S3.18 Rare, Well Done: Progress and challenges in rare genetic disorders

Kat: Hello, and welcome to Genetics Unzipped - the Genetics Society podcast, with me, Dr Kat Arney. In this episode we take a look at the progress that’s been made in tackling rare genetic disorders, and the challenges that remain. And we hear from a prenatal genetic counsellor about how new tests are helping people carrying genetic variations make decisions about starting a family.

Before we start, a reminder that my new book, Rebel Cell: Cancer, Evolution and the Science of Life  is out now in the UK, and you can find all the links to buy it from your favourite retailer - as well as signed book plate stickers and limited edition signed hardbacks - at rebelcellbook.com.

How should we tackle rare genetic diseases?

Kat:  When it comes to rare diseases, the clue is in the name - it’s a term usually used to refer to conditions that affect fewer than one in two thousand people.  In many cases these disorders are caused by changes in single genes, but in other cases it’s a bit more complicated. But although each one may be rare in itself, it all adds up. There are somewhere between 6,000 and 8,000 rare diseases known, with a couple of hundred more being described every year as our ability to delve into the genome grows. In fact, a rough estimate suggests that around one in fifteen people worldwide is affected by one of these rare conditions. So, maybe not so rare after all. But what do we do about them?

Someone who is passionate about making more people aware of rare diseases - and what needs to happen to understand and treat them better - is Dr Ron Jortner, or Roni to his friends.He’s the founder and CEO of Cambridge-based Masthead Biosciences and is also a trustee of the Cambridge Rare Disease Network - a charity focused on making a difference in the lives of those affected by rare genetic conditions.

I caught up with him to find out more about how to turn our growing understanding of the genetics underlying rare diseases into meaningful advances for patients, and the challenges that need to be overcome in order to achieve this.

Roni: First of all, it's a very tedious and very long process to bring something from, even from a discovery in the lab where you already have a model, already have an understanding of how a mutation causes a problem in phenotype. Even when you have that understanding, it's still, you know, at least 10 years, probably more and there's a big argument about what sum, but probably around two and a half billion US dollars to bring this to a therapy that is on the shelf. And I'm talking about average because you have to take into account all those failures that will happen on the way. So it's a huge risk and it's very, very difficult and not everyone is able or willing to undertake this kind of risk of developing a therapy.

Kat: So how do we actually go from that knowledge of looking at a family, looking at an individual and saying, okay, so this genetic variant that is causing your rare disease to going to a treatment. Because this is kind of the dream, I suppose, of molecular biology. It's been something that I've always had in my mind. You find the genes and then you find the drugs and that's how it works. It's not that simple is it?

Roni: It's not that simple. There are a few stages on the way. Now, once someone undertakes that, of course there's many different routes to take and, you know, therapies can include things that treat symptoms or things that treat the problem in a more removed way or peripheral way. For example, very often, if there's a genetic problem that a particular protein either doesn't get produced or gets produced in an ineffective way. So the protein isn't functional. So for example, if it's an enzyme, one thing that you could do is develop an enzyme replacement therapy. In this case, patients would go to a hospital or to a clinical centre, let's say once every few weeks, once a month and get an infusion of an enzyme that is working and that they would have to repeat every once in a while. Now that is treating the problem sort of at the periphery at the heart of it. If you want to actually go and fix the problem, this is gene therapy. So you're basically, if you wish to use the analogy of like an engineered system, going back into the computer code and fixing the line that is wrong.

Kat: I think sometimes when people think about these kinds of rare genetic diseases, gene therapy is all they think about, but it's interesting that there are many ways to approach this. But gene therapy, I guess, is that really the dream? Is this where everyone is focused and has it stopped people thinking about more lateral ways to approach this problem?

Roni: Well, gene therapy is still very new. It's really been around only for a few years and still is facing a lot of hurdles. I think in the end, this is indeed the dream. This is indeed the method to approach these diseases at the heart of the problem. I even think that the dream in the end would be to have some kind of platform gene therapies. So rather than having to, so to speak, rewrite the code for every problem separately, find some kind of more general solution, but we're talking years, years down the line. I just am trying to think further ahead. I think the more bread and butter solutions such as enzyme replacement therapies, which have been for many years now, they're still going to solve a lot of problems in the shorter term. And I still think it's worth developing these directions.

