MM_S3_E1_CHARLES SABINE_v2.mp3: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.
Narrator:
Welcome to the Molecular Moments podcast.
Chad:
In today's episode, we sat down with our guest, Charles Sabine Emmy, award winning television producer, journalist and rare disease advocate. As a journalist, he covered nearly every major international news story of his time, including Bosnia, Kosovo, Chechnya, Syria, Haiti, Rwanda, Iran in Northern Ireland, just to name a few. He cheated death many times in war zones, but couldn't escape his own genetics. We'll hear from Charles all about his transition from journalist to patient and Huntington's disease advocate. Also with me today will be Biology Clinic's in-house gene therapy expert. Chief Scientific Officer Jim McNally to shed some light on the finer points of the treatments and possibilities in genetically caused rare diseases such as Huntington's. We're talking science as scientists do. So without further ado, here's another episode of molecular moments, gentlemen. If you had each, briefly introduce yourselves and let's start with Charles.
Charles:
Hi, Chad. Yeah, I'm Charles Sapien, and I am not a scientist or a researcher. I am a one time war correspondent and NBC journalist who has lost his father, brother, two brothers and an uncle to Huntington's disease and tested for the positive for the gene that will give me the disease, knowing that that will develop in me in the coming years.
Chad:
Thanks, Charles and Jim. Maybe you can briefly introduce yourself as well.
Jim:
Sure, Chad. So Jim McNally, Chief Scientific Officer for Biological Physics. You know, part of my relationship to Huntington's is in my prior life in biotech and pharma, where I was leading gene therapy programs and specifically a gene therapy program around Huntington's. So it's a disease that I have some familiarity with, really looking forward to talking to Charles to get his perspective today and being part of the podcast. So thanks for having me.
Chad:
And Charles, I think one of the aspects of rare diseases and genetic diseases is that, as you mentioned, you're you're positive for the for the genes. And so you will have the disease. And I think you mentioned maybe you're having some some symptoms, but up until that, you had a long career in journalism and I would love to hear a little bit about it because it's an exciting life that most of us only see on TV. And as I mentioned when I looked at some of your videos in preparation, I said, Hey, I recognize that guy from from from some of the NBC footage that I watched. So how did you end up in journalism and as a war,
Charles:
You know, as a war
Chad:
Correspondent, can you talk about that career a little bit?
Charles:
Well, yeah. But I, funnily enough, never set out to be a journalist, let alone a war correspondent. What I wanted to do was work in TV because back in the early 80s, when
Charles:
I was training at the BBC,
Charles:
All all I wanted to do then was work in television, and there were only a few channels either side of the of the Atlantic that you could work for, and one of them was NBC. And because they were advertising for a production assistant in their London bureau, I applied for that job thinking, Oh, I'll just stick with it for a couple of years and go and then go and work in something like sports or drama or something like that, which I thought would be more my kind of thing because I never thought of myself as someone who would end up in war zones. And then twenty six years later, and, you know, fourteen wars and about six revolutions and more earthquakes and suicide
Charles:
Bombings than I
Charles:
Can recount. I came out of that career, a very different person with very different perspectives. And it, you know, seeing what I did see, which was I was uniquely positioned to be able to do that because I was in this kind of odd situation that I was being working out of NBC's London bureau. I was the sort of go to person once I'd done a couple of wars early on like Sarajevo and one site that only you know and Beirut, then you kind of just get tagged as the guy to send to war. So, you know, whenever Tom Brokaw, who I worked with a lot in those days, would would go somewhere. I would
Charles:
Go and work with him
Charles:
As his producer and writer in those days. And then when MSNBC came along, I switched over to broadcast because that suddenly completely changed the demand at NBC. We went from needing to cover ourselves for, you know, primarily one evening show, you know, on weekdays and maybe a little bit in the mornings for the Today show to having to need to cover 24 hour news. And that suddenly, you know, instilled a whole new set of demands. And so I. Kind of saw that whole change in the way that broadcast television works, you know? But I
Charles:
Started very rarely in the
Charles:
Old school of, you know, the kind of journalism that people have, you know, our our will will recall, which is such a different one to what people, you know, observe today as their ways of getting news. In those days, there was really pretty much one way that people could get news apart from newspapers. It would be to turn on their television sets and and all watch the same evening broadcasts, which is and that nightly news was the product that I mostly worked for in all of those years. And in doing so, I was always going from one war to another. A lot of them were very happy stories, you know, funnily enough, in the course of the, you know, in the late 80s, there was an extraordinary series. I think we all forget that there actually are times when they're in, you know, in the not too distant future past when things were good, things were happy. Things were, you know, the news stories were actually happy stories. And at that time, you know, I was jumping from South Africa, where Nelson Mandela was being released to Northern Ireland, where peace was breaking out to all of the different countries in the Old East Bloc who were suddenly finding freedom. And these were all extraordinarily happy stories. We don't seem to get them so much these days. You know, the news is is kind of a different set up now. But on the other hand, it was an extraordinary experience, both the happy stories and
Charles:
The sad stories. They were all
Charles:
Equally inspiring and and and created in me a set of experiences that I could take on to what what became actually a more important role still, when I left that and moved to what I'm doing now.
