Antisense Oligonucleotides (ASOs)

Episode 9: Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are being developed as treatments for rare genetic disorders such as SCN2A. What are they and how do they work? To help gain a better understanding of ASOs and their role we talk to Dr Stanley Crooke, founder of Ionis.

Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A.

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Guest interview:

Dr. Stanley Crooke is the founder, chairman and chief executive officer of Ionis Pharmaceuticals. Under his leadership, Ionis pioneered development of the revolutionary antisense technology platform and created one of the largest, most advanced pipelines in the biotechnology industry. Today, Ionis has more than 40 medicines in development.

Prior to founding Ionis, Dr. Crooke was head of R&D at SmithKline. Earlier at Bristol-Myers, he established the first broad anticancer program, bringing nine drugs to the market in five years.

Regular Hosts:

Ms Kris Pierce RN MHSc MWellness, is a rare disease advocate and mother to Will who has SCN2A. Kris has held a range of board, project management, advocate and consumer representative roles and has been instrumental in working with local, state and federal governments to secure funding for multi-million dollar projects. Kris is highly skilled in building teams to work together collaboratively and is a co-founder of Genetic Epilepsy Team Australia (GETA) and SCN2A Australia, and a RARE Global Advocacy Leadership Council member.

Follow Kris on LinkedIn or Twitter.

Dr David Cunnington is a sleep physician and father to Will who has SCN2A. He is director of Melbourne Sleep Disorders Centre, and co-founder and contributor to SleepHub. David trained in sleep medicine both in Australia and at Harvard Medical School in the United States. David’s clinical practice covers all areas of sleep medicine and he is actively involved in training health professionals in sleep. David is a regular commentator on sleep, both in traditional and social media.
Follow David’s posts on sleep on Facebook or Twitter


Intro: Welcome to SCN2A Insights bringing you the latest research and clinical updates on SCN2A and genetic epilepsy from around the world.

Dr. David Cunnington: Hi, I’m David Cunnington.

Kris Pierce: And I’m Kris Pierce.

David Cunnington: And welcome to this episode of SCN2A Insights. In this episode, we are going to talk about antisense oligonucleotides, ASOs. You might ask, “What the heck are they?” But at the end of this episode, I hope you will have a good understanding about ASOs and their role in treating rare disorders including genetic epilepsies.

Kris Pierce: Earlier this month, the American Epilepsy Society annual meeting was held in Baltimore. And we found this year that there was an exploding interest in ASOs, to the point where a standing-room-only in these presentations.  

David Cunnington: If you are looking for a summary of what was talked about regarding ASOs and genetic epilepsy at AES, Look for Dr. Ana Mingorance’s post and we will put a link to that in the show notes. Follow her on Twitter. She provides lots of good information about genetic epilepsies @CNSDrugHunter.

Another point that I found interesting at AES was this change in terminology from rather than talking about genetic epilepsies, talking more about developmental and epileptic encephalopathies or DEEs. So that terminology is coming around a bit more which really recognizes that the genetic epilepsies or what has been termed genetic epilepsies actually encompass a lot more disability and a lot of other symptoms apart from just epilepsy.

Kris Pierce: Yeah, and that’s something that we’ve been struggling with here in Australia. And part of again, what came out of our roundtable was that genetic epilepsy which we’ve been labeling as in the past suffers from a different identity crisis. What does that mean to someone who doesn’t understand how SCN2A presents or Dravet or KCNQ2? It’s not just seizures.

We have children with intellectual disabilities with eating problems, movement disorders, behavioral issues. It’s a very complex disorder, any of the presentations, but also on a spectrum. There’s a large spectrum across any of those specific genetic epilepsies and trying to explain that or get recognition for that is quite difficult and that’s evolving and it’s really good to see that evolved this year through – at the AES.

Dr. David Cunnington: Yeah, with that change in terminology I think better reflects that complexity and the multiple symptoms. If we are going to talk about ASOs, who better to interview than Dr. Stanley Crooke. Dr. Crooke is the founder, chairman and chief executive officer of Ionis Pharmaceuticals. As you will hear, Dr. Crooke started Ionis 30 years ago with the aim of developing a platform for the more efficient development of treatments.

So thanks very much, Stan, for helping us out with the podcast.

Dr. Stanley Crooke: Oh, I’m glad to do it and looking forward to it.

Dr. David Cunnington: So what actually are antisense oligonucleotides?

