Gene genie: New therapeutics are unlocking our biological blueprint to help the body heal itself

There are few neurodegenerative diseases as devastating as Huntington’s. It’s sometimes likened to having Parkinson’s, ALS and Alzheimer’s all at the same time, with symptoms that include progressive motor dysfunction, cognitive decline and behavioural change. It’s also hereditary — if a person has the faulty gene that causes the disease, there’s a 50 percent chance their children will have it, too. In the fall of 2025, however, scientists announced that, for the first time, they could reduce the progression of Huntington symptoms using a new gene therapy. While that clinical breakthrough came with several caveats, it also heralded a possible new paradigm for drug discovery. In this episode, we explore how this innovative therapy works and what it could mean for the treatment of other rare diseases.

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Narration: You hear the word breakthrough a lot, but what does it really mean? That question runs through all the episodes we work on — what counts as a breakthrough. The idea behind today’s episode came from my producer, Ellie, and it’s a really fascinating one. I’ll let her explain.

Ellen Payne Smith: So I was digging through some of the biggest stories from the past year, and I came across this one from September 2025, about a trial for a new genetic therapy, a one-time treatment for Huntington’s disease. Now, Huntington’s is described by doctors as a rare, neurodegenerative brain disease. It brings on mood changes, trouble with movement. The decline is quite devastating and ultimately fatal.

Manjula Selvarajah: Hmm.

Ellen Payne Smith: And what’s especially cruel about this is just how it affects families. If a parent has it, there’s then a 50/50 chance their kid will have it, too. And so it means if these results hold up, this could make it the first time ever that doctors have been able to slow down or treat Huntington’s disease in patients.

Now, it’s still very early. There have been recent regulatory challenges. And it’s worth pointing out: gene therapies, once approved, are known to come with some very high prices. So there are some real caveats to get into. But it was a big moment for the field, and it’s got scientists excited because of what it could open the door to.

Narration: I’m Manjula Selvarajah and this is Solve for X: Innovations to change the world, a series where we explore the latest ideas in tech and science.

To really understand what’s behind this breakthrough, and what this could mean, Ellie and I spoke with Huntington’s disease expert Rachel Harding.

Rachel Harding: I remember exactly where I was when I read those results. Because I actually received the results under embargo about 14 hours before they went public. And so I had to sit with this news and think about how we were going to communicate this to the broader Huntington’s communities and all the families who would be impacted by this.

Narration: Rachel is an assistant professor at the University of Toronto and a principal investigator at Structural Genomics, a global research group focused on open science and drug discovery. She studies proteins at the molecular level, searching for clues that might one day lead to new treatments. And while she wasn’t involved in this study, she’s been following the results from last year very closely.

Rachel Harding: A really important thing is to possibly start with the caveats. Like the data from that trial is for an experimental gene therapy. But because it’s a gene therapy, it could only really be given to a very few people at the very beginning. And it’s also really difficult to think about how do you control, and so they used an external comparator group. Which basically means they collected data from lots and lots of people with Huntington’s disease who weren’t being given the drug and kind of averaged it out to see what it looked like. And so some people have reservations about that. But nonetheless, the data that was reported in the press release from this company, uniQure, for their drug, AMT-130, suggested for the first time that it was possible to slow down the progression of symptoms of Huntington’s disease.

And this is something that no one has been able to show before — in a big trial, in a small trial — with any other type of therapy. It was a really exciting moment, and I know it offered a lot of hope to people at the time.

Manjula Selvarajah: Now the technology, I think it’s sort of like silencing the gene? I don’t know if that’s the right language, but can you explain the technology behind the treatment?

Rachel Harding: Yeah, absolutely. So this gene therapy is delivered by a special type of brain surgery. It takes about 12 hours to do. What happens is that the drug, which is packaged in a harmless type of virus called an AAV — or adeno-associated virus number five in this particular case. Packaged up, and it’s injected into one of the deepest parts of the brains of people with Huntington’s disease. So in this case, it’s a part of the brain called the striatum. And there the virus can get into cells and it releases its package and contents. And essentially what’s inside is something called a micro RNA. And when this happens, that RNA message gets turned over, and so the protein isn’t made as much, and so we reduce the levels of the huntingtin protein that are made just in this part of the brain. So, yeah, pretty cool technology.