Chad:
Wow. As I mentioned, you know, it's an amazing career and I really can't imagine having gone through what you went through in your journalism career. You won an Emmy along the way as well. How did that feel? Again, can't even imagine being an Emmy Award winner.
Charles:
Well, that was yeah, that was back for the
Charles:
I'm sure
Charles:
You two guys are way too young to remember this. But back in 1989, the extremely unpleasant dictator running Romania, a man called Ceausescu was shot dead in the midst of a revolution on Christmas Day. It was. And that was that I was there. It had just moved there from all the other dominoes that started in Gdansk and Poland and then gone to Budapest for the Hungarian Revolution and the Czech Republic for the for that one and then onto Romania. And it was around that time, of course, at the Berlin Wall fell. It was an extraordinary period of history. I mean, just, you know, so much was happening. It's such an enormous rate and pace that it was very difficult to to keep up with it. I think probably the only thing that people who are younger might be able to equates it to would be the Arab Spring, which kind of had a similar sort of domino effect. But this was so much more significant because up until that point, all of us had lived in a fear of a war with the Soviet Union that dominated every moment of everyone's lives. You know, I remember as a kid, you do actually having exercises for nuclear attacks. You know, we would actually have to
Charles:
Go and, you know,
Charles:
Have exercise about where we would go in our classrooms if when the when the Soviets attacked, because that was the kind of thought it was and that that that completely dominated everyone's lives until that extraordinary set of events in the course of really about one year. You know, at the end of the 1980s, and that really was a momentous moment to have been able to experience because it was so defining in our history.
Chad:
Yeah, without a doubt. And Charles, you know, that was sort of my high school years was that that late 80s and I know younger, I'd say, in the
Charles:
70s and early 80s when we
Chad:
When we played, we played on the playground. We either played Star Wars or we played Russians and Americans. And I don't. Maybe the kids now still play Star Wars, but I don't think they play Russian now.
Charles:
Now I think that Star Wars is supposed to be between the Russians and the Americans. It may be. It is a different kind of Star Wars.
Chad:
Yeah, I'd love to spend the whole time talking about your journalism career, but we're a science based podcast, and I want to move to talking about the, you know, what's dominated your life in the last 20, 20, 30 years? Charles, I want we're going to talk about rare diseases, and I thought I'd turn it over. Her dad, Jim McNally and Jim,
Charles:
Maybe you can explain
Chad:
Sort of what qualifies something for a rare disease and what a what a genetically caused rare disease is?
Jim:
Sure. So I think from the what is a rare disease, it kind of is almost exactly what it sounds like, right? It's a disease that occurs in small numbers of patient populations. I think interesting in the biotech and pharma space is that because they're such a small number of patients that are suffering from these diseases. They've been underserved by having drugs developed for them because the ability to recoup the investment that goes into the R&D efforts to create that therapy and deliver it to the patient population becomes challenging. So there are a lot of efforts, a lot of things like orphan drug designation that allow to make it possible to develop drugs to help these. We've seen a boom in the past decade really in the gene therapy space, which is something that we'll talk about through the course of the podcast. I'm sure because you have these genetic changes or, you know, compromised proteins that in Huntington's disease, for example, a malformed protein that simply needs to either be shut down or eliminated or fixed. And gene therapy provides the possibility of giving a lifetime of return of function of that protein to people. So as opposed to taking a drug for your entire life to control the disease. Gene therapy actually has the chance to make as close to a permanent modification as possible to hopefully catch and prevent further development of disease in these rare disease spaces.
Chad:
And Charles, you you mentioned in your introduction when when rare disease Huntington's disease first touched your life with your with your family. Can you tell that story to us? Sure.
Charles:
Sure. Yeah, it was nineteen ninety four. You know, as you can imagine, my life around that side was was basically gauged not by months, but by news stories. And I was just heading out with Tom Brokaw to be with the then young President Clinton and his visit to the Czech Republic and Vaclav Havel, who was kind of the poster boy for the for the for the new the new order that, you know, I've just described. And we were just heading out in the beginning of January, and I had a call from my mother to tell me that my father was suffering from something called Huntington's disease. I'd never heard of it, nor had anyone else. Pretty much I knew nothing about it, but it soon discovered that there was this kind of wave of of information that was like a very nasty tsunami, because first of all, I discovered that he was going to die from this disease in a not pleasant way at all. Soon, one two that I had a 50 50 chance of having that disease myself, and if I did have it, then that would the same thing would happen to me in a matter of years. And equally, my brother John, who at that point had four children, had the knowledge that they too would be at risk for the disease because he he, like me, had had a chance, a 50 50 chance. And if he had the disease, then that nightmare would just goes on. And that is one of the perhaps the most significantly horrible aspects of a really horrible disease. Truly horrible disease is the fact that people tend to see it in their loved ones before they then progress into the same illness. That, along with the fact that that there are absolutely no treatments up until now or or any hope of any kind of treatments or
Charles:
Methods of slowing
Charles:
The disease. As I say, up until now, that was certainly the case in 1994. At that time, you know, there there is real, no, no real understanding. We were still six years away from the genome being mapped. Luckily, at that time, there were people who were in the early stages of discovering, you know, even though we were in the early stages of understanding about DNA. I wasn't, but there are people who were were able at that time to to to to locate the gene that causes the disease.
