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Sounds of Science is a monthly podcast about beginnings: how a molecule becomes a drug, how a rodent elucidates a disease pathway, how a horseshoe crab morphs into an infection fighter. The podcast is produced by Eureka, the scientific blog of Charles River, a contract research organization for drug discovery and development. Tune in and begin the journey.
Mary Parker:
I'm Mary Parker, and welcome to this episode of Eureka's Sounds of Science. According to the National Institutes of Health, one in 10 people may be affected by a rare disease, either as a patient or a carrier. But with more than 10,000 known rare diseases, what insights can we gain from studying diseases that only affect a handful of patients?
To answer this question, we have gathered an impressive panel of experts. Dr. Lauren Black is our distinguished scientist for Charles River, and a big part of her job involves guiding rare disease researchers through the drug approval process. Dr. Monkol Lek's lab at the Yale School of Medicine researches the genetic mechanism of rare diseases. Welcome, Lauren and Monkol.
Lauren Black:
Hey there, how are you doing?
Monkol Lek:
Hey, great to be here.
Mary Parker:
Let's start with introductions. Lauren, you've been on the podcast a few times, so can we start with you? What have you been up to recently?
Lauren Black:
Well, lots of different projects. We have had, as you know, a lot of involvement in different product modalities, gene therapies, CRISPR studies, oligonucleotides, and many of the projects that I'm involved with involve expanded access or, N of one INDs that are destined for the FDA's desk within the say, next six months or so. Over the last several years, we'd been working with Dr. Tim Yu at Boston Children's Hospital and we worked with the Mila Project and the oligonucleotides that were designed for personalized use. That started a wave of new research that a number of different institutions are picking up now. I met Rich Horgan through Tim, and helped with Terry Horgan and his new CRISPR studies, and that's how I met Monkol.
Mary Parker:
And just so that people in the audience might know, an N of one study is a study that it only involves one patient getting one treatment, yes?
Lauren Black:
That's right.
Lauren Black:
Monkol, how did your path cross into mine?
Monkol Lek:
Oh, how did cross? I can start from the beginning. I think where it crossed is that I got the good fortune of meeting Rich Horgan, whose brother Terry had a rare form of Duchenne muscular dystrophy. When I say rare form, a rare mutation. Duchenne is one of the most common forms of rare diseases, but many mutations cause that disease. His brother had a rare form and he was also quite advanced in age in terms of, I think at the time, in his late twenties. He didn't qualify for many clinical trials. Rich reached out to scientists to see if any of them could help him. I had a look at the mutation and saw a way that we could potentially help Terry in designing a very customized therapeutic based on his mutation. We needed regulatory guidance and this is where our colleagues at Boston Children's Hospital, the department that Tim Yu is from, recommended reaching out to Lauren Black and the rest is history.
Mary Parker:
Monkol, how did you get interested in studying rare diseases in particular, in the first place? How did you get started in your research?
Monkol Lek:
Yeah, you probably don't know because I'm on a podcast, but I have a rare form of neuromuscular disease also, different to the one Terry has. There are many different genes that cause muscular dystrophy and that got me started on my journey to get into research. At the time I was working at IBM and I had a clinical diagnosis that I had a form of muscular dystrophy, but they didn't know what gene caused the disease.
Year after year, I'd go and see a neurologist and they would tell me round about the same thing; that my muscles were getting weaker and they were still looking for the gene that caused my disease. Working in IBM, it started to become dissatisfying that I could be using my talents to be doing something else. I wanted to do rare disease research. I didn't know anything about it, I didn't know how hard it'd be, but I was just 20 year old, I didn't think much and just took the plunge, went back to university and then got a PhD. The two things that I wanted to address, and the they're the two things that my lab also does now is identifying genes that cause rare diseases and also working on genetic therapies to address the root cause of the disease. That's really how I got into research, because of the strong desire to do both of those things.
Mary Parker:
Yeah, that makes perfect sense. I did not know any of that.
Lauren Black:
How did Rich meet you, Monkol?
Monkol Lek:
Oh, yeah, Rich met me because he approached Dr. Lou Kunkel, who is luminary in the field because he was the one that discovered the Duchenne gene. My wife was a postdoc in Lou's lab doing research, neuromuscular disease research, and I think Lou must have dragged Angela into the meeting and that's how Rich met Angela, my wife, and then that's how I eventually met Rich.