Kat: And we sort of come at this point to the economics of it because, you know, disregarding the idea that there may be some more kind of plug and play platform, again, by their very definition, rare diseases are very rare. There's a very small number of people affected by each particular disorder, which is in a particular gene. So how do the economics actually stack up to make it even worth thinking about developing a treatment, any kind of therapy for such a small patient group?

Roni: So this is a problem that will always be around. This is going to hump the field by definition. And the problem is the math just doesn't work out. So you have a disease that affects several thousands of patients all around the world. You have the costs of developing a drug, which is probably two and a half billion dollars to develop a treatment. You divide one by the other and you get a very, very expensive drug that no payer can afford to pay. No public health system can cover. And only the very, very, very rich can have access to such a treatment if it ever makes it. One option is something called drug repurposing. And the idea is, you know, maybe a pharma company has started developing a drug for a particular condition, maybe a common condition, something like that. And in the end, this was abandoned for either commercial reasons or because it didn't show enough efficacy.

It may still be a perfectly good molecule for something else, maybe for a related, rare metabolic condition. This could still work. There is a drug that was developed and approved in France many years ago for vertigo and vertigo is not a rare condition and this drug is sold over the counter, but only in France. And it so happens that for a particular set of lysosomal storage disorders, for example, Niemann-Pick and Tay-Sachs, this drug has benefits. And this was found serendipitously because some neurologists here in the UK together with patient parents decided to try this for a tax year in children with these conditions. And it was found that this drug has benefit for these conditions.

Kat: So that's repurposing the drugs that are already existing and have been developed for other conditions. What are some of the other ways of approaching this problem?

Roni: One way, which is again, not new is to give, let's say certain incentives for companies developing treatments for rare diseases. And again, this is not new. So, the idea with the orphan drug act is to give companies first, all tax breaks, and second seven years of market exclusivity. If they develop drugs for a condition that has very, very few people, and that's actually how they defined an orphan disease in the US, that is how a rare disease is defined there now. And this has been used by many, many companies. Now, there are lots of orphan applications going on all the time and the orphan designation is very sought after because it's a huge help for the companies. So that's a second way. Then there's a third thing. So once a drug has been approved by a company, it needs to be approved by payers. And for that, you need to do a health economic assessment to see what benefits this drug gives patients and how much it costs and whether this is worth it for the health system to reimburse that.

Kat: Do all the maths basically.

Roni: Exactly. And that is a major hurdle that companies face even after approving a drug. So this is called the market access problem. And for Duchenne Muscular Dystrophy, again, a terrible neurodegenerative disease, affecting boys, life limiting, and a very, very cruel disease. Basically a patient organization here in the UK collaborated with several pharma companies - in the end nine pharma companies - to do a huge project called the Hercules project, an international project, that included making that data package for the disease to allow for health technology assessment. Now, these pharma companies are competitors among themselves, but they share a common interest in being able to make the case for Duchenne Muscular Dystrophy needing that kind of therapy. And they basically joined forces with the patient groups from several countries in the world. To me, it's the poster child of how patient groups and pharma companies should work together to tackle a problem.

Kat: So we've got these different angles, we've got the scientific research angle, sort of understanding these diseases, developing novel therapies. We've got the angle of repurposing drugs that we already have. We've got the angle of manipulating the financial aspects, you know, making it actually worthwhile to do it. And then finally involving patients in getting the data to get these approaches approved. So what really needs to happen next? Have you got a few things that you would definitely be like, that's my tick list to happen in the next couple of years to make a difference?

Roni: Yes, I have a tick list. So one of the major problems that rare diseases still face is what we call the diagnostic Odyssey. Typically, the way it goes is a parent comes with a child to the GP. Something's we don't know what the GP looks at the child and has no idea what is wrong because this GP may have come across the name of the disease once in medical school and never seen a patient since. And sure enough, they will not know what is wrong. So either they will not know and send them to a specialist, or they will come up with a diagnosis which is wrong. And even after going to the specialist, chances are the specialist will make a wrong diagnosis again, because it's a very rare disease. So the patient goes home with the wrong diagnosis. After a few months, something else appears, which breaks down that diagnosis. They go back. This ping pong can go on for a while. Again, for years, I know examples of diagnoses delayed 20, 25 years even, but the average is 4.8 years, and this is unacceptable.