Charles:
And so my
Charles:
Father became one of the first people to get the genetic test, which was in 1993. That was the first time that basically people were able to be tested with certainty genetically about whether they would get the disease. That that was a test, which I then that that the idea of having that test or not having that test then dominated my life for the next 10 years. My brother got tested immediately, tested positive, which meant that, you know, he then had the worry not only about his own immediate future, but even more of concern to him about the fact that he had four children. I didn't get tested because I didn't have children of my own at that time. And so I sort of took the decision to take the path, which most people do, who are in that position around 85 to 90 percent of people who were in who who are in my position then do not, you know, today still today, do not get that, take that test. And that's something else we can come back to and to talk about because it's a very interesting point. But but I chose to to leave leave it for the time being until I was. I got to my around my 40th birthday and I realized that then I was in the sort of, hey, the really bad times of the of the Baghdad, the Iraqi war, when it was
Charles:
Really turning bad in
Charles:
Baghdad. And, you know, it was a sort of a particularly depressing war to cover because there was kind of just no upsides to it. You know, it was just relentless, you know, story of misery. And it was to that backdrop that I decided that I needed to empower myself with the decision of knowing what my future was going to be. So I took that genetic test and tested positive. And the guy you know, such such as the, you know, is the finality of that test that the the the neurologist who gave me the test results just simply said to me,
Charles:
There's nothing that you can do
Charles:
About this disease, just live your life as well as you can. And that was kind of it. Ironically, I use that quote a lot when I'm speaking to audiences around the world, as I do now, which is because whilst he said there's nothing that I could do about the disease as I then spent years later on exploring and understanding more about the disease and what we what you know, the people who were involved in it and the possibilities of it, I realized that in fact, there's everything I can do about the disease. The problem is just finding the time to do it.
Chad:
Yeah, that's a that's a great quote. Well, let's go back to Jim. Jim, maybe maybe you can tell us again, we like on this podcast. I always say we're going to talk about science as scientists do so so so hopefully we can we can enrich our scientific audience. So Jim, could you explain to us what is Huntington's sort of, you know, as at that bachelor's scientist level? Hopefully.
Jim:
Sure. So so let's start maybe with a bit of the test because it kind of tells us really what the genetic disorder is. And for Huntington's, there is a protein, the Huntington protein, as everyone does, you have two copies of it in your genome. And people that suffer from Huntington's disease have one copy that has multiple nucleotide repeats of a CAG repeat. In most cases, they have upwards of 30 extra copies of that repeat inserted into one copy of their gene. As a result, that gene produces a malformed protein that almost swamps the system, so you still have the healthy protein being produced from your other unmodified copy of the gene. But the malformed version of it kind of overwhelms the system and then manifests itself down the road as the symptoms that Charles was alluding to that occur later in life. One of the interesting things about Huntington's as a monogenic genetic disorder is that it does occur later in life tends to manifest its symptoms in people 30 or 40 years of age, and later they've been suffering from it, probably over time. But as that builds up, they start to manifest the exterior symptoms. And there's an interesting challenge that that again, that Charles mentioned, which is testing of people that. If they have a parent that's had it, they have that 50 50 shot of coming down with it, and the question becomes, do they want to know the sooner they know? In a circumstance, though, where there are no treatment options, it can be quite a burden, which is why many people resist the testing element of it.
Jim:
I think it would be interesting to get Charlie's perspective of what this looks like because he speaks with this patient community a lie. Is that starting to shift a bit because there is some hope now there are some treatments out there. I know we're going to talk about the therapy that Charles was, the trial that Charles was a part of. There are a number of other gene therapy and antisense oligonucleotide therapies and other treatments that are out there. So is that an ounce of hope starting to provide an increase in testing from the patient population to help? Because if you think about it, because of that later onset of the disease and Huntington's, you actually have a chance if you have a therapy to do something about it before it progresses, if you can catch it early enough. But getting over that, that element of do I really want to know this? Is it going to affect me from being able to live my life to the fullest? Or is it going to be a burden? I think is just it's an amazing perspective from the patients and curious to hear what Charles thinks about that part of it.