Dr. Stanley Crooke: Antisense oligonucleotides are small bits of chemically-modified nucleic acid. You can think of them as small bits of genetic information that have been modified to make them effective medicines.

Dr. David Cunnington: And how did they actually work?

Dr. Stanley Crooke: They are designed to bind two specific sites in target RNAs through the basic interaction that provides a specificity of genes which is Watson–Crick hybridization. The genetic code as you know is just four characters so it’s a vastly simpler code than the amino acid code which begins with 20 amino acids.

And the rules for binding are well-understood and obeyed by all biological systems. And so, we began with an opportunity to use knowledge about the determinants of where ASOs will bind in RNA to actually design medicines that do exactly that. That’s very different from attempting to do the same thing even after a hundred years of effort with proteins because it’s just a simpler process, a simpler way to think through making a medicine.

Dr. David Cunnington: How does that differ from that traditional small molecule medicine, isocyanate to epileptic medication to reduce seizures?

Dr. Stanley Crooke: First, proteins are of course the agents that do the work of the cell in the body and they are transcribed or translated from RNA which uses the language of nucleic acids. And so, translation is a term that really matters. It means that the cell is translating information that has been stored in the language of nucleic acids into the language of protein. Small molecules are designed to bind the proteins and alter their function and thereby alter the disease process.

The problems with that approach remain really rather daunting. First, proteins are enormously complex or highly structured. They are often in places that small molecules have a difficult time working.

Small molecules have very little information. They are small. They contain very little information. And so, discriminating one protein from another is not easy for small a molecule. So, specificity is an issue.

The third problem with small molecules is that the best majority of molecular targets that we understand today are not druggable as small molecules for a variety of reasons. And so, the playing field is very narrow for small molecules.

And then the old adage that if you change methyl, you change the drug, is absolutely true. And so, with small molecules, if you make even a tiny change in that small molecule, you can change the properties entirely. And so, every new medicine is a new game. You can’t really learn from what you succeeded or failed at in the past.

And so, it’s an extremely inefficient time-consuming, very costly process that is still associated with a 99% failure rate. The difference in antisense that I’ve seen 30 years was first, that we would understand the rules of engagement. We would use Watson–Crick hybridization rules to direct our medicines to the sites and RNAs that we wanted. It’s an intrinsically simpler process.

Second, it’s a far more specific process and it’s no more complicated than just information content in the medicine molecule. If you have more information content in the medicine molecule, you will have a more specific interaction, all of the things being equal.

Third, we would learn from our mistakes because within a particular chemical class, basically all the molecules are exactly the same except different genetic ZIP code. And so, it would be dramatically more efficient.

And fourth, it would be dramatically more reactive because all proteins come from RNA and ASOs are designed to bind to any RNA. And so, the vast majority of opportunities are druggable with ASO technology. And so all of those things were the reasons that we pursued this technology through these years.

Dr. David Cunnington: And you mentioned that ASOs are chemically-modified, antisense oligonucleotides, why the modification? What are you hoping to achieve with that?

Dr. Stanley Crooke: Natural DNA and RNA don’t work and they are unstable. They don’t have the properties necessary to have them administered in some site in the body and then go throughout the body and where you want them to go. And so, they have to be chemically modified just as most natural things in the body don’t serve as drug molecules. And so, they are chemically modified to enhance their stability so that we can dose them in frequently.

Natural DNA or RNAs are graded in minutes. They are chemically modified to enhance their affinity for target RNAs, the only thing to do that is to increase potency. And as we’ve modified, learned how to design these ASOs and modify them chemically, potency has increased from essentially nothing to now extremely potent molecules where we can – we are contemplating dosing a human being with 50 milligrams in a year and being able to dose quarterly or even semi-annually if we like.

And they are modified to reduce side effects. This is the standard thing that medicinal chemistry does. It is meant to design better medicines. And over the years, we’ve learned a great deal about how to reduce side effects while increasing potency and broadening the activity. And all that comes from making them chemically-modified, using the knowledge that we have about the molecular mechanisms by which these medicines produce a various effect.

Dr. David Cunnington: And ASOs work via mRNA and transcription. And so arguably, a gene-based therapy. But how might they differ from other gene therapies like viral vector gene therapies or CRISPR technologies?

