Innovation on Rare Disease Day: Recode CMO John Matthews on changing the future of genetic medicine [podcast]

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In observance of Rare Disease Day, our latest episode of the Genetics Podcast presents a fascinating conversation with John Matthews, who was recently promoted to Chief Medical Officer at ReCode Therapeutics. This special episode not only commemorates the day dedicated to raising awareness for rare diseases but also showcases the innovative strides being made in the field of genetic medicine for the diagnosis and treatment of rare diseases.

John, a seasoned expert in drug development, shared his journey from his early days in Malawi to his current role at ReCode Therapeutics. With a rich background that includes significant tenures at 23andMe, Roche, Genentech, GSK, and Novartis, John brought a wealth of experience to the discussion. Particularly interesting was his transition from clinical practice to the forefront of therapeutic development, which was driven by a passion for leveraging genetics to create transformative treatments for rare diseases.

The episode touches on the collaboration between ReCode Therapeutics and Sano Genetics, which is providing hope in the form of free genetic testing to patients with Primary Ciliary Dyskinesia (PCD). This partnership is a crucial first step in understanding the genetic underpinnings of DNAI1-related PCD and advancing our knowledge and treatment of rare diseases. John and Patrick discuss the evolution of disease understanding, from the identification of genetic markers to the development of therapies that can potentially cure diseases at their genetic roots.

In addition, ReCode's innovative use of lipid nanoparticle technology for delivering novel mRNA and gene correction therapies was a focal point of the discussion. This cutting-edge approach has the potential to revolutionize treatment for rare lung diseases, offering new options to patients who have long awaited effective therapies. John's explanation of the technology and its applications provides listeners with a glimpse into the future of medicine, where targeted genetic treatments can offer personalized care for rare disease patients.

Rare Disease Day is a pivotal moment each year to spotlight the challenges faced by the rare disease community and the urgent need for research and development in this area. This episode of the Genetics Podcast serves as a powerful reminder of the impact that genetic medicine and collaborative research can have on the rare disease community. As we continue to push the boundaries of science and medicine, the ongoing efforts of researchers, clinicians, and companies like ReCode inspire hope and drive home the importance of continued investment and interest in rare disease research and treatment.

Listen to the full podcast here, or check out the transcript below.

To learn more about Recode’s work in PCD, visit


Full transcript: 

Patrick Short (00:03):

Hi everyone and welcome to the Genetics podcast. I'm really excited to be here today with Dr. John Matthews, who is the senior VP of Clinical Development at Recode Therapeutics. Prior to joining Recode John spent more than three years at 23 and me as a senior clinical fellow and senior clinical development leader. And prior to that he spent I think about 10 years at Roche Genentech, five years at GSK, and two years at Novartis. So all that is to say John has extensive experience with drug development, both in large and [00:00:30] small organizations, biotechs and 23, and me obviously being an interesting example of a consumer and data focused company that started to build a drug development organization internally. So we're going to talk today about learnings from John's career and go deep into some of his work at Recode developing novel genetic medicines where they're starting with two rare lung diseases, PCD, primary ciliary, dyskinesia, and cystic fibrosis. So John, thank you so much for taking the time to join us.

John Matthews (00:58):

Welcome. Thanks. Good to [00:01:00] be on this podcast.

Patrick Short (01:01):

I would love to start maybe with Malawi. I read during some of my prep that that's where you grew up and during this time the seeds were planted for you to become a doctor. Actually, it'd be great to start here. What got you interested in medicine in the first place, and then how did you transition from seeing patients day to day into therapeutic development where you've spent close to 20 years now?

John Matthews (01:20):

Yeah, wow. So yeah, I was born in Africa. My father did a PhD in Africa and my mom was working as a nurse, so she was the inspiration really to be medically [00:01:30] minded. But on my father's side, I had a microscope and he was the one that showed me bugs and small things and how to, I was good at trying to observe things. I wasn't a great scientist doing experiments at a young age, but my uncle was a pathologist. And alongside my mom, I definitely had a sort of medical track pretty early and at school people would come to me with grazes, things in their eye, and I was definitely attracted to medicine and [00:02:00] wanted to do it from an early age. And then transitioning to science that came about, I kind of wanted to be an academic physician. It's kind of my father's a professor, went to med school, did an integrated BSC, sort of did everything I could to get the science background thinking I'd be an academic physician.