Charles:
Yeah, OK. There are several things I can I can talk about here. Yes, the guess I have, I saw I have seen signals. If we want to use a kind of a sort of current term of a research type term, you know, within the Huntington's population with the news that that came about about the early results of the Roche ASO trial, which we're going to probably talk about more. But with that, I definitely detected, you know, a major change shift in certainly organizations, family organizations like the IDSA
Charles:
And the United
Charles:
States and the FDA here, which are organizations that people go to and they are the best ways places for people to go to for information, by the way. We definitely saw an increase in in in inquiries to those organizations big increase from basically the first announcement of the successful early stages of the. That is what I expected. And I do think that as soon as we do get an effective therapy, we will see a lot of people coming out of the woodwork and putting their heads above the parapet and getting tested. Right now, we are still at the stage where there is just simply
Charles:
Too much
Charles:
Downside for most people to do that. I did it. A lot of people who did have done it. But as I said, the figure is for the United. For Europe, it's a 15 percent of people who who do what. I didn't get tested. And then the United States is slightly less. It's around 10 percent. And that is because they understandably, you know, perceive that there are so many problems that they are going to bring about, not least with insurance companies, with health insurance, but with employers and, you know, family potential family and partners, you know, whether they could have children and so on. All of these downsides, which are, you know, complicated issues which
Charles:
Just at the moment
Charles:
Outweigh the fact that there was very little, very little perceived upside. That's where I come in to try and educate people on that. However, that is that is definitely the case. Up until now, and I think that that will change as soon as people realize that there are, you know, there are there is some kind of a of a real therapy on the horizon. However, there is there was a there was another point here which, you know, is is another key one, which is that there are other reasons which I happily engaged in explaining to pharmaceutical companies. There are other reasons why
Charles:
This is
Charles:
A disease well worth their attention, which I'll come onto later, which are about the fact that this is by no means a disease which is just at what you know, which is just one four four four one part of the population to be concerned about. In other words, what has been the assumption up until now has been that, you know, if you if you're from Huntington's family, you really need worry about Huntington's. And if you're not, you don't. That is actually one of the many myths that surrounds Huntington's disease, and it was, in fact, you know. It was the foundation of the fact that the the Nazi Party, the first people that they put into gas chambers in 1939 before the Jews were people with Huntington's disease and other similar genetic disorders. So.
Charles:
And they thought that
Charles:
That was the solution just to eradicate people with the disease and you eradicate the disease. What we've actually now discovered with just in the last 10, 15 years is that we've discovered, first of all, that the disease is far more prevalent than anyone had realized because of the shame and stigma largely that surrounds it, that that had that had caused, you know, untold numbers of people to be misdiagnosed and, you know, death certificates to have wrong things written on them. And that's across the world. But once we had in my in this country, in the UK, when I set up an All-Party Parliamentary Group here into the disease and we
Charles:
Had some proper
Charles:
Prevalence work done here with and I did this in collaboration with Sir Michael Rawlins. And we we established that for people are kind of a British type, you know, of a of a European ethnicity that the disease was indeed twice as as prevalent. We then took I then took worked with Michael Hayden in Vancouver, and we took the research one step further. And Michael's guys, Michael's lab lab there at UBC did something very clever, which is that they they realized, well, everyone, only only people who ever get their CAG repeats measured are people from Huntington's families. What would happen if we
Charles:
Just took random sections
Charles:
Of the population and to see what their CAG repeats are? And the key thing here, the elephant in this little room is that I have to point out something which is very, very significant and forgotten by so many people, which is that c a that everyone has this gene. They all have these CAG repeats and B they never, almost never go down from generation generation. They go up from generation, you know, either up or stay the same. So in other words, this is something which is increasing in every bloodline. Right? So everyone, at some point in the future, if it's even if it's 1000 years, is going to have the 40 CAG repeats that I have, which caused the disease okay. But you bring that forward a bit and say, OK, so how many people given that there can be a jump of five or six repeats from one generation to another? How many people then could actually have a child with HD and they've never been tested because they've never even it's never even occurred to them to do that. And it was a staggering figure of just over five percent of the population. Well, you know, so all of a sudden you and of course, this is this is a message that I've been taking to Big Pharma who are then realizing, my god, this is going to be a very, very big exponential problem for the for us all.
Charles:
Because because this is
Charles:
A huge drain drain, I mean, this makes I mean, you know, it makes Alzheimer's look simple. You know, when you get into the involvement of care for people and if you're going to see an exponential growth of the kind that we are with this disease, my goodness, it needs their attention.
Chad:
Yeah, without a doubt, Charles, so we've talked a bit, you know, we keep mentioning that the disease is terrible, but I if you don't mind me asking, can you talk about some of what happens? You know, what's the disease progression as as it gets really terrible?
Charles:
Sure, your audience is is a much more sophisticated one for.
Charles:
Than this.