Dr. Stanley Crooke: Well, antisense is the most direct form from the gene to the patient. And antisense as we practice it and we’ve advanced it, we have a choice of many different mechanisms. So we can use antisense medicines to over splicing as we do with Spinraza, the medicine that affected essentially a cure of a catastrophic genetic disease, SMA. We can use these to cause degradation of the RNA to a variety of mechanisms that we understand. Or we can use ASOs to actually increase the production of specific proteins through other mechanisms. So ASO technology today is vastly more versatile than the other things that you talked about.

Second, ASOs are designed properly, distribute throughout the body. They can be administered by essentially all routes of administration. And we think we are on the verge of having commercially attractive oral administration in man. So we’ve proven that they can be delivered by all routes of administration and they can be used for a wide range of diseases in our pipeline today.

We have good medicines for severe emergencies. But we have an even larger pipeline for the much more common health problems. And so we, our partners and regulators believe that technology is ready for primetime, that is tackling diseases like hypertension and diabetes and cardiovascular disease and Alzheimer’s and Parkinson’s.

The other technologies that you mentioned are still in development. Gene therapy requires either delivery with viral vectors or some other means that limit its utility. And the vast majority of diseases are not single gene diseases that can be corrected by replacing the gene. The vast majority of diseases are multi-gene. A disease that also interacts with the environment so that genetics predisposed and then the environment chooses.

So there are numerous differences between these various technologies today that are simply a product of the progress made in each the different fields over these years. And you didn’t mention monoclonals, but monoclonals have contributed significantly to help benefit and they are more broadly applicable than the other technologies you mentioned. That once again, they work by binding the proteins but they have more specific information and so they tend to do a better job as drugs but they are limited to either proteins that are secreted in blood or proteins at the cell surface.

And so, all of these technologies, some of which are very mature like small molecules or monoclonal antibodies and others that are mature and moving along and ready for primetime like ours and then gene therapy and cell therapy and a bunch of other things are all efforts that take decades and they are going to take disappointments and failures and that is just a nature of this and that we all hope will come together as more opportunities to improve the health of other human beings.

And so, there are big differences but obviously, as human beings, we root for all of these efforts to be successful at some point.

Dr. David Cunnington: So you say that ASOs are ready for primetime and you’re really excited about being able to even roll this out to more common disorders, where are some of the other gene therapies in that same development timeline?

Dr. Stanley Crooke: Gene therapy, it has now been almost four years in development 35 and I think perhaps $30, $40 billion has been invested. If you look at the history of monoclonals, I think that’s very exemplary. The first paper suggesting monoclonals might be a useful therapeutic occurred 50 years. It was 30 years and probably 20, 30 companies and about $30 billion before monoclonals matured to the place that it was clear that they could be generally useful.

Gene therapy has proven to be more difficult and they are certainly evidence that gene therapies can deliver some value today and a good many efforts and drugs in development. But gene therapy will always be challenged by delivery and be limited by the fact that you need a disease that will respond to a replacement of a single gene.

CRISPR is an exciting research tool and we use it every day. And I would guess, most biological labs do. But it’s early and it will require a process that really will embrace it more or the process that happened with monoclonals, would happen with RNA-targeted therapeutics, it has happened with gene therapy. It will take time. It will take effort. And there will be disappointments and failures along the way. And it’s difficult for me at least as a practitioner to predict exactly when or if CRISPR-related approaches will yield a broad-ranging therapeutics.

And so, I fully understand the desperation of patients and parents. I’m a physician and I feel that desperation keenly. And my advice to people who are desperately hoping for new technologies to help them and their loved ones is to temper your enthusiasm with the reality of the challenges of actually developing a technology to enhance health. They are meaningful. Most ideas fail. And it takes time. And as much as I would like to give instant hope to all patients in the world, that’s a disservice to everyone involved.

Ionis is a company, I found it 30 years ago. And prior to Ionis, I had a very fortunate early career in the first five years – of my first five years in the industry, I led the building of what was the first – brought in a cancer program that we put I think 9 new anticancer drugs on the market in those first five years. And I’m very pleased with that because it then led to many other companies participating in cancer and we’ve seen how spectacular advances have been in cancer over these years. Thanks to many, many efforts.

But one of the most exciting moments in my early career was I actually got into the industry because I was taking care of a patient with testicular cancer. And in those days, some testicular cancer was the most common cause of death in young men and I had to tell him he would be dead in 6 months. And we offered him a new drug called bleomycin which turned out to be a drug I got interested in. And that’s how I ended up in the industry. And then when two of the drugs that I was involved with were added to vinblastine, we essentially cured testicular cancer. So that was a very meaningful moment for me and my career.