And then when I did my PhD, I had the benefit of collaborating with pharma scientists. So these are physicians in a lab in the UK that were also [00:02:30] looking at. My PhD was on asthma and I had peripheral blood cells and we were doing experiments to look at drug effects in the test tube. And what I found was that they just had this incredible scale and rigor that as a lab scientist I couldn't do if you're doing triplicates and a 96 well played, I would always be wondering which well did I miss and so on. And I looked at my error bars and my data compared to what came back [00:03:00] fakely the same sample of blood, but was testing up to 12 drugs with triplicate, with beautiful tight error bars. And that really inspired me to say, wow, this industry is where I want to be at. But out full disclosure, the other thing was I was just pretty exhausted at the end of doing three or four years of 120 hours a week. The end of my general training was before the time directive came in from Europe and protection of junior doctors' hours. And [00:03:30] I realized I operate a lot better when I've had a good night's sleep. And that was another motivation to go to outside of acute medicine to move away from hospitals and just once I join pharma, just never look back.

Patrick Short (03:44):

Yeah, acute medicine in particular is probably a pretty intense training environment and I think, well, I know you work pretty hard today anyways, but I suppose there's a comparison to 120 hour weeks and life or death situations, literally some days where you're [00:04:00] in there compared to having a little bit more time to think carefully about what's in front of you.

John Matthews (04:05):

Completely. Yeah, it's around the acuteness of it and those individuals in front of you that you're managing versus a population which could be a trial population or entire drug development program. We do medical monitoring and 24 7 stuff, but generally, yeah, it's not the coalface.

Patrick Short (04:27):

And you've got extensive experience in lung in [00:04:30] particular. You've done a lot of work in asthma and rare disease as I mentioned earlier. What is it about that area of biology that's interesting to you?

John Matthews (04:40):

I think physicians tend to go towards the specialties that really appeal to them for many different reasons. I suspect for me, the lung at the time I was a junior doctor probably seemed a little less complicated than say the heart. So it's a little [00:05:00] more accessible than kidney, liver or heart. So a little more accessible in terms of the lung, there are a few reasons why I was inspired by really great physicians at my hospital where I was training people like Nigel Bateman, Peter Bony, just people that were involved in asthma and lung diseases. And I think I could get my arms around it in a way that perhaps cardiology or was a little more complicated and a little more inaccessible to me at the time. So it was kind of [00:05:30] just early influences and probably just personality types. I think physicians tend to congregate in self-identification ways.

Patrick Short (05:42):

Yeah. I'd love to talk a little bit about asthma. I'm not a expert in the area, but from my vantage point, it does seem like one of those diseases that maybe seemed simple years ago, but over time has unfolded into many different maybe distinct biological drivers. Some [00:06:00] forms of asthma are probably really treatable today, but others are pretty intractable. I'd love if you could talk about that a little bit. What's changed in the last decade, say, or take a longer or shorter time horizon, if that makes more sense? What's been solved or what's where we made enormous progress and what's still a little bit tricky?

John Matthews (06:19):

I think the enormous progress is being made because of genetics and the ability to identify subsets within diseases at scale. And [00:06:30] so I think asthma early on, the concept of inflammation and adding inhaled steroids was great and help vast numbers of people. And so I think the remaining problem for asthma is around the people that don't get benefit from the existing treatments. And we still really dunno what's driving that, what's driving the relatively very small subset now that we can be confident don't have classical type [00:07:00] two steroid responsive disease. And so I think ultimately we've still got a long way to go. I think the progress has been made by collecting registries, aggregating well characterized populations where you can start to do genetics at scale. Still got a long way to go yet, but I think that's where it's evolving.

Patrick Short (07:24):

And then maybe we can talk about some of the rare diseases you work on. So it would be great. I gave a very brief intro to Recode, [00:07:30] but you could talk a little bit about what drew you to Recode, what's the company about, and then maybe familiarize people with PCD and cf, these two diseases that you all are very focused on right now.