Charles:
This, however, what what a simple way of putting it this way I sometimes describe it to a lay audience is that it's effectively it's like having Parkinson's, Alzheimer's and schizophrenia all rolled into one because you get those three kinds of symptoms you get, you know, you get a motor loss, you get a cognitive loss and you get a personality disorder. Those three things happen, you know, in any kind of order. Sometimes, you know, because sometimes people will start with, say, bad movement. So they look like they've got Parkinson's. Some others
Charles:
Will tend to have a
Charles:
Personality issues first and so on. But but one way or another, all three of those impact the person over a course of anywhere between 10 to twenty five years to the point where basically they lose all of their abilities to function all bodily functions, you know, all all abilities to to eat and talk and, you know, look after themselves and and usually the cause of death is usually pneumonia in the same way that it used. It used to be for HIV aids. The same point that, you know, people tend to tend to die from AIDS. They would die from pneumonia. The same thing people tend
Charles:
To die with Huntington's
Charles:
Disease of pneumonia. That's, you know, choking as the, you know, it's the kind of usual way, you know, that's all. That's how I've seen all of my relatives die with this disease. So it's, you know, it's not nice.
Chad:
It's not it's not nice. It's not nice. Let's let's turn the discussion to the hopeful side of it that we've alluded to and talking about some of the treatments and the clinical trials that are ongoing. And Jim, maybe you can talk about a couple of the different treatments that you're aware of specifically, you know, the gene therapy treatments that are really that are really hopeful out there.
Jim:
Sure. I think one I definitely want to let Charles talk a little bit about the one that he was part of, for sure. But there's really, if you think about it, a couple of big categories to how the genes being treated. The one that Charles was part of and there are some other comparable clinical studies out there, are using either antisense oligonucleotides as a way to suppress the MS. the misquoted malformed gene so that you can maintain the function of the primary healthy gene. So simply by knocking down the mutated version of it. With all of this repeats in it, there are other more, let's say, aggressive gene therapies that are now relying upon the approaches of gene editing. So people that are familiar with CRISPR as a technology. This is something that lends itself very well to that type of technology when you think about it, because if you have too many CAG repeats the ability to go in and simply cut out the excess ones and then return to, let's say, a more normal range of CAG repeats in there is a strong possibility for a therapy in this space. So really, there's those two buckets of can we correct the genetic issue that exists or can we suppress the genetic issue that exists? And I think those are the probably the biggest areas of the trials that I'm aware of.
Jim:
I think at last count, when I was presenting on this, there were six or seven active programs. I'm sure there are a lot of others in pipelines elsewhere that are coming forward, but that's really kind of where the current state of affairs are. And again, this period of time where there wasn't a lot of hope because we didn't have these genetic tools available to us. And now the advent of these tools has made it possible to get to some of the the root cause of genetic diseases. The next challenge will be in particular for something like Huntington's, because it has a neurological aspect and a muscular aspect. The ability to treat all these different areas to get the benefit will be the next. Sort of horizon for these types of therapies. But I'm sure Charles, again, I'd love to have him share some of his experience with the ASO trial and his familiarity with that program and what his experience was there in that bucket of therapies.
Charles:
The first thing I should point out is with relation to this, and I'll come on. I'll tell you the whole story of my involvement with the ASO. But before that, I just need to explain one thing, which is that
Charles:
What people may
Charles:
Forget or may not be aware of is that the Huntington's gene is essential for life. Everyone has it, and without it, you die. Now that's a very important point. And I'm talking there about the one with the mutant protein, not alone, let alone the wild type one, which is also equally important. We need both of those things, you know? So in other words, you know, the simple thing otherwise would be, Well, let's just cut out this huntingtin protein. I mean, you know, it's just cut it out. Oh, no. They tried that with mice and the mice died. So that isn't going to work that whole. That all leads into an entirely other whole field of which a fascinating field, by the
Charles:
Way, which is
Charles:
Connected to the fact that people that the higher the CAG repeats in people, the greater their functioning and cognitive abilities until they get the disease. But that's a whole other story about evolution, which Lady called Elena Cattaneo is working on right now in Milan, but we won't go into that. So the point is, you need to be aware of the fact that this is we all have this Huntington's gene and it's essential for life. Ok, so I became involved with a work going on in about 2006 2007, where the company was then called ICIS Pharmaceuticals, which for reasons
Charles:
You might
Charles:
Not have to think too much about, had to change its name in the course of the following sort of six years to Ionis Pharmaceuticals because of other associations. So anyway. But when it was ICIS, I went over to over to because I had been told this was really the best good bit. The best big hope for people were my disease and, you know, for me, for my advocacy, to work with. So I went over to Carlsbad, Southern California, near San Diego, where where a guy called Frank Bennett was leading this research. And basically the idea of this ASO was that it. What they
Charles:
Were finding is that in
Charles:
The in the animal models, it was successfully reducing the protein, the the mutant protein in the cells of these on the blood of these animals. In other words. So, so in other words, that's the mutant protein, which everyone has, you know, for years, regarded as the cause of the disease. The disease is without the rays and the glutamate in the mutant protein. You don't get the disease. So the logical ipso facto surely, therefore, that is the cause and effect. Okay. So that was where we all were then. So then I worked a lot with Roche in here in Europe, in Basel, specifically
