, launched last year to develop new ways of treating cancer.

Robert Copeland: It’s really, as with most cancer therapies, it’s about correcting a defect in the cancer cell. So in some cases a cancer cell will have too much of a particular modification on RNA. In other cases perhaps too little of a particular modification. And we’re trying to sort of reset that rheostat if you will.

Ryan: That defect could be a mutation on one of those reader, writer, or eraser proteins. Simply having too many or too few of these epitranscriptomics proteins could also cause problems. Accent is currently focused on targeting “writer” proteins, the ones that lay down the RNA modifications.

Robert Copeland: We see these modifications across a broad spectrum of cancer cells and normal cells. So the real question is, can we identify specific cancers that for one reason or another are more dependent on the activity of that enzyme than are other cancer cells, and most importantly normal cells? And the answer is yes.

Ryan: Academic researchers have found a link between abnormal activity of enzymes that tack a methyl group onto RNA and specific cancers, including acute myeloid leukemia and glioblastoma. So Accent is trying to find these enzymes, or writer proteins, that certain cancer cells can’t live without, but that healthy cells can live without. The idea is to then design a small molecule to shut one of these writer proteins down and, hopefully--remember, this is all theoretical--kill the cancer cells.

Even though the biology of this epitranscriptomics field is complicated, the drug targets themselves are proteins. And, as we’ve discussed, drug designers are really good at targeting proteins with small molecules. So if developing the epitranscriptomic drugs actually might be more straightforward than drugging RNA itself, why hasn’t this been tried before? Well, a lot of the tools that have allowed scientists to imagine the possibility of designing drugs to bind RNA--they’re the same tools that have ushered in this epitranscriptomics field.

Robert Copeland: About five or six years ago, there was a quantum leap in analytical methods that allowed, for the first time, real quantitation of the amount of modification in different nucleosides in RNA and also improvements in analytical methods for sequencing where along the RNA strand those modifications occur. And those technological advances really lead to an explosion in scientific knowledge.

Ryan: For now, Accent is focused on cancer, and just the writer proteins, but the reader and eraser proteins might be druggable too. And academic scientists are starting to look at the role of epitranscriptomics in other diseases beyond cancer.

Robert Copeland: The fact is that today the vast majority of approved therapeutics are small molecules, and we at Accent believe that there are good scientific, clinical, and socioeconomic reasons to think that small molecules will continue to hold a dominant position in human medicine.

Lisa: Of course, Bob has a vested interest in small molecules maintaining their dominant role in our medicine cabinets. But now is a good time to mention that while Alnylam was plugging away at its delivery problems, and antisense oligonucleotides were maturing, and mRNA was reaching the clinic ...

Ryan: And while technology was allowing people to figure out how to control RNA with small molecules...

Lisa: During that time, some truly game changing technologies came of age. The most notable near-term competitor for all of these? Gene therapy.

Ryan: Next in line? CRISPR gene editing.

Lisa: Okay, CRISPR therapies are a long way off from the market, but it makes me wonder about gene therapy, which is being hyped as a one-time treatment—that use DNA to cure disease. The FDA approved the first gene therapy just over a year ago. As a reminder, gene therapy uses the hollowed-out shells of viruses to deliver a gene, made of DNA, into cells. The goal is to provide a permanent set of instructions that lets cells produce proteins that are broken or missing. Couldn’t gene therapies step in and render all of these RNA therapies obsolete?

Ryan: A lot of people are asking that question, because Novartis spent $8.7 billion last year to buy a gene therapy company that’s developing a really promising treatment for spinal muscular atrophy.

Lisa: Hold up. Didn’t we just talk to them about a small molecule drug that targets RNA for that same disease?

Ryan: Yep. And they’re anticipating an FDA approval of the gene therapy this year.

Lisa: So what will happen to their small molecule for SMA?

Ryan: Well, Novartis says that the compound is still in development. But after all the money the company spent on the gene therapy, I’m not sure that the future looks too bright for that small molecule program.

Lisa: And on top of all that, there’s already one therapy approved for spinal muscular atrophy, an antisense oligo drug called Spinraza.

Ryan: You’re right. Still, the companies we talked to are convinced that RNA therapies will be competitive. And there are cases where they may not actually need to compete with these other drug modalities. For instance, RNAi silences genes, whereas gene therapy introduces genes. So there will likely be cases where one is clearly a better choice than the other.

Lisa: On the other hand, gene therapy and mRNA therapy both have the same end result. They both give the body instructions to make new proteins. So those classes of drugs could compete.

Ryan: True, but mRNA therapies are temporary, while gene therapies are forever. So different conditions will probably be better suited for one or the other. Alnylam’s John Maraganore thinks there will be room for everyone.

John Maraganore: We need more complex therapeutic approaches whether it’s a gene therapy approach whether it’s a cell therapy approach whether it’s RNA. You know, these are all the modalities of the future. I do believe that that much of the future of medicine is going to be rewritten by these types of new modalities.

Lisa: I couldn’t help but notice that he didn’t mention small molecules targeting RNA. I’m wondering what he thinks about those?

John Maraganore: Look, I think it’s incredibly exciting. Don’t get me wrong. And obviously in the future that could be competitive to us and it could be a threat to what we do, so I’m not I’m not dismissing that at all. But I think they still have a long way to go before they are there ultimately there.

Ryan: And John thinks RNAi has an ace up its sleeve, at least compared with small molecules. The allure of RNAi is that once you’ve perfected the process of making one RNAi drug, you should be able to make many more using the same process, just with a different RNA sequence to silence a different gene. He says that’s radically different from small molecule drugs, where every new product essentially needs its own discovery program. RNAi could potentially deliver a platform, not just a single product.

Lisa: So, suffice to say, RNA drug development has promise, but in terms of actually getting medicines to patients, it’s still early days.

Ryan: Right, and it’s going take some time before we know whether any of the things we’ve talked about today will be successful. But we’ll be watching.

John Maraganore: Ultimately, the products will have to speak for themselves and at the end it’s actually good for patients to have competition. It’s good for patients and physicians to have choice.

Lisa: That does it for our first episode of 2019. Let us know what you thought by heading over to iTunes and giving us a rating.

Ryan: Or by tweeting at us. I’m @RLCscienceboss.

Lisa: And I’m @lisamjarvis.

Ryan: The music you’re hearing right now is “Wireless” by Lee Rosevere. The music that kicked off the episode was “And... (Insert Problem Here)” by Grey.

Lisa: You also heard a lot of Podington Bear, including “Robot Park,” “The Confrontation,” and “Raccoon Family Robinson.”

Ryan: Be sure to join us for our next episode in early February when we’ll go all Tina Turner on chemistry and ask, what’s love got to do with it?

Lisa: Got to do with it. Thanks for listening.


And...(Insert Problem Here)” by GR∑Y is licensed under CC BY-NC 4.0.

Raccoon Family Robinson” by Podington Bear is licensed under CC BY-NC 3.0.

Robot Park” by Podington Bear is licensed under CC BY-NC 3.0.

The Confrontation" by Podington Bear is licensed under CC BY-NC 3.0.

Wireless” by Lee Rosevere is licensed under CC BY-NC 4.0.


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