John Matthews (07:42):

So I had my own eye on Recode. It was a company that I was aware about here in the Bay Area. And really when I was approached because there was a need for scaling up on the clinical development side, approaching an IND, [00:08:00] you just need more hands on deck. And so it was a good opportunity to engage with the company 23 and Me was just a fantastic nearly four years, just a month shy four years. It was just an amazing run and very happy there and a very productive time. But I was kind of drawn because of the lung and because of the need for these two rare diseases to get into the clinic in a relatively short space of time. And as I'd done my general junior training in the London, [00:08:30] I'd been exposed to primary ciliary dyskinesia at a specialist hospital in my junior doctor years.


And even during my PhD when I had some blood samples that I wanted to look at at a deeper level to try and see, I could see visually that there were changes with treatment and I wanted to, what's going on and how could I measure this? And so in that naive way, as a curious PhD student, early on my PhD, I went to the electro microscopy lab and I met a wonderful scientist [00:09:00] and she kindly showed me how to make resin blocks and to look at my cells under the electro microscope. She gave me a lot of time, but through that I learned that the Brompton does all of this nasal biopsies and so they have this massive database of primary ciliary dyskinesia patients. So for the audience, we all have CLIA cells, these are hairlike projections that move our mucus up out of our nose and sinuses and in our lungs up and out that we swallow our mucus without noticing it.


[00:09:30] And in primary DYS dyskinesia, they have loss of function mutations and so the Celia physically don't move. And on electron microscope you can see in the ine, these are these highly conserved structures that allow the CLIA to move the outer dine arm proteins, for example, a physically missing. And you can see that at the resolution of an AL microscope. So the gene loss of function leads to a visible structural loss of presence. So it was a curiosity and [00:10:00] being familiar with it and being able to have in my mind what a drug development path looks like for four years at 23. And me, it was looking at all of these genetic insights and the question is, well then what's a useful medicine going to be out of this? We're all familiar with the big stories, the SCLEROSTIN or PCSK nine, the observations of loss of function out there in the clinic that lead to these genetic insights that then you can get a therapeutic for the [00:10:30] core stories that drive us to use genetics to develop relevant therapeutics.

Patrick Short (10:37):

And interestingly, I think a lot of the common disease stories are about using loss of function as a way to get at inhibition as a therapeutic PCSK nine. The very short story is loss of function is protective and so then therefore a small molecule or a SO or something else that can inhibit the gene in people who don't have the natural knockout then may get benefit [00:11:00] where you all are approaching it almost from the opposite and more classical rare disease perspective. Right. In PCD, you've got loss of function in dozens of genes. You can talk a little bit about how many genes can break Celia function, but maybe this is a good opportunity to talk about cystic fibrosis as well because people who are familiar with it will know that there is a treatment for a subset of patients that carry a certain subset of mutations but not for the loss of function. So what you all are looking at are there's myriad ways [00:11:30] to break the function of Celia that results in CF or PCD and in that case you need to go in and restore gene function rather than correct it with a small molecule or something else. Is that right?

John Matthews (11:42):

Yeah, so in primary similar dyskinesia about 50 genes that are importantly able to break that ciliary function and the top five most common loss of function account for about half of primary ciliary dyskinesia. So there is an ability to go in and provide [00:12:00] effectively a replacement therapy using mRNA transduced in the lung airway cells to replace that missing protein with the mRNA instruction. And that we can show vivo in a test tube. You can take air liquid interface experiments, you can see Celia moving under the microscope and see in either primary human tissue or knockout models the restoration of function with the mRNA coming in delivered with the A MP and the cystic fibrosis. [00:12:30] Yes, the 10% of CF have this complete generally nonsense mutations where they're not producing CFTR the chloride channel. That's important in CF where we could with a mRNA replacement help that subset that are not going to be able to benefit from the modulators that have been transformative in cf. And so it's this remaining subset of the rare disease that are really lacking in any potential treatments unless we can come in and restore that function.

Patrick Short (13:00):

[00:13:00] And one thing that always caught my eye about recodes was the delivery platform. Actually, I think as I mentioned to you John, I've interviewed a lot of people on this podcast about gene therapies and one of the common challenges is actually delivery to the right tissue or organ system. And you all have a platform that we probably won't have time to go into excruciating detail today, but maybe we'll have follow-up where we go into the science and we'll link some of the papers in the show notes. But maybe you could talk a little bit about the tissue specific [00:13:30] delivery platform that you have and how it works.