Charles:
Encouraging
Charles:
Them to get involved with Ionis with this because, as you know, companies like Ionis cannot cannot possibly power clinical trials. You need hundreds and hundreds of millions of dollars. You know, it's only Big Pharma can do that. That's the way these things work. So Roche came on board, they bought into this. They bought the, you know, they made a deal with Ionis and said, OK, well, we'll set up these clinical trials and they invested two three thousand four hundred million dollars. I forget the figure, but it was that sort of money into setting up these the clinical trials in humans. And a couple of years ago, maybe three years now, ago,
Charles:
There was a landmark moment,
Charles:
Which was that the Huntington protein that had been shown to be reduced in animals. Was successfully and accurately lowered in human beings, and there was a way of showing this, there was a graph showing the more of the ASO people got, the less of the protein, the mutant protein that they exhibited. This was an extraordinary moment. This was this was, you know, this was like, you know, the moment that everyone had been waiting for because this causes that that mute protein causes the disease. So this surely when we're there now. Ok, so there was enormous, you know, there was enormous hope rippling around the world for the research. And, you know, the family communities are suffering from this disease. Then they went into another stage and this is where I was involved in this, which was a stage three, which was then to measure the disease progression or symptoms, efficacy, if you like. And you know, basically there was kind of an assumption that this was kind of going to be a formality because in the in the animal models, it had worked, you know, it improved their functioning.
Charles:
So it was
Charles:
Just a matter of how much what was going to be the degree, really. I mean, how much, you know, how are we going to be able to to get the dosing right, things like that. And then about, oh, we must have been about three or four months ago now, there was a very shocking moment when I'll cut to, I'll cut to the miserable, you know, the miserable part of it, which, you know, through the through the point through the through how the data got released. But the data was showed that people were not improving. They could measure in my blood. They form the because basically the I'll tell you a little bit, the dosing of this was through my spinal cord, cerebral spinal fluid basically being taken out to be measured. And then they injected the ASO in so that it goes and then it gets to the brain. Ok, so they could measure when each time, each time there was a dosing and the dosing were. And I started off every four, every four weeks. Then they became four and six, then eight and then eight and 16 because they kind of the good news that they thought was, well, look, whatever happens, we know that, you know, early on that we don't need to give this to people every month. So, you know, so that's good. But the problem was that whilst they could
Charles:
See the protein levels
Charles:
Lowering, people's symptoms were not improving. In fact, in some cases, they were getting worse. So enormous setback. I mean, you know, not knocked to the floor, as you can imagine. You know, so many people just just aghast say what? How is this possible? So that's where we are right now with that. Okay, let me just then say a few things about. The, you know, the context of that. The first thing is that there were a lot of people who who thought that because the Roche
Charles:
Aso is not
Charles:
A real specific. In other words, it knocks out both the Huntington illegals equally, that it is possible that the wild type which was getting reduced was causing the problem or was stopping, in other words, stopping any improvements because the wild side. And there are, in fact, now moves in other boat back back. But Iona's is now looking at ways of perhaps having a real specific one. And also there's a company in Boston called Wave, which is already looking at a wave and a little specificity specificity. Anyway, that was one thought, and that's still out there. Another thought is that the dosing was wrong. And in fact, most of the people involved in the trial think that it was too high, that the dosing that I got was one 120 and it should have been, we should they should have really been looking at a maximum of 50, perhaps 30 because you're trying sort of 30 and 20, 30, 50, though, and that kind of thing. And also the fact that for many of us, there was a loaded aspect to it, in other words, front loaded aspect of the trial. So you've got a big dose, you know, you've got a big dose of a thing to start off that that might have just caused problems in itself. So. So there are thoughts about that. There are also
Charles:
Thoughts about the fact that
Charles:
Most of the people involved in the trial were quite far into the disease and that that might have been a significant factor. So there are all sorts of thoughts now. And the good news is that Roche have not walked away from this. They are going to make their data available to the whole community, the whole hunting community, and that is a big one. And to say, why OK, why didn't this work? What went wrong? You know, is it dosing? And there is, I have to say, there is a general and I'd be interested to hear what general view is. But but there is a general view amongst people who understand these matters that it is. They really do still believe that hunting and lowering as a principle has to work.
Charles:
I mean, they can't it can't
Charles:
Really honestly be the case that it, you know, cannot in some form work. It's just that there might be some problem with the dosing or the alleged specificity or something else here or the fact that they have to give it to people earlier. But I think that, you know, I don't think that anyone is saying, OK, well, that's it, obviously, because there are now around 20 different. You mentioned Jim, I think you said you thought about five or six last time you looked. It's now over 20 now different and more coming from Big Pharma. Novartis has just come into this field
Charles:
With a with a
Charles:
Small molecule aiming to do the same thing. So there are, you know, a lot there are a lot of different targets on shots on goal here. And most of them are based on the on the sort of logic that surely if we can reduce the mutant protein, it has to be a benefit. But so far, that has not been shown in the drug that I received.