Manjula Selvarajah: Now are we talking about actually curing the disease here? What could it do for patients and the patient community?

Rachel Harding: Yeah, so I think we have to be very careful in how we think about this. You know, the limited data suggests there’s a possibility we might be able to slow down how fast symptoms progress. You know, Huntington’s is very similar to some other neurodegenerative diseases, where over time the symptoms just get worse and worse and worse. So if we can extend time for people, give them more time with their families and loved ones, or in work, or doing all the things they love in life, then that is still an amazing breakthrough and a huge achievement for the field.

Manjula Selvarajah: Why is this so significant, this development for scientists who are watching this space closely?

Rachel Harding: You know, there’s never a competition between who has the worst disease, but most neurologists would agree that Huntington’s is one of the most devastating. So there is a really urgent need. Any glimmer of hope is fantastic. And I think the results from uniQure offered that hope. Not only just for their drug, but for this approach of reducing the amount of this huntingtin protein that is being made.

There are many other companies waiting in the wings or already in clinical trials, and so we’ve got this amazing competition in this space and it feels tangible. Like it feels like things are really changing. And so it was really the first domino falling in terms of how we shift our mindset of what we think about this disease and the possibility of treatment.

Manjula Selvarajah: Now, does that mean that people could use the same kind of technology, the silencing treatment, to approach other diseases?

Rachel Harding: For sure, a huge number of diseases are all related to what we would call autosomal dominant gain-of-function. Which is the fancy genetics way of saying that these are clear things where you’d want to switch it off if possible. You can imagine thinking about how you could repackage this technology and these ideas and then apply it in other use cases. And certainly uniQure, who developed this particular drug for Huntington’s, other companies who are considering similar technology will be doing that or are already doing that behind the scenes.

Something that I think is interesting, and that we have to remember, is that it’s taken uniQure a long time to really carefully test this drug in all kinds of different animal models and then in lots of safety studies. Like you don’t just put a drug that’s a permanent change to someone’s genetic code into someone’s brain through a very arduous surgery without being very careful and very cautious.

What’s really interesting is that actually the technology they’re using is from quite a long time ago. And you know, I look around at all these conferences now, and people have better versions of these viruses or better ways to deliver these kinds of payloads of drugs. So it’s kind of like, yes, the uniQure idea could be applied elsewhere, but actually there are whole new ventures of technology. Which is even more exciting in my opinion.

Narration: This is groundbreaking stuff. New gene therapies, along with recent advances in CRISPR gene editing, are opening up possibilities for rare diseases and conditions that were once untreatable — often in just one treatment. And while the idea of putting a virus into the body might sound odd, viral vectors have actually been used for decades to help deliver gene therapies.

Think of them as tiny delivery vehicles, carrying instructions to cells, getting them to behave or express genes differently. What makes this approach particularly innovative, though, is how it targets parts of the brain that are otherwise difficult for medicines to reach.

Manjula Selvarajah: I wonder: are we entering a new era for disease treatment?

Rachel Harding: I think the days of traditional therapies, of trying to find small molecules for a target that you thought would or would not change, you know, how disease symptoms arise is still a very active part of drug discovery. But there’s so many new technologies. We used to think about having to design a drug for every single disease individually. And one of the really exciting things about these new technologies is that there’s the opportunity to test-run an idea or test-run a new technology and then potentially having the opportunity to almost copy-paste and take it from one rare, or one genetic, disease to another. So once we see that some of these technologies are working, we could be in this explosion of therapies, of new ways that we could treat diseases without having to do all that startup investment. It could be really exciting and move things much more quickly.

Manjula Selvarajah: I find it interesting that there’s all of this movement, all of these innovations that are happening. But I get the sense that there’s still a lot of unknowns in the science side of it. Can you give me a sense of sort of some of the mysteries that you’re chasing, some of the molecular mysteries that you’re chasing?