Now this is improving because awareness is increasing, because tools are improving, but it's still unacceptable that diagnosis takes so long. So that's one thing that I would like to see improve. The second thing is just awareness. So awareness has improved. It's much better than it used to be, but it's still not high enough. And this is actually one thing that we at the Cambridge Rare Disease Network are working on nonstop. I have a fantastic example, which I will close with maybe of the previous CEO of the Cambridge Rare Disease Network. She had two children with Alstrom syndrome, again a terrible disease with multiple manifestations in different systems in the body. And she used to go to every single conference and present a poster about this condition. And one day in one such conference, someone from a company that was developing a treatment for another condition, not a rare condition, saw the list of symptoms on her poster and saw the fibrotic element - fibrosis in vital organs, which actually is the life limiting step in this condition - and realized that there could be used for their drug for this. And then the result was a clinical trial. So this is what I believe. These are the kinds of synergies that can be done from raising awareness and from making the right connections. And this is what we're trying to do at the Cambridge Rare Disease Network. 

Kat: Roni Jortner from Masthead Biosciences. RAREfest - the Cambridge Rare Disease network’s festival of arts and science celebrating rare diseases planned for the 28th November -  has understandably moved online this year. To find out more, head over to CamRareDisease.org or go to the page for this podcast at GeneticsUnzipped.com for the link to register for free. 

• RAREfest free registration

You’re listening to Genetics Unzipped - the Genetics Society podcast. Find us online at geneticsunzipped.com and on Twitter @geneticsunzip - and while you’re at it, why not tell a friend, so more people can discover and enjoy the show

Testing times

Kat: At the same time as we’re understanding more about the variations and faults in DNA that cause rare genetic conditions in order to treat them, there’s an increasingly sophisticated range of tests designed to help people who have these variations make decisions about whether and how they want to have children - or what to do about a pregnancy where a genetic abnormality has been detected in the fetus. 

This is a difficult and emotionally challenging journey to navigate, but there are people like Kira Dineen to help guide the way. She’s a New York-based prenatal genetic counsellor working with people going through a pregnancy or trying to conceive, and is also the host of another podcast about genetics, the excellent DNA Today. I started by asking her to describe some of the tests that are now available for her patients.

Kira: There are so many tests now, we're coming from a place where we used to offer invasive procedures, and that is something that we still continue to do, but less people are going through these procedures because of the new technology we have. Some of that new technology is carrier screening - so that's identifying if someone is a carrier of a condition or they have a change in their genes that doesn't affect them, but if their partner also has that change and their child inherits both of those changes from both parents, then they could have a condition from that. And so carrier screening is something that has been offered, but now we have these very large what we call 'panels'. So we're looking at sometimes 273, for one panel I'm thinking of, that's how many conditions we're able to screen for to say, are you a carrier of this condition and your child has a chance of inheriting this, even though you're a healthy individual. There's also screening that is actually taking a blood sample, just like we do for carrier screening, but a blood sample from the pregnant person. And we're able to actually isolate fetal DNA that is floating around in this pregnant person's bloodstream, it's coming off of the placenta and we're able to isolate that and look at that and say, do we see any genetic changes? And a lot of this we're looking at aneuploidies. So do you have an extra or missing chromosome like in Down's syndrome? So we're actually being able to look at the DNA for that.

Kat: And I guess now we're seeing the rise of these techniques, like you mentioned, where you can look at a sample of the mother's blood and look for the presence of fetal cells and fetal DNA and access to that much more sensitive DNA sequencing techniques. I mean, what kinds of conditions can we pick up?