Chad:
So, Charles, I'm curious if there's an. Have there been in maybe Jim, maybe you know this. If there have been any antibody therapeutics. So kind of, you know, the idea that it was sort of go around and mop up the the extra Huntington's protein,
Jim:
I'm unaware of anyone taking that approach. There's certainly a lot of times where there are things that are in people's pipelines that never make it to sort of the public awareness. So maybe it's been explored, but I'm not aware of anything like that. You know, and I guess to add to one of the things that Charles mentioned again, one of the additional challenges for this type of disease, and I think people ask questions often about why do we not see a lot of Alzheimer's and Parkinson's drugs and so on, and the proof of neurological endpoint in clinical trials is very challenging. So that's definitely a component that's part of this, too. But I think, you know, again, it's strange to think, but we're in early days for treating Huntington's disease and we will learn from the Roche therapy. And it sounds like that they themselves are ready to continue to invest in it. And there are other companies that are taking the approaches that Charles is suggesting about being a little specific to only knock down the mutant version while not altering the wild type version. So keeping that balance of not overall suppression of Huntington's, maybe that's the key element in a lot of these diseases. It's probably a piece of every bit of that, right? It's about getting to the therapy soon enough. It's hitting the right balance of knocking the mutant down without affecting the wild type. Just a whole host of things, because this is an incredibly complex disease.
Charles:
Yeah, it's it's also something that I hear. This is something, you know, you would understand more about the ramifications of it. But once once something that I hear a lot from the scientists that I talked to is the where the drugs are with this case, the ASIO. But whatever where they are actually going to be having effect, whether in other words, whether how far into the brain they are going or not going. And I and the realization again are, you know, in in just in the last decade that this is a disease of
Charles:
The whole body,
Charles:
That whilst it is a disease that you know. Problems come from the brain. Every cell in the body has this mutant protein problem, is that significant? I mean, is it is it? Is it something, you know? Is it then the case that we shouldn't just be giving drugs in the brain? You know, even though that seems to be where the problem manifests itself, should we, you know, should we be looking at? And that's something that I hear discussed.
Jim:
So absolutely. And I think that's another element here where it may be a combination of different therapies that perhaps systemic delivery of an ASO and a gene therapy directly into the brain, some sort of combination because there are so many different target cells that need to be addressed. And we talked about this a little earlier in the podcast is that with this type of systemic disorder, it may not be a one size fits all type of therapy that you're going to have to come at it with an incredibly powerful toolbox of multiple tools to address this. There are some of the gene therapy so. So Charles mentioned you're you're receiving it through sort of CSF. There are some gene therapies that are using MRI guided delivery directly into the brain and to hit there are specific regions of the brain that are more severely affected by Huntington's than others. Again, everything's affected, but some more so than others. So directly targeting those regions of the brain may be a path to a better resolution. So something that treats there. And then maybe it is lifetime treatment with an ASO, something along those lines for the systemic consequences. It's just amazing, though, that you speak of hope. It's amazing that we can even talk about these types of tools, the things that we're able to do here. We haven't gotten it right yet, but we're a lot further along than we were even a decade ago to give the possibility of being able to do something about these genetic disorders. It's just amazing.
Chad:
Yeah. And I guess twenty seven years ago, you know, when your when your father passed Charles,
Charles:
You were
Chad:
It was palliative care, right? I mean, it was trying to make him as comfortable as possible.
Charles:
But if you were lucky. Yeah, I mean, that was that's if that's if you were. I mean, I mean, we would, you know, you know, not long before that, you know, Woody Guthrie was put in a, you know, in a in a mental asylum, you know, in a prison vest, you know, I mean, you know, in the, you know, in that was in the 80s. I mean, you know, so you know, you know, we are coming a long way, you know? And you know, you know, the fact is that, you know, at the very least, having people
Charles:
Recognize the existence
Charles:
Of this disease is a big step forward because, you know, that is something that simply just didn't happen. I mean, no one, you know, at least now pharmaceutical companies and researchers around the world are noticing this disease and realizing that that it does tell so many stories about all of our futures. These are these are decisions that people are making, which everyone is going to have to make in the future, who doesn't necessarily have Huntington's disease, but it's going to have to make decisions about whether they should or shouldn't have children or whether they should or shouldn't have CRISPR technology used.
Chad:
Charles, what's next for you in? Well, just I'll just say, what's next for you?