Rachel Harding: Yeah, certainly. I mean, I think, you know, one thing that with new technologies, we have to be really cautious in terms of how we might think that they could be used for treating people. Like, we have to be so careful, particularly when we’re making permanent changes to someone’s, you know, genetic makeup or you know, how their body works. That’s something that you need to approach with absolute caution. The other thing that is interesting and complex about many rare diseases is, we have known for some of these diseases, for example, in Huntington’s and this class of repeat expansion diseases that it comes from, many of the underlying mutations for those diseases have been known for in excess of 30 years now. These are some of the first disease-related mutations that were ever mapped.

And, even with that information, and even knowing exactly what has changed at the genetic level, understanding how that gives rise to disease is really tough. And it’s something that has been really complicated and difficult to try and understand. And that’s why people like uniQure took the approach they did — is that you don’t have to worry about the downstream biology if you just target the thing that changes at the beginning. But that doesn’t mean there might not be consequences that we haven’t understood yet. So we have to be careful — it’s not always as simple as switching this thing on or off to make everything better.

Manjula Selvarajah: So it’s interesting that people are innovating even though they don’t sort of have a blueprint for what they’re working with.

Rachel Harding: If you went to a Huntington’s disease conference and you asked 10 people in the room, where do you find Huntington in a neuron, you would get lots of different answers. And what does Huntington do in the cell? They would probably give you different answers as well. It’s because the biology is very complicated. And something that I think is really interesting is that there’s parts of the results of these human trials that will answer things that in the lab are much harder to understand. And so there’s actually, I was just at a meeting where we were discussing that it’s kind of amazing that we will have answers about some aspects of the biology of specific protein molecules based on the outcomes of clinical trials, probably faster than we will be able to figure it out in the lab. So that’s kind of amazing as well.

Narration: It’s incredible to think that tiny changes at the level of proteins can add up to have such a huge impact on our lives. And that outcomes from clinical trial data could advance our understanding of some of the more elusive parts of our biology. Now, it’s one thing to try to imagine these molecules. My producer, Ellie, asked Rachel if she can show us what they look like.

Rachel Harding: Sorry, would you mind passing me the orange and white thing. That’s actually the huntingtin protein.

Narration: Rachel held up the huntingtin model, blown up millions of times its real size.

Rachel Harding: I love 3D-printed proteins because they allow you to really appreciate and understand like all the nooks and crannies and spaces and sort of contortions of these kinds of molecules. And I always bring this to any meeting I go to with HD — Huntington’s family members — so that they can see that I’m like, this is it, this is the protein that has changed in your body, and this is what we’re studying.

Narration: Her lab uses cryo-electron microscopes to see layers of single protein molecules, and from that they build up a 3D picture of its structure.

Rachel Harding: I always think of it as like a bao bun, with, like, filling in the middle. It kind of, like, wraps around…

Narration: Looking at the model was kind of like staring at a Rorschach test. Rachel saw a delicious bao bun. Meanwhile, Ellie saw something quite different.

Ellen Payne Smith: It’s so complicated, though. It looks like coral, like when I go snorkelling or something.

Rachel Harding: It does look a bit like coral.

Narration: Rachel explained, that coral is actually quite a useful analogy for thinking about how complicated things are in cells. Much like a coral reef, everything is interconnected.

Rachel Harding: I think the complication is that looking at a single protein in isolation is actually not as difficult as understanding, in the complexities of a cell, how does this one molecule do all the things that we think it’s doing, right? That is the bit that’s really tricky and really difficult to understand. And how do the changes in the shape of that molecule confer different things in the cell? Like that’s what we are really trying to figure out and pin down. And that is tough.

Manjula Selvarajah: Tell me if I’m pushing things a little when I say this, but it sounds to me like understanding the 3D shape of that protein could actually help researchers discover less invasive methods of treatment. Am I out there when I say that?

Rachel Harding: I would have to agree with you. I think that gene therapies are amazing innovations and they open the opportunity to drug the undruggable. There are lots of things where you could imagine you couldn’t make a pill, you couldn’t make a small molecule drug to target what you need to do to get benefit in a specific disease.