Kira: So when we're talking about the blood tests where the pregnant person has a blood sample taken, we're still talking about that high to low risk area. So we're getting a risk level for that. But in terms of what these screening tasks are, these blood tests are looking at with risk level, we talked about Down's syndrome, but there are other chromosome abnormalities that it can look at. So looking at the sex chromosomes, there's something called Turner syndrome, Kleinfelter syndrome, where women tend to have XX and men tend to have XY but sometimes we can see changes there that can lead to genetic disorders. And so that's something that's picked up along with other aneuploidy. So for Down's syndrome, this is trisomy 21. So instead of having two copies of chromosome 21, you have three copies. And so there's other trisomies that are also looked at, but the difference is that with this cell free DNA, we're looking also at micro-deletions. And so something like DiGeorge syndrome is fairly common. And so we're able to see, are they at a high risk for having this by looking at the DNA? And so there's a lot of microdeletion syndromes that we're able to look at, and this is a newer area. So this test started being offered in 2011, 2012, around that time. And so over time, we've been able to add more conditions to this, to be able to have patients have more information in terms of not just the chromosome abnormalities, but also the chromosome aneuploidies, or having too many or too little chromosomes, but changes within the chromosome. So with DiGeorge syndrome, we have a deletion on chromosome 22. So we're looking to see if that deletion is there or not in the screening.

Kat: So we've sort of got a picture of various types of tests. So people who want to become parents can have carrier screening to see if they're likely to have a child that carries a genetic disorder. Then you get onto the screening that you can have while someone is pregnant. So you're looking for either the fetal cells or fetal DNA in the blood, or then this sort of more invasive amniocentesis or placental testing. But all of this at every step, I guess, we can get very carried away with all the precision of the tests and the number of genes, things like this. This is real people trying to make really difficult decisions. So how do you start engaging people in this process? You know, why would someone come to you as a genetic counselor? What do they want to know? And how do you start engaging them in what's actually going on and what it means for them and their prospective family?

Kira: So it really depends on where they are in the parenting journey. If we're talking about preconception, so they're not currently pregnant, but they're planning on becoming pregnant, carrier screening is one thing we talked about where this gives information so that if we are able to identify that someone and their partner are both carriers for condition, they have a lot of options at this point to say, would they like to conceive naturally and see if their child would be affected by this condition? Most carrier screening is identifying that both parents are a carrier of a condition. And so their child would be one fourth risk of having and being affected by that condition, whatever they're a carrier for. And so if that is something that they wanted to look at other options, there's a lot of PGT, we call it preimplantation genetic testing. And so we're able to take embryos created in the laboratory and test them to say, is this embryo affected by the condition?

And so doing that, we can pick the embryos that are not affected by the condition that will be healthy from this condition specifically. And so looking at that couples have the option of then choosing those embryos to implant. So at that point in the process of their preconception, there are so many options and obviously a lot of pathways to parenthood there. And so that's just one of them. And carrier screening is often done as well when someone is pregnant to have some of that information. And if someone is pregnant, there are a lot of options as well of learning about the health of their child in terms of these conditions, so that they have options at this point in pregnancy, if they would like to continue the pregnancy and if so, learning about that disorder ahead of time, possibly lining up specialists that if we know that the pregnancy is affected by a certain condition, we can say, well, we know right away, they're going to need to see a cardiologist.

So starting to explore that and saying, okay, what cardiologists can we line up? And so being able to have a lot more options and also mentally prepared is something that a lot of people are able to do during pregnancy if we are identifying this ahead of time. And as I said, there's also the option to not continue a pregnancy. And so with all of this information, this is giving the patient much more to make a decision on these. And as time goes, we have more and more decisions because of the technology that we have. So there's a lot of information, and that's why it's really advantageous to meet with a genetic counsellor, to go over all this and see how it applies to a person specifically.

Kat: It does seem with all the different technologies and all the kinds of tests that can be done, it's quite a complex road ahead. And, and also I think this idea that even though we have so much technology now, we don't necessarily have all the answers. I have an example. I have some friends who were both carrier screened for cystic fibrosis, and it came back saying, no, you don't have the cystic fibrosis mutations. And their child had cystic fibrosis because they had mutations that just weren't in the panel that was being tested for. So, you know, I think it's this idea that as well, if you do have certain genetic changes and pass them onto the child, that you can't always predict the outcome as well. You know, many of these conditions are a sort of a spectrum. And how do you sort of start to explain that? I always sort of talk about that there's many a slip between genotype and phenotype, just having a genetic variant isn't absolutely predictive of what the outcome's going to be.