Charles:
Well, I'm doing this now, and this is what I'm going to keep doing. Covid has been a real pain. I don't suppose I'm the first person to say that and the last. But as soon as I can get back on an airplane, I'm going to going to then embrace my mission, which is to make this disease hidden no more. That's a foundation that I started. And which I was, you know, delighted that Pope Francis, when we took some children and to see him with Huntington's disease, and he became the first world leader just about four years ago now to the first world leader to even say the words Huntington's disease, let alone publicly meet someone on stage. And he said then
Charles:
I was very happy and proud
Charles:
That he took my words and said, This is the time for the world to say that this disease should be hidden no more. This is the time to do it, and I now want, you know, to get some other world leaders to do that. And as soon as I can get on a plane to go and push them into it, cajole them into doing so, saying those words, then I will do it.
Chad:
And Jim, I wanted to ask you, you know, for a future perspective on gene therapies and what you see. You know, what do you see next to overcome some of the challenges we talked about?
Jim:
So I think as I mentioned delivery, making sure that the gene therapies and the therapies are getting to the right place. As we're doing a lot of this work, finding the right dose very critical, much different than a lot of the other drug and pharmaceutical development. When you think about someone takes a pill every day, for some some disease, this is different, especially when you're delivering genetic material. We've learned a little bit about that during COVID. Also finding the right, the right levels to receive to get that right response. I think the other element of this is simply awareness. People being willing to identify get the testing earlier because I do think that this, along with a lot of other genetic disorders. The best thing in our favor is early identification to deliver therapies as soon as possible. This is something that clearly suffers from a cumulative effect over the years. And clearly, the sooner you catch it, the better off you're going to be. We just need to make sure that we have something to deliver to folks when they get that news that it's not just, Hey, you've got this disease and we really can't do much for you. It's you've got this. We've got a plan. We think we know what we can do. We've got some things to try and we want to work with you to do that. And with every sort of clinical trial, we learn more in, the next one gets better, hopefully, and that's that participation helps also. The sky's the limit, I think, with a lot of our genetic work, but we were still we're still early days. So people, I hope, are patient and looking forward to the future.
Chad:
And Charles, I want to close the question that you've heard before, and I found your answer then inspiring. And I think you'll recognize the question. Tell me something that you know for certain.
Charles:
Yeah, that was a question that was asked for being asked to me by a young person from a Huntington's family who I wanted a very certain answer, and I had no idea what to say other than the fact that I couldn't lie. And I said to her and the spur of that moment, I said, no generation, yours included, will ever have to fear this disease as much as minded. And that is true because of the extraordinary collaboration, which I have been honoured to be a part of over the last 15 years, which involves families and researchers from every corner of the world. And I just say to them once again, thank you everyone for making it possible for me to say that to that poor girl.
Chad:
It's it's hard to hard to say much after that. I don't know if Charles or Jim, if you have any other closing thoughts, I don't, you know, and then then we'll probably wrap it up.
Jim:
I guess just for me, I was fortunate enough to connect with some of the Huntington's patient advocacy groups and one of my prior roles. There is no more powerful message than the one that comes from the people that are suffering from the disease. It carries weight with the pharmaceutical companies. It carries weight with the governments that need to find a way to fund it, the insurance companies that need to reimburse for it, every sort of part of the package. And I think also it drives people in the field to do what we do. We talk about being patient centric and that what we're trying to do is deliver for patients. And it's because people like Charles that we're aware of what goes on that helps drive and sustain us through what we do. We're lucky to be a part of it here at Biogen, and it's what gets us out of bed every morning to do what we do and just thank you, Charles. As soon as they let you back on a plane, I hope you're on it and doing what you do best, which is advocating for this patient population. And it's you're doing an amazing job for these people. So thank you.
Chad:
Any other closing closing comments, Charles?
Charles:
Well, I can only just echo Jim's thoughts, though, about the, you know, the heroes apart from the apart from the scientists who are the people, the the people who. I live in these families and do the most extraordinary getting from day to day, you know, I've had a lot of I've had a lot of different roles in Huntington's disease over the last, you
Charles:
Know, 20
Charles:
Years, but not the one that is by far and away the hardest and most difficult. And that is being a carer. I've never had to care. You know, I've seen my father die with this disease. I've seen my brothers die with it. I've never had to get up in the morning and and face this. And those people who do that are beyond words. What they do and how they can do that unpaid, you know, is a testament really to the fact that, you know what, as I I've learned so many times in my life, both at NBC and since that
Charles:
It is in the darkest
Charles:
Moments that the human spirit shines brightest.
Chad:
Well, Charles, it's been an amazing, amazing conversation. Inspirational, educational. Just thank you. Thank you so much. And that's all for this episode of molecular moments. If you enjoyed today's episode, be sure to subscribe on Apple Podcasts, Spotify or your favourite podcast app so you never miss a conversation. If you'd like to hang out with us by watch clinics outside of the podcast, we have many webinars and other presentations available for your enjoyment and education. Visit my wedge politics.com to see what's coming up and how you can stay in touch. And don't forget to keep an eye out for more episodes of molecular moments coming soon.
Narrator:
Thanks for listening to the Molecular Moments podcast.
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