John Matthews (13:32):

Yeah, so I mean that's the great Simon I had about Recode is coming and learning that the company formed by bringing the discovery, Dan Seward great scientist who was able to work out how to apply these lipid nanoparticles to be able to have tissue specificity to be able to go beyond the liver. So typically when a classical lipid nanoparticle goes [00:14:00] into the body and the bloodstream, it's a bit like the endogenous transport of lipids that happens in the body. So A-V-L-D-L particle through a P OE binding will end up in the liver. And so that's what happens with the vast majority of lip and peas. What Danser discovered was if you can add a sort lipid into the particle structure, you can get tissue specificity. So in the case of lung, to get beyond liver and [00:14:30] to be predominantly coming into the line and not going into the liver, first of all, so it's not a mechanism by which it's sort of liver and then a bit more goes elsewhere.


But it's primarily going into the lung is to the publications. And what he was able to show was that the protein corona, that is part of the way the LMP works. Once it gets into the body into the bloodstream, you get a desorption of things like pegylated lipids and that allows different proteins [00:15:00] to then by, and we call that bind and that we call that the protein corona. And so in the case of the lung mechanism, he's identified that a protein called vi actin is the more enriched protein that's binding to these particles with that arrangement of specific lipids. And that allows binding to alpha v beta three and lung cells express that. And so there's a specific binding that happens. And so he's demonstrated [00:15:30] proteins for the spleen and I think this work is ongoing, but the excitement is that we can now deliver lipin nanoparticles for our two leap programs. It's nebulized, so we're actually going nebulized root that allows to go directly into the airway cells and the progenitor cells, and that's a very rational way of delivering directly to the lung. But we're also working on ways to achieve that through giving an intravenous route of administration

Patrick Short (15:59):

And I guess other [00:16:00] organ systems you can think about changing the, changing the sort sort code or if we want to use a banking analogy to figure out how to get it to, I think you can do the spleen, you're looking at some other tissues as well. Maybe you could

John Matthews (16:13):

Talk a little bit about that. Heart brain we're looking across at ways to deliver and some of Dan's recent papers the end of last year in terms of the lung is being able to transplant basal cells, so progenitor cells in the lung to [00:16:30] really get long lasting transduction so that the next wave is going to be I think genetic editing where you can get corrections that allow potentially many more diseases to be applied and particularly in the case of CF, to then start to go towards more curative approaches.

Patrick Short (16:47):

Yeah, amazing. You mentioned 50 genes, five or so of which contribute to the bulk of PCD diagnoses. I wonder if you could talk a little bit about the genetics of this disease and what we know [00:17:00] about what percentage of patients are diagnosed undiagnosed, what that journey looks like For those who are really interested in this. We've been working together ano and recode on a program called Think PCD, which is a free genetic testing program for patients who are either diagnosed or suspected. So you can visit think if you want to learn more about that. But I wonder if you could talk a little bit just about what we know today about the genetics and also some of these are still open questions, I think actually of how many patients are undiagnosed and may have [00:17:30] something else like bronchiectasis or some other kind of disease, but it'd be great to talk a little bit about that diagnosis challenge.

John Matthews (17:35):

Yeah, so I mean in primary C dyskinesia, about half the subjects by chance will have organs situated to the wrong side of the body, theus inverters. And that fundamental problem is just because in the embryo there's sinus node, if it's not functioning in a specific direction, there's a random chance that the organs will end up on one side [00:18:00] or the other. But cartina syndrome, classical heart on the right side of the body, there's a clue there as to why somebody might be having a wet productive cough. And so it was recognized early and so there's a clue. And so about half of PCD patients will have this clue that allows the genetics to be tracked down early, but there's a group that will have heart normally situated on the left and they end up in adult bronchiectasis clinics [00:18:30] where because we haven't got, I think, consistent genetic testing across the board thought for adult bronchiectasis, we're just not picking up people that have pathogenic mutations that would diagnose the underlying reason why they've ended up with bronchiectasis, these dilated airways that are as a result of the colonization and the chronic infection in lungs where the CELIA or not moving.

Patrick Short (18:57):

I'd love actually maybe to go back to the cyto [00:19:00] versus, because this was something that was new to me when I started to learn about this condition and it's frankly amazing biologically, and maybe you could talk a little bit more about that, and it sounds like it maybe gives a good handle on prevalence of the disease if it truly is, is it 50 50? It's a stochastic process where they may go one way or another? Yeah, maybe you can go back and do a little more detail on that from why is it that it's 50 50 and then that I guess tells you what the prevalence is, which solves a problem in a nice way?