But there are also cases where gene therapies kind of demonstrate proof-of-concepts and they can be a clean way to show that changing one specific target or changing one specific protein does give benefit. And I think this is the excitement that came from the uniQure data — that if this shows benefit, are there other approaches that we could take in the clinic with different types of drugs or different modalities that would give the same outcome?

And so currently chasing these ideas are folks like PTC Therapeutics and Skyhawk Therapeutics, both of which make splice modulators — a different way of reducing the level of the huntingtin protein — but both are oral pill drugs. So you could imagine they also have their own liabilities, their own issues. But you can imagine that would be much more attractive, potentially cheaper and more accessible for people. And this is something that I think about a lot in terms of these communities who are impacted by many of these rare genetic diseases. They don’t have access to a clinical neurologist to even diagnose people in a lot of cases, let alone be able to get access to a gene therapy. It’s not accessible to everyone. It’s good to have those therapies and I don’t think we should stop developing them, but we also have to be mindful about treating the whole community as well.

Manjula Selvarajah: I mean, that’s the other thing, when you talk about things that are, you know, 12 to 18 hours of surgery, you’re talking about all of this equipment… At the end of the day, you might have that, but it might not be accessible to communities around the world. Is that something that you worry about? Whether these, gene therapies and, and breakthroughs that sort of make the news definitely exciting, but, you know, are they accessible?

Rachel Harding: I think the accessibility is a big issue and something that, you know, we think about a lot. I think there’s also complicated aspects of the market forces around how these drugs stay profitable enough on the market for the companies to keep selling them, right? And there’s been examples of gene therapies, which we know absolutely seem to confer benefit for patients, but they don’t stay on the market because it’s actually not cost effective to deliver them or to manufacture them, or you know, other things. So we have to be really careful about the promises we make to these communities when we are communicating this kind of information.

Narration: Rachel brings up a really good point. There’ve been examples where science proves it can achieve amazing things, but the market has its own rules. Take for example, the world’s first approved AAV gene therapy, Glybera. This was targeted at a rare genetic condition that causes severe pancreatitis. The therapy was a huge milestone developed in part from research out of the University of British Columbia. And for patients it was life changing. Even so, the drug company decided that it wasn’t financially viable. They withdrew it, citing the high cost of producing the drug and the small number of patients.

Rachel Harding: These are all different aspects of the drug discovery pipeline. It’s not just about the science and the invention, the technology, the results of the clinical trial. It’s about that management afterwards. So how are we doing large scale manufacturing? How are we going to set up clinics to do all this stuff? You know, how are we going to ensure access for as many people as possible at a price point that makes sense for either government healthcare systems or for private payees. It’s a huge part of the equation.

Manjula Selvarajah: I mean, that’s the other thing that I was thinking about, whether healthcare systems are ready for all of these new treatments. You think they are?

Rachel Harding: I would like to hope so. I mean I think it’s a bit out of my expertise, but my suspicion would be that, you know, for therapies like this to become mainstream for many different disorders, you know, there would probably have to be significant changes in many hospital settings to ensure that patients had access to the best possible care that they could access.

Manjula Selvarajah: Now you’ve talked about some of the work that you are doing with Huntington’s. Can you talk to us about some of the other treatments that your team is exploring? I heard that some of it was around contraception and fertility.

Rachel Harding: Yes. These might seem like very unrelated areas of drug discovery. But I like to think of them as sort of areas of neglected understanding and therapeutic starting points. So for us, you know, rare diseases fit one side of that category. The other one is women’s health, which I think many would agree is an underserved area of therapeutic development. So we are really fortunate to be partnered with, and working with, the Gates Foundation on a new project thinking about non-hormonal contraception. And so this particular project is super interesting biology. We are looking at proteins only made in sperm. And not only are they only made in sperm, but we know from infertility clinic data and genetic studies, if you have changes in these particular proteins, then folks can often suffer from infertility and that can be, you know, that’s basically how these data sets have arisen. And so the idea is we would want to target these proteins. These proteins don’t exist in women except for when there are sperm around in the female reproductive tract. And so, therefore, you could target them with no changes — hormonal, you know, patterns and cycles. But it would stop the sperm from working properly.