Lauren Black:
Does Rich view himself as a matchmaker as well as a scientist?
Monkol Lek:
Yes, I think so, in the work he does with the foundation also, in trying to meet a lot of patients and their families and understand the rare disease, the mutation that causes it, and also use his large network of scientists and also people in the industry to try and connect people. Some of them he can help through the foundation and some of them he can't help, but at least he's connected them with people that could help them on their journey. Yeah, I see it as a matchmaker in that way.
Lauren Black:
That's awesome.
Mary Parker:
Yeah, that's a good point. He mentioned that. He came on the podcast once, and I think he mentioned that aspect of networking, bringing people together who can help each other. It's definitely one of the most valuable things that his foundation has done, for sure.
Lauren Black:
I like to think of collaborations that arise from these rare meetings. If we could bump into each other in Madrid on the street, it would be about as frequent as how you might run into each other just in academics. We're all in our different fields. We don't necessarily go to the same meetings.
But the gist of it is that Monkol is a PhD, but he goes to genetics meetings, and I'm a pharmacologist and I go to drug discovery and development meetings. And so we would never meet otherwise, except for Rich. Rich called us individually about different aspects of the collaborations that he needed. He wasn't a scientist and he wanted to get a treatment for his brother and he needed to get a whole network of scientists to work together around Terry to make his treatment possible. And I've really seen that in every single different case, Terry being an example, but just every rare case I work on, I often meet the entire family.
I learn stories about their lives and I learn things about myself I never knew, stretching my abilities to areas of science I never understood. But behind each one of these individuals who needs a treatment is a disease and a person and a plight that needs to be solved. For those of us that have engineering and conceptualization and a regulatory experience, this becomes a problem to solve, like any other problem. And we can demystify it for ourselves and then work together and say, "This needs to go first and second." And the next thing you know, it's six months later and we've learned something that wasn't known before.
Mary Parker:
Yeah, that segues nicely into what I was going to bring up next. What do you both see as the benefit of studying rare diseases, particularly if there's only one patient? Besides the personal of helping a patient who needs it, which is a big deal of course, there are scientific benefits as well, aren't there?
Monkol Lek:
Yeah, I can jump in and talk about the scientific benefits. Although that a lot of these therapies may be individualized, the process is very similar. The choice of the platform, the delivery platform, the choice of the editing platform or the approach will be very similar. Even though it's very individualized, there are components that are very similar. For each one of these that we do implement, we do learn a lot, even though it's only on one patient. These therapies we can learn a lot, even if they're individualized to one muscle disease or one muscle disease gene, one mutation, just the way we develop, say, the virus that we deliver the therapy will be very similar across all the muscle diseases.
I think there's a lot to learn that we can learn more broadly for that particular disease. I think that there is a lot to learn, and there's also a lot to learn across different, say, ultra-rare diseases. Because if one ultra-rare disease sees that path forward and sees that it is feasible and it's not... This won't happen in the lifetime of this patient or their child, then it actually gives hope also. There's the what can we learn from it scientifically and also the hope that it brings, which you can't put a value on.
Mary Parker:
What do you think, Lauren? What do you see the value of it?
Lauren Black:
Well, I work with animal models a lot, including rodents who might have a type of a disease state that might have been... GMO rodents that have... They'll take the gene in the rodent that encodes for a special protein that's absolutely required, and in people as well, and they'll do what's called, for instance, a knock-out rodent of a particular type. And for instance, we'll take that protein and make it unavailable in the rat. And in some cases, that can develop the same sort of disease in the rodent that a person who has a mutation that's blocked their protein pathway exhibits. When we see that, we say that there's a phenotype in the rat that mirrors the human phenotype of the disease patient.
I would say it's pretty rare that we have a perfect disease model to study drugs in and that's one of the things we struggle with in drug development all over the world and for everything.