John Matthews (19:30):

[00:19:30] Yeah, my understanding is somewhat superficial that as in the embryo, if your organs organogenesis is being sort of almost managed by the fact that our CLIA are fundamental, the structure is highly conserved. And so it's a very powerful mechanism by which fluids are moved around. So I suspect if it's not there, then by random chance things are going to end up in the body around [00:20:00] just where they locate. So I suspect there's a dividing line that happens in early embryology, but I'd love somebody in your audience tell me more about it. That I think is fascinating, but I think ultimately in terms of the genetics though, it is a rare disease, but it's not ultra rare. And so if you take PCD as a whole, if you're starting to account for 30% of adult bronchiectasis, you're getting up to pretty large [00:20:30] numbers of people that are impacted.

Patrick Short (20:33):

And what do we know about penetrance in terms of the percentage of people who are, it's a recessive disease or compound heterozygote, so you need two hits, does everyone go on some

John Matthews (20:45):

Disease? So for the actual loss of function to be clinically, you need BIC mutations, and so you need the loss of more than 50%. There are some excellent cases. It's generally ultrasound [00:21:00] or recessive pattern, and I think that's because of the needing to be BIC to cause expression of the condition. So BIC mutations either X-linked or but predominantly autosomal recessive.

Patrick Short (21:15):

You joined Recode as you mentioned, because of this push into the clinic, and I was wondering if you could talk a little bit about your experience with rare disease drug development versus common disease. What's easier, what's harder? One of the things that brought me into [00:21:30] this field, I come from a genetics background obviously, but I've been shifting more and more towards the clinical trials and clinical development side of things because for two reasons. One, the impact on patients is obviously pretty clear from the work that you do, but also maybe a little bit to the story you told earlier. The level of rigor of the science that happens in randomized control trials and the kind of work that you do when you're bringing a drug really into the hands of patients is pretty amazing. I always explain to people how incredible these experiments [00:22:00] are from, we were talking before this about multi-thousand page documents and data that you're pouring over. I wonder if you could talk a little bit about what you found to be easier in the rare disease worlds and what's harder and vice versa for common diseases?

John Matthews (22:15):

I think what's easier is that rare diseases have these incredible communities that pull together because they have to come together and work together in order to get the traction, get the effort to solve their problem, [00:22:30] and whether it's an N of one or any rare disease. I think that aspect of community building patient advocacy is so incredibly strong in the rare disease area. That makes it easier because when you're doing a clinical trial and you're looking at patient engagement, I can look at a registry, a collection of 120 patients with a rare disease, and I'm pretty confident that [00:23:00] we're going to have very high numbers coming into clinical trials. But if you look at common diseases, a fact that I think always shocks me is that even in the setting of an oncology trials, we only have about three to 5% of people engaged and participating in clinical trials.


And so the question is why is that happening? And I think it's in rare disease, there's a need to do rigorous clinical trials. There's a need for therapies. And [00:23:30] so if you've got that community engagement, you can get them done in a reasonable timeframe, whereas in more common diseases, somewhat cynically people are replaceable. If somebody X is not coming in, then you've got wires around the corner, you can find people and it's just at scale. You can move at the numbers, which we like to have in drug development. We like to have at least a hundred people treated for one year and a safety [00:24:00] day. So based of 1500 people, 3000 people by the end of phase three, we want to have large numbers to be able to be confident about small signals, but in rare disease, we have to get more comfortable that with smaller numbers, we can bring the rigor that this is a clinically meaningful drug, but it may take us longer to gain that safety experience. And so it's a question of balance.

Patrick Short (24:27):

Yeah, that makes sense. Some of our listeners are going to be really [00:24:30] familiar with designing and even running major clinical trial programs, but many will not be. I wonder if you could talk about in a typical common disease clinical development program, something like asthma, maybe, what do the major steps look like? And then in contrast, a rare disease program, what's different? Where my mind going is going is things like natural history studies, for example, you may not need to think about for common diseases. Also, you can skip some steps in rare diseases if you've [00:25:00] got breakthrough designation or other negotiations with the FDA. Maybe you could talk a little bit about what those look like.