Kira: Yeah, that's a really good point. And I think that also points out a limitation of our genetic testing that no test is perfect, but that it is important to see what kind of test is being done, and what does it look at? A lot of these panels as we're referring to them are looking at certain genetic changes. They're only looking for those. They're not looking at any change that could be there, but it is something to talk about with patients and for people to understand the limitations in that, especially when we're talking about screening - it's screening, it is not a diagnostic test. And I think that's a really important concept for people to understand the difference between that, of looking at a risk level versus looking at, do you have a condition or not, or could you pass on a condition or not? And so this is information that, you know, in genetic counselling, we're able to sit and really talk through and understand and talk about how this affects a person specifically.

I think one thing to mention with this is that, especially with panel testing, unfortunately we do have a disparity in genetics where some of the panel testing, especially as you mentioned for cystic fibrosis, is pretty good at picking up genetic changes for people of European descent. It is not as good at picking up genetic changes in people that are of non-European descent. And so there's really this disparity in genetics that is slowly being addressed, but needs to be addressed more to be able to offer more accurate information to all people and not just people that are of European descent.

Kat: Yeah. I think that's such an important point. And I'm also interested in that as more research comes out of genomic sequencing programs. So I'm thinking, for example, at the Sanger Institute, they have the developmental disorders program where they're just gathering many, many, many families, parents and children that are affected by developmental disorders of genetic origin and identify more of these variants, more of these genes that are tied to these changes. So how can we see that feeding through, into the tests? You know, are we going to ultimately see whole genome sequencing being done on cell free DNA from maternal blood? Where's this going to end?

Kira: And I can certainly see that that is where we're headed. I think in terms of now that we've been doing the cell free DNA blood tests for years now that there is a move to be able to look at more and more. So, as I mentioned, the different conditions that that test can look at, but as we add more and more and get closer to doing whole exome or whole genome, that's definitely a possibility. But one thing to think about with that is when we're looking at this free DNA that is coming off the placenta and floating around in the pregnant person's blood, we're looking at little pieces of DNA here and there and kind of putting it all together. So it's definitely difficult to be able to do that and get a full picture, but as technology increases, that's something that I can definitely see possible in the near future of looking at doing whole exome from this fetal DNA that is floating around and we're able to isolate because we have to isolate that from the pregnant person's DNA and saying there's two different sets here and which is which, so it definitely becomes difficult, but something that is definitely one that we may be seeing in the near future.

Kat: Yeah. I think it also is interesting that the more we find out, the more complex this gets, and you start to get into the territory of, well, what is a disorder, and what's just like a version of normal? And I'm interested in the psychology that, particularly as well, if there are families who are already affected by conditions and they say, well, you know, we've learned to live with this and our family, and we don't want to end a pregnancy if we discover that there's this particular variation or change,. So how do we live with this as a society and as individual couples about the psychology of where this starts to take us?

Kira: It is interesting, especially if someone has someone in their family that has a condition that their pregnancy also has. They may have a different perspective than someone that has no exposure to this condition, and it's very foreign to them. And so it's important to think about, especially in genetic counselling of where the patient is coming from and what their experience has been so far, particularly if they themselves have the condition. A lot of genetic conditions like autosomal dominant conditions, where if the person has it, they have a 50% chance of their child also having this. So flip of a coin. And so that's something to explore in that that's going to be in their mindset when they are making decisions about pregnancy. And you also have the dynamic of if the person has a partner of what their thoughts are, and being able to, in a genetic counselling session, bring in both of their perspectives and have that conversation so that is explored and people are being heard and thought through because we have all this genetics, but when it comes down to it, it is really affecting people's lives and how they are understanding this information and how it applies to them and their families specifically, especially if other people in the family, again, have a condition and how that may have affected their family and made it a little bit different. And so these are the kind of concepts that we explore in prenatal genetic counselling and seeing where the patient's at and what questions they have around this.

Kat: It's sometimes we get this impression with the kind of genetic counselling, particularly around pregnancy, that it's very difficult and it's very painful, but are there ways that people do find kind of peace and answers? Obviously, there's going to be people who have positive outcomes from this and difficult outcomes from this. So how do you feel about working with families? You know, what are the highs and the lows that you experience as a genetic counsellor in this area?