When we look at the opportunity to study a person who has a specific disease that we need to learn something about to help others and that patient is willing to try to undertake experimentation, they have to be intellectually involved, they have to be spiritually ready, they have to have the wherewithal to make changes in their lifestyle to accommodate a lot of doctor's visits, but if they're willing to contribute to science and say, "My contribution in the early stages of a product development will make it possible for us to make medicines for more people later," that's a wonderful opportunity for science and for the person.
And then you have to have the informed consent to ensure that this is a experiment that's ethical, and then you have to have the approval of an ethics board at the hospital, and then you have to have FDA approval. There's a lot of checks and balances here that protect the patient from just taking a leap in something fruitless.
Mary Parker:
Yeah. Well, speaking of which, Lauren, the FDA Modernization Act 2.0 was passed last year, which opens up options for safety testing in models other than animals. Does this offer accelerated options for preclinical testing for ultra-rare disease patients?
Lauren Black:
Well, actually, Monkol might be better at this. Animals are pretty important in understanding the physiology and the biodistribution of drugs. But Monkol, can you talk about an in vitro experiment that might have been really important to understanding either the benefit or a safety problem with a drug?
Monkol Lek:
Yeah, I can talk in both directions. First of all, in vitro model, in the muscle disease field, we are starting to explore in vitro models in terms of 3D muscle cultures that can contract and have similar properties, both how it contracts, its electrical properties, its calcium handling properties, as real muscle. And that then allows us to use the patient's cells to actually model the disease itself.
So that's one of the advantages, especially when a lot of the technologies now act on the patient's mutation rather than just a gene replacement strategy. It's highly advantageous in that because creating the mouse model can be quite time-consuming, trying to put in the patient's mutation in the mouse model. And sometimes that has to be the human gene with the human mutation. But on the other side, some of the genes that I study; one of them is FSHD, the other one is GNE myopathy, there is no mouse equivalent. Sometimes the assumption is that you can always model a human disease in the mouse, but sometimes you can't.
In the case of FSHD, it doesn't have the gene the human has. And so by inserting it in, you don't really quite get the same disease. And with GNE myopathy, there is a gene that's missing in humans that's not missing in mice, and they create a different form of sialic acid. And again, you don't create the same disease in that situation. Sometimes people in the rare disease field are frustrated prior to this because sometimes creating the mouse model is actually harder than creating the therapy itself. It's to remind people we're trying to create therapies that help people, not to cure mice.
Mary Parker:
For sure. That's a really good point.
Lauren Black:
And I think the first thing that happened when we had the Mila case is I got asked by the Yu lab, Tim asked me, "Well, does that mean we have to create a mouse model of Mila?" And I'm like, no. Because really in that particular case, you're trying to change the way her gene was expressed and it was in an altered form and he thought he could re-alter it using an oligo. He had her own cells in vitro and they represented their disease, because it's a lysosomal storage disease, which means that vacuoles or packets of various lipids and fats build up in the cytoplasm and the cells look like, under the microscope, they look like a hamster that ate cheeks full of nuts. It's not subtle. And then you look at the after picture when the drug has been marinated on the cells and culture and all the vacuoles have dispersed and the cells are empty and they look happy as... They look really happy to be released of their burden.
And that burden is poisonous, so the poison's gone. And I thought to myself, that's the best proofs of concept I've ever seen. We don't need a mouse. And actually I find, in consulting different rare disease groups, I find myself saying it over and over again, how good can we make your human models and cellular models and organoids? How well can we craft those so that we can get as much information as possible?
Mary Parker:
This next one I think is probably mostly going to be for Monkol, but Lauren, feel free to pitch in. How can you determine which ultra-rare diseases might be treatable with current technology like CRISPR or gene therapy, as opposed to being treatable with older, existing drugs?
Monkol Lek:
I'm not sure about older existing drugs because a lot of older existing drugs, the vast majority of them don't address the root cause. Rare diseases are caused by normally a mutation in one gene so that a lot of these are monogenic, and a lot of the existing drugs really only address the symptoms of the disease. A lot of the boys with Duchenne muscular dystrophy take steroids and other drugs. They are only addressing the symptoms. They do an effective job of addressing symptoms, but they don't address the root cause. A lot of the genetic therapies that are available, such as oligonucleotides that address the gene that's causing a particular disease, or gene replacement therapies through AAV or other delivery methods, and also antibody oligo conjugates, which are also delivering skipping technologies, are addressing the genetic root cause. As a geneticist, it's much better to address the root cause rather than the symptoms of the disease.