John Matthews (25:06):

Yeah, so I mean at a high level, once you have a clinical candidate, the first in human is the starting point and you need relatively less than a hundred subjects are going to come in and be the people that expose the lowest dose, a reasonable dose to start to get your safety experience, build up a single [00:25:30] and multiple ascending doses. And then in phase two, moving towards proof of activity, the ability to show that you've got a clinically meaningful drug and still relatively small numbers. But in phase two, we're getting up to perhaps the a hundred to 400 mark. And then in phase three, which is your confirmatory stage, you need to be able to show with the rigor of replications, so two independent trials and the required safety experience [00:26:00] that I mentioned earlier to them to be able to go and say that this is a drug that should be approved and out there, I think in rare disease that isn't very much different and there's nothing different than the principles. And really it's a question of doing that phase one, getting the safety experience, moving as quickly into patients as possible, addressing the question, is it a clinically meaningful, and then moving to a confirmatory stage that's reasonable and appropriately balanced for [00:26:30] the patient population. So if in a rare disease, there's just very few people that you can draw on, I think as a community we have to accept that we can do what's reasonable, but they're not matched for matched in terms of scale.

Patrick Short (26:44):

Yeah, makes sense.

John Matthews (26:46):

But things like breakthrough designation and applying all of the ways to try and speed things up when we've got some incredibly, I think that applies both to rare and common diseases. And I think [00:27:00] it's a question of finding the path that shows everybody that you've got a drug that's really actually making an impact and the risk benefit ratio of benefit to risk and safety issues has been addressed.

Patrick Short (27:14):

One of the areas that I'm following and interested to see how it evolves is how more rare disease companies are using natural history data to in some cases even eliminate placebo arms in their trials. We had Warren Huff, who is the CEO of Reta pharmaceuticals [00:27:30] episode, I think it was 105, and they weren't able to completely eliminate their placebo arm, but they had really good natural history data. They'd worked with the patient advocacy group for a number of years and were able to basically show very convincingly what a patient's journey would look like in the absence of a treatment, and then essentially make the argument to the FDA that they could reduce the size of placebo arm because they had really good data to back up what essentially would happen in the absence of treatment. And I think it's one of the, I guess, themes [00:28:00] and rare diseases that I'm interested in following because the patient numbers are so hard. Like you said, people are motivated but not motivated to be on a placebo often if there's an option not to. So I'm interested to see how this evolves just from a policy standpoint of what you can do.

John Matthews (28:13):

Yeah, it's a critical area where clearly we can bring the rigor of the natural history study to be able to describe what happens in a disease if left untreated does provide that extra information that can supplement. I think clearly [00:28:30] a well controlled trial where there is a placebo group, as we know when you have imbalance randomization, you lose power. And so you have to supplement it in some way. And I think clearly the natural history study is a way to do that, and I think that's going to be a key advance that's going to help us complete while controlled studies, but designed appropriately for the available patient population where you bring in that understanding. And it's surprising [00:29:00] that we've probably not done this more earlier. If I look at diseases like interstitial pulmonary fibrosis where large phase three trials were done in order to show the lung function decline was less on treatment, and the FDA required very large randomized controlled trials to demonstrate that. And you wonder if perhaps more effort had been made to create natural history of IPF the [00:29:30] data to show what happens, might've been able to save and have more innovative clinical trials that could have got the answers sooner.

Patrick Short (29:39):


John Matthews (29:39):

This is, but I'm say in common diseases also need to be doing adapt history studies, so take the world to severe asthma. I think that the more we understand the people who are not responding to existing treatments, they also become a rare disease. Severe asthma is this, whether it's two or 5% of people that really don't respond to existing treatments, [00:30:00] that becomes a rare disease within a complex disease. And there they have a challenge because then how can they get all that community engagement that happens in a rare disease to get behind their problem statement? And whether it's even say nash, the NASH community I think have been struggling to get their drug that's really going to help them. And they have an amazing patient advocacy group and have been really pushing for natural [00:30:30] history studies of non-alcoholic fatty liver to be able to get what are the biomarkers that show progression, how can we enrich for the people that are going to end up in a really clinically difficult spot that they have the unmet need and they need treatment.