Kira: Certainly. And so think with this it's that, as you mentioned, oftentimes we are able to come up with an answer maybe to something that they have been struggling with. So I think of couples that have been trying to conceive for many years and are not able to do so, or they've had multiple miscarriages. And so if we are meeting with these patients, we may be able to offer them genetic testing to see if there is a genetic reason for this. And so in those cases, sometimes we're able to identify what that reason is. And that can be really good information for someone to have, not just to know, oh, this is why it's happening, but also emotionally to know, okay, it's nothing that I did. And so there can be a lot of guilt surrounding this. And so being able to identify and say, this is what we found, and this is more information about this, and now here are options so that if you want to continue trying to conceive, and here's some ways that you can do this now that we have more information. Now, we're not always able to find this information, but when we do it can be really gratifying for patients to have an answer because the unknown can be really scary. And once you're able to identify that you're able to have a conversation around it. And there is a center point in that conversation.

Kat: And just coming back to your own journey as a genetic counselor, I mean, what does drive you? You've talked about being able to find answers for people, being able to help them on their journey towards having a family. What's been the real driver for you in choosing this career?

Kira: I think for me, I've always really liked educating people about genetics. I've been doing it on my own show for years. And so being able to do that at a patient level has been very satisfying to be able to help someone in their journey, whether that be previously as a student in different areas, but now that I'm a new graduate, I'm able to meet with patients on my own and, and help them to understand their genetics and kind of that 'aha' moment. Genetics is very complex as listeners are learning, and so being able to break that down so that patients can understand it, no matter what their background is, is really exciting to be able to reach someone and be able to answer the questions they have. And so I think being able to educate on that one on one level is really exciting and it's a very rewarding career and area to be in. So definitely highly suggested for people that are interested in genetics.

Kat: Genetic counsellor Kira Dineen - and if you can’t get enough of genetics podcasts in your ears, do go and check out her show DNA Today - go to dnapodcast.com, search your podcast app, or grab the link from the show notes for this episode at GeneticsUnzipped.com.

In search of sponges

Kat: And finally, it’s time for a quick look at what’s in the latest episode of the podcast from Heredity, the journal of The Genetics Society. Host James Burgon speaks with a couple of marine biologists who voyaged across the Caribbean in search of a poorly understood organism – the vase sponge - that was dying in massive numbers. Here’s Dr Sarah Griffiths from Manchester Metropolitan University and Prof. Donald Behringer from the University of Florida to shed some light on this much maligned species.

You can find the full interview in the latest Heredity podcast - just search for Heredity in your favourite podcast app, or follow the link on the page for this podcast at Geneticsunzipped.com.

That’s all for now. We’ll be back next time with more from the world of genes, genomes and DNA - and before that, there’s another bonus episode of Genetics Shambles to fill your ears.

For more information about this podcast including show notes, transcripts, links, references, music credits and everything else head over to geneticsunzipped.com You can find us on Twitter @geneticsunzip and please do take a moment to rate and review us on Apple podcasts - it really makes a difference and helps more people discover the show.

Genetics Unzipped is written and presented by me, Kat Arney. It is produced by First Create the Media for The Genetics Society - one of the oldest learned societies in the world dedicated to supporting and promoting the research, teaching and application of genetics. You can find out more and apply to join at genetics.org.uk  Our theme music was composed by Dan Pollard, and the logo was designed by James Mayall, and audio production was by Hannah Varrall. Thanks for listening, and until next time, goodbye.

• Roni Jortner: Founder and CEO of Masthead Biosciences and trustee of the Cambridge Rare Disease Network. @camraredisease #RAREfest20

• Kira Dineen: Genetic counsellor. @KiraDineen @DNApodcast

• S. Griffiths et al, Oceanographic features and limited dispersal shape the population genetic structure of the vase sponge Ircinia campana in the Greater Caribbean (2020) Heredity

• Behind the paper: How sponge mass mortalities in Florida led us on a Caribbean sponge-hunting odyssey 

• Image Credit: Genetic modification. Guy Tear. Attribution 4.0 International (CC BY 4.0)