Mary Parker:
Are there any other classes of diseases that are suitable to gene therapy or other modern approaches?
Monkol Lek:
Yeah, the other organ system that's easy to target is the eye.
Mary Parker:
Oh, okay.
Monkol Lek:
Mainly because it's sort of a immune privilege. I think the immune system that interacts with the eye, I'm not an expert at this, but I'm just replaying what others have said, it's immune ocular privilege and it's very localized in delivery also. It's another thing that people have targeted in terms of genes that cause blindness and other defects of the eye.
Mary Parker:
Okay, that makes sense.
Lauren Black:
It's a wonderful time, isn't it? We've got Luxturna, which is the first approved drug for blindness, and that was only approved, what, about five years ago? Maybe seven? And I think it's opened up whole new fields of possibilities because it was very common until then.
It's kind of like you crack open a door that was locked and then you can start walking through the door and then you start to see other doors and open them and open them. That's the way I see... The first drug for a disease just makes it so much more possible for other opportunities in that area. That's why I also say that we can learn from the first person because we can apply immediately what we learned from the first person to the second. Then we know way more than we did from animals.
Monkol Lek:
Yeah. I sometimes say data from a human clinical trial is probably worth more than a million mice. There's only so many mice experiments you can do before you need to translate and see is this effective in humans? Because we've shown it's safe and effective in mice. Let's not cure the mice 1,000 different ways.
Lauren Black:
Well I think that's why I wanted to bring up jacifusen. Mary, you had a few words to say about Jaci, right?
Mary Parker:
I did. Well, I recently did an article about her and her treatment from her mom, who's giving an update on where it's going. Just a brief synopsis for anyone who hasn't read that, Jaci and her twin sister Alex both had a very rare form of ALS. Unfortunately, Alex passed away at a younger age and then Jaci passed away in her early twenties. But while she was still alive, Jaci participated in a trial to develop a drug for her and her mutation. And since then, unfortunately... I think it did help her a little. I'd have to read the paper on that.
Lauren Black:
No, absolutely. Absolutely.
Mary Parker:
But yeah, it wasn't a cure but it has gone on to be picked up by Ionis Pharmaceuticals, and they're doing more clinical trial testing in people with similar mutations. Her work and her family's work, because they really pushed it through hard, is now going to be going on to help a lot of people with the same disease that Jaci and her sister had. That's why I was bringing that up, Lauren, to give you a chance to talk about that as another reason that ultra-rare disease research is so important. Go ahead Lauren, take it away.
Lauren Black:
Well, Jaci, like Terry Horgan, both of these folks you can look up online.
But she was a very brave gal. She was 25 and she knew her sister had passed from a nasty disease, but her sister wasn't even diagnosed until the end of life. It was an uncertain whether she'd get that disease or not. And finally they got a molecular diagnosis when she was 24 that she actually did have the mutated gene, but she had no symptoms. There was still all this reason to hope that there was some epigenetic or other mechanism that might not lead her mutation to be expressed. That wasn't the case, unfortunately. Within months of actually hearing her molecular diagnosis, she started to develop symptoms.
I had a chance to meet Jaci in person. My son and I went up to meet her with Bob Brown, who's essentially a godfather in the area of the mechanism of ALS or Lou Gehrig's disease. I had a chance to meet her whole family. Jaci was about on her third dose at the time, and she was receiving them in New York City under the care of Neil Schneider. It was a wonderful opportunity to see hope being incubated there in that room. Later on, folks that weren't in such an advanced stage as JC was when she started, later on, people that were earlier in the disease and as I understand it, who have the mutation, are now able to get drug before the disease actually starts.
Mary Parker:
Yes.
Lauren Black:
And I'm like, that's what we're talking about, being able to get early diagnosis with genetic information and being able to start a drug before the disease starts to take away key neuronal functions. Jaci started it and the next people right after her benefited from the fact that the trial was already started, the drug was already made and they could get enrolled quickly and the FDA was warmed up to the idea and the rats were started. That momentum built so fast over a year that by the end of the year, from Jaci's start, I'm talking within six months, several other patients were treated. And now they're in a phase three trial, which means that it's galloping down the course for approval, God willing, right?