Patrick Short (30:47):

Yeah, I think that's a great point. There's an interesting movement in that field, I think led by the liver forum that I would love to see across more diseases to pool placebo data across the major trials as well. To me, [00:31:00] this seems like a no-brainer from these very large studies being run, and people just aren't, I understand why some companies might not want to share data on their active investigative drugs, but I think there's a movement to pool placebo data, which will be really interesting. You effectively get very large high quality natural history data at a huge scale that could help solve this kind of problem.

John Matthews (31:21):

Yeah, I think we have to find ways to allow the registries to foster and be owned by basically the patients themselves, [00:31:30] and then companies come in and get access to that data to supplement their programs. And I think that's an area that I think is building. I think there's been some very innovative work in the UK using, effectively it's like having patient passports because within a large healthcare system like the National Health Service in the uk, that system owns an entire individual's life [00:32:00] of data. And so there are completely ethical and rigorously scientific ways of getting access to that data. And there've been some preliminary work done in the asthma world to look at literally a randomized phase three clinical trial done out of pharmacies in the community and randomizing people within the community with an inhaled drug and a placebo. I think that could be another incredible podcast to invite the people behind that innovation [00:32:30] and how they got to do that trial.

Patrick Short (32:33):

Yeah. Do you know the name of the program by any chance?

John Matthews (32:35):

It's around the Northwest Health Authority, a group in Manchester. And I apologize, I am doing name recall block.

Patrick Short (32:45):

I'm Googling

John Matthews (32:45):

In background Well, but our conversations kind of reminded me of that work, and I can find a paper we can post to attach to the podcast. I know it's infuriating when somebody's giving you a lead, but you don't know where to go. Oh, no,

Patrick Short (32:57):

We will find it. Yeah. I'm continually [00:33:00] impressed by all the innovation happening in the uk. You've spent a lot of time here. I guess you're from Malawi originally, but you grew up here. Where did you grow up in England?

John Matthews (33:11):

I was five when I came back. And so yeah, I pretty much born and raised, born in Africa, but raised in the uk. Went to school, medical school in London, St. Guys, St. Thomas' Hospital.

Patrick Short (33:23):

Yeah, obviously I've lived here for 10 years, but there's the uk, besides the flagship things like Genomics [00:33:30] England and the Genomic Medicine Service, there are lots more innovative things happening. There's late last year, they announced a very cool rare disease focused a SO program where patients could get access to and basically n of one kind of antisense oligonucleotide therapies. So I just think the UK is really doing so much on a big scale, but also this is a good example of using the NHS as a platform to actually do really interesting science and not just deliver medicine. [00:34:00] So I think the future is bright over here

John Matthews (34:02):

Completely. And I think for PCDI was so excited when they included PCD in the birth genetic panel such that at birth people are going to be able to find out very important genetic information that because for PCD, really the loss of function happens mean incredible descriptions of at the age of nine, having a lung lobectomy because of Celia not moving and impacting at an early age. [00:34:30] And so I think there's a disconnect with our understanding of actually how severe and important primary ciliary dyskinesia is on those individuals, which ostensibly in most of the literature quotes, that they have a normal lifespan. Actually, it's not true. On average, there's at least a seven year reduction from the actuarial numbers around survival. And so yes, the 10% of CF patients that have nonsense [00:35:00] mutations and don't have the ability to produce protein at all, they have a terrible shortening of lifetime still in the thirties and forties.


I think the median is 34. So PCDI think has got a long way to go to really show that we need to start treating early, potentially from the age of one or two, you could give a nebulized treatment that could restore ciliary function and prevent somebody from needing to have [00:35:30] a lobectomy in childhood. So I think we've got a long way to go. But yes, the innovation I think is coming in England. I think they have the ability to recognize that genetics is going to be a guiding principle, but also sharing data, that whole ability to use the deep patient database that's owned by the patient, directed by the patient, but used for the benefit of an N of one, great. But if it's for more, then get all about it.