So it’s a pretty radical idea and super interesting and we’re uncovering all kinds of cool biology along the way as well, which is really interesting. I think many folks don’t appreciate that after the discovery of birth control, all the way back in the sort of ’50s and ’60s, there wasn’t really a lot of funding to work on reproductive biology. And so there’s some really basic questions around sperm-egg fusion and the precise molecular mechanism by which that happens, which we don’t really know. And I find that so interesting because I had always assumed, you know, as a female scientist, the reason that we didn’t know anything about women’s health was because the male scientists of yesteryear were spending all their time thinking about diseases and things that affected men. But turns out they weren’t looking at male fertility either. So, yeah, there’s like a lot of new areas of biology that we can look into, and it’s been lots of really exciting discoveries along the way, which is super fun.

Manjula Selvarajah: Now we’ve been talking about some really cool breakthroughs through our conversation. But I start to wonder, now what? I mean, there are some cautionary tales from earlier gene therapies, and now we’re also seeing new CRISPR-based therapies entering the market with huge price tags like the one for sickle cell. I think it’s called Casgevy. I could be saying that wrong. You know, when you hear these stories, what lessons do you think we should take from these experiences?

Rachel Harding: Yeah, I mean, I think there’s many aspects of this, right? And I think some of this needs to come from the top down as well. You know, the scientists are busy in the lab making discoveries. Many of these patient communities are really well organized and ready to go for clinical trials. And the kind of infrastructure that we need and the regulations that we need kind of aren’t quite yet in place. So there is a new paradigm that I think needs to happen, and this kind of comes from the government, right? They need to think about new ways that they can ensure all this work and innovation that’s being done in rare disease drug discovery is really having the impacts that it needs to within, you know, the general population and for the public.

Manjula Selvarajah: But what do you think needs to change then?

Rachel Harding: Oh, boy.

Manjula Selvarajah: I mean, if we have all of this fabulous work that’s happening. [laughs] In one minute or less. No, but what do you, I’m curious, what do you think needs to change?

Rachel Harding: The cost of some of the drugs is just, like, just breathtaking.

Manjula Selvarajah: When you say breathtaking, what are you talking about?

Rachel Harding: You know, so we are talking in the order of just millions and millions and millions of dollars per patient, right? So, if you were lucky enough to have access to Casgevy, you know, you would have a price point in the order of two million. And that’s actually a little bit on the lower end compared to some other drugs. There’s a cost benefit analysis as well that health agencies and drug approving agencies in different countries have to make in terms of the cost of long-term care and other health infrastructure support and so forth. But nonetheless, these are still extremely expensive and it’s a whole new paradigm.

Manjula Selvarajah: The other thing I worry about is also this idea that sometimes I hear about treatments and the focus isn’t on worldwide access. Meanwhile, in some of these diseases, actually, the effects are felt in other places.

Rachel Harding: Yeah, that’s a great point. The identification of the Huntington’s gene came because of a community of people really heavily impacted by it in Lake Maracaibo in Venezuela. And this is a community of people who helped lead the discovery of the gene and helped spark all of this research in Huntington’s drug discovery. But those folks are not involved in any trials. They will almost certainly never have access to a uniQure gene therapy or many other therapies unless we take significant action. And I think that kind of inequity is not uncommon. And we’ve got to be really mindful that often a lot of genetic research is done in communities who will then never benefit from the downstream impacts. And that’s something that definitely needs to be addressed.

Manjula Selvarajah: From your perspective, what could the next decade of molecular medicine bring?

Rachel Harding: Oh, wow. I think to look forward, you sometimes have to look back. I think about the first Huntington’s and rare disease meetings I went to 10 years ago. And at the time I was sitting in this meeting, we were being shown clinical trial data of people being given vitamin therapies to treat a neurodegenerative brain disease. And I remember thinking, this is bananas. Like how is this ever going to work? Is this the best that we have for all these people?

And now you sit here having just come back from my 10th meeting in this space, and