Mary Parker:
Yeah, absolutely.
Lauren Black:
That's the kind of thing that makes you get up in the morning.
Mary Parker:
To take us out, Monkol, can you tell us a bit about what you're working on now?
Monkol Lek:
Yeah, I'm working on a few different CRISPR therapies. I can talk about two of them. One of them is looking at an exon 20 to 25 duplication. This fits into one of the questions that you asked earlier regarding being able to use other things, other than animal models. Because to produce a duplication model of particular exons in a gene, these are the regions in the gene that code for the proteins, and some of this stretch is quite large, to actually produce that mouse is probably actually harder than actually producing the therapy itself. A lot of the work has been done in the patient cell model that has this unique mutation. And so one of the advantages of working with a duplication in the DMD gene is we can cut out the section that's duplicated and you can actually make the correct gene.
Not a truncated version of the gene, not a compromise, but if you can cut it out precisely where you have two copies of, then you can actually get exactly back the normal gene. We're working on that. And one of the challenges on that is how can we bridge not having that mouse model? As Lauren was saying, what could we test in the mouse that could be predictive of the effectiveness of therapy, and what can we do in the patient's cells with the exact mutation? Because this is an individualized therapy, just targeting N of one of just this mutation. Another one we're working on is still in the DMD gene, but it's a deletion of exons, I think 57 to 59. In this case, it's the exon skipping strategy. Which bits of the DMD gene can we edit on the DNA level to skip one of the exons to put it back in frame?
Similar to some of the exon skipping therapies that are on the market, but it's the exon we want to skip, there is no therapy for, mainly because it's an ultra-rare mutation which there may be only a handful of people in the United States this would benefit. Again, there isn't anything out there. They're the two exciting things we're doing in the DMD field. We're also working on a gene replacement therapy in the case of a form of limb-girdle muscular dystrophy. It's a common form of limb-girdle muscular dystrophy, and that's caused by the FKRP gene and its reduced enzyme activity. You can't have complete knockout because I think it's essential for life.
These patients have mutations in the FKRP gene that lower the enzyme activity. In this case, instead of editing the gene, we're actually replacing the gene because it's not detrimental if you have a working copy along with the not-so-working copy of the gene. It's just delivering the FKRP gene, a working copy via AAV. We have the mouse model in this case, so we can then look at the differences in terms of muscle disease progression, also the improvement of muscle function in this case. They're the three that I can think of on the spot that we're working on.
Mary Parker:
All right. Thank you so much. Thank you both for joining me for this discussion. I really appreciate it and I applaud all of the research that you're doing and hope that everything goes well going forward.
Lauren Black:
It's been exciting being part of Monkol's accessory entourage of scientists. I'm a big fan, Monkol, so we hope to hear a lot more in the future from how the progress of these are. And you know that you can count on us to try to help wherever we can.
Monkol Lek:
Yeah, I'm really looking forward to it. And I didn't get to say at the start, Mary, that it's been great being connected by Rich, who's connected me to Lauren and the folks at Charles River, mainly because as a basic scientist or a translational scientist that doesn't work with patients and don't work in the regulatory, it's eye opening to see this other world and also to know that if we do have the patients in mind in the first place when we do these translational projects, that I always say this now, the first thing we should do is talk to Lauren and people like her with her background of regulatory. Because at the end of the day, I didn't get in the rare disease research to cure mice. I got in the rare disease research to help people.
I don't want to be at the end of my career, have 10 Nature publications, but cannot point to one person that I've helped. Because that is not the career that I want. It may be good for some, but this is not the career I want. That's why when we go on this journey, we always put... If you want to put the patients in mind first, you should be talking to the regulatory people, you should talk to the clinicians, to make sure that the work you're doing can truly help people, rather than something that looks scientifically cool, novel, sophisticated, gets you the Nature publication, but has no hope in helping anyone.
Mary Parker:
Right. No, that's a good point. That's a good point. Well again, thank you both.
Lauren Black:
My pleasure. Thank you.
Monkol Lek:
Yep, thanks.