I then went on to be president of R&D at SKB, SmithKline Beecham, which was one of the largest pharmaceutical companies in the industry, still is. And I learned a great deal there and among them are some things that I felt were – that needed to be fixed. And one was that the productivity of the industry was declining and it was going to continue to decline because it was dependent on inefficient technology. So I resolved to try to create a disruptive new, more efficient technology that could make better drugs. And that led to the founding of Ionis and the attempt to create RNA-targeted therapeutics.

And so, we are the pioneer in this technology and we persevered through 30 years of hard work. And as a result, today, we are a successful company. We are reporting our fourth year of operating profitability. We have the first RNA blockbuster medicine that is marketed by a partner, Biogen, and it’s called Spinraza.

We have five other drugs that we have commercialized. We have a pipeline of 40 plus medicines in development which quite a number of them are in phase 3. And they include medicines for severe to moderate diseases and many, many medicines for the much more common problems.

There is no magic. We simply had a plan to develop the technology. We persevered in continuing to create an advanced technology as we are today. And so, the main message I would give is that we are a technology-based company that’s built on a different business model that doesn’t recreate the fully integrated company because I think it’s detrimental to – that model is detrimental to innovation. And we’ve succeeded. And technology is still changing rapidly for the better.

And so, the medicines we are making today are better than what we did two years ago and the medicines we are going to make two years from now would be better than the medicines today. We have one medicine in development for every 11 or 12 people at Ionis, which is a testament to the productivity of the technology. Compare that to – in the other technology, I think you would feel very fortunate if you had one medicine in development for every thousand or two thousand people in the company. I think you can see why we and many others are so excited about what has been done and what lies ahead in the future that the technology has in front of it.

Dr. David Cunnington: Congratulations on the very innovative work you’ve done thus far, and really, providing that platform that’s really going to allow much better precision medicines for a range of conditions.

 Dr. Stanley Crooke: Thank you. And I do agree with that. And I think one of the lessons of modern science is that even for what look like simple one gene diseases, the number of types of mutations that may be involved, take SCN2 disease, which is a disease we would like to see something done about where babies are born with terrible epilepsy and developmental problems. Sounds like a simple one-gene disease but when you get into it, you find that there are hundreds of different kinds of mutations with different effects.

And so, we also need technology efficient enough that we can tackle genuinely personalized medicines. I don’t know that they can be done commercially but I’m hopeful that our technology can at some point in the near future be provided charitably to these ultra-rare diseases where you may have one or two or ten people in the world that actually have the mutation that needs – that maybe a technology like this could help fix.

And so, we are in this remarkable moment where the knowledge is sufficient to teach us a great deal about each patient and the challenge is finding technologies that are efficient enough and specific enough to take full advantage of all the knowledge we have and no single technology is going to do that. But we are looking forward to playing our role in diseases that range from the N1 to 10 sorts of disease that I described to illnesses that impact tens of millions of patients as well. And that’s an exciting future to contemplate.

Dr. David Cunnington: Thanks very much for your time today.

Dr. Stanley Crooke: Appreciate the opportunity. Thank you. Good luck with your podcast.

Kris Pierce: Fantastic information from Stan. And just listening to his enthusiasm and pride really about the development of ASOs have come from and his involvement, that was really quite inspiring and he said we still got a long way to go but where we are at is a great place to be.

Dr. David Cunnington: One of the things I found really helpful was Stan putting in that timeline perspective of where ASOs sit. We’ve had small molecules and monoclonal antibodies with ASOs. It really sort of currently just breaking through and where there’s sort of more other gene-modifying technologies are going to come, so CRISPR. But it does show this tool is some years away in terms of being ready as a sort of primetime, whereas, ASOs are becoming ready now.

Kris Pierce: And he talked about the current methodology of giving ASOs and that they are often through a spinal tap but that is evolving as well. And that that’s evolving to potentially be a medication that you take orally which was something I have not heard of. So that was a really interesting point that he made.

Dr. David Cunnington: So you can keep up-to-date with the latest on genetic epilepsy and developmental and epileptic encephalopathies by subscribing to this podcast.

Kris Pierce: Or get your updates on SCN2A through SCN2A Australia’s Facebook or Twitter @SCN2AAustralia. Thank you very much for joining us.

Dr. David Cunnington: Thanks a lot.

Outro: This podcast is not intended as a substitute for your own independent health professional’s advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider within your country or place of residency with any questions you may have regarding a medical condition.