Patrick Short (36:00):

[00:36:00] And just for the benefit of listeners, we're doing a little bit of a deep dive into some of these newborn screening programs. So we've spoken to Wendy Chung who leads a program called Guardian out of Harvard and Boston Children's Hospital. They've sequenced around 8,000 newborns with whole genome sequencing. Also, Holly pa, who leads the program out of North Carolina, that's I think sequenced a thousand newborns in their first month. They're across the whole state, and they've both got really interesting triage methods where first they sequence genes that have, [00:36:30] they focus on return of results around genes that can have an impact within the first two years of life and are very actionable. But North Carolina Group has also a couple other tiers where they're potentially actionable, where something like PCD may fit into that group, and they also have a trials pathway, so if there's a big enough group of trials, then they'll work closely with the North Carolina sites. I just think there's a lot of interesting stuff happening here, and in 10 years from now, I think we're going to see newborn whole genome sequencing is [00:37:00] just part of the deal. And I think patients and families are going to be way better off for it. And it should make programs like yours even easier to scale and run because people are going to be spotted potentially a few years before they become symptomatic. And that ought to be the very best time to treat in the vast majority of cases.

John Matthews (37:19):

I mean, the more we can move towards preventative medicine and before pathology sets in, clearly that's so much more impactful [00:37:30] in the way we should move.

Patrick Short (37:32):

Yeah, absolutely. I'd love to maybe close out here with a question that I really like to ask a lot of our guests. It's one of my favorites. It just helps me to expand my horizons a little bit. But I'm curious about a technology or an approach, a theory, it could be a person, anything really that you're excited about that you think is somewhat underappreciated today? This is deliberately wide, so it could be a technology concept, whatever you have in mind.

John Matthews (37:58):

Well, I mean, I didn't want to say [00:38:00] the sort platform. That would be ways too. So I'm going to exclude that from my answer. I think registries are underappreciated. I was involved in the formation of a severe asthma registry 20 years ago that the asthma community came together, industry put in some seed money, the database was formed, and that's grown to 8,000 Samir asthmatics in the uk. And I think it's just a little bit underappreciated [00:38:30] because I think as all the geneticists in the audience, we'll know that you really need that scale to start to get genetic information. So even 8,000 is too small. And so I think we need to find a way to develop registries which are going to give that deep phenotypic information at scale that's going to really start to be transformative. And that's clearly happening, whether you start with the decode and Iceland and Estonia, [00:39:00] finjan UK Biobank. I mean, these things are happening, but my suspicion is that the registry part of it, the patient ownership part of it is less than it should be. That could be transformative to really bring the patients to the fore and then have the unmet needs driving the deep data discovery that you need in order to drive therapeutics.

Patrick Short (39:24):

Yeah, I couldn't agree with you more on that. I'm doing multiple episode plugs on this episode, but for me, the king of [00:39:30] registries, I don't even know if they've called themselves a registry, but the UK Biobank has just been so transformative. We had Professor Sar Collins on episode 40. It's actually, we replayed it for episode 1 0 9. It's so good and just evergreen. But what struck me about that is how many years they basically just built the resource. They had a lot of people wondering, when would this come to fruition? When will it return value? And they started, I think in the early two thousands, and we can just see what an enormous impact it's had now. So registries often [00:40:00] fly to your point under the radar for many years while they get to critical mass, and they do require some visionary leadership to say, what could this look like if we really plug away at it for a decade and think ahead? So I couldn't agree with you more on that.

John Matthews (40:15):

Great. Yeah, no, I think we could bring some more registry people along and talk about those challenges being visionary, but then having to really be tenacious and persistent to grow it. And the CF community, I think is a huge example [00:40:30] of a great success where we are going to be able to draw on Recode's program, we can go to centers that have registries of 250, 500 people. There are many more than that, but I'm talking about an individual center where they're known of these class one mutations, 10% nonsense mutations that are not producing protein. So the CF field, I think really led that effort in terms of having the ownership by the patient group, the [00:41:00] accessibility so that the patients know where their genetics are and then drive the need to solve for what their issue is.

Patrick Short (41:09):

Yeah, absolutely. Well, John, I'd just like to say thank you so much for your time. This was a great conversation. We've obviously known each other for more than a year now, but it's always nice to have this time to just talk about your career, some of the work you're doing, and share it with a wider group of people.

John Matthews (41:23):

Thank you. Yeah, no, it's been great to connect and yeah, look forward to the follow-ups.

Patrick Short (41:29):

Great. And thanks everybody, [00:41:30] as always. We really appreciate you listening. If you liked the episode, the best thing you can do is just share it with a friend or colleague that you think would like it. And of course, you can leave us a review if you like, but sharing with a friend is more important to me and of course, feedback. If you liked or disliked the episode, I'm sure none of you disliked it, but if you did, then don't be afraid to let me know. Thanks again, and we'll see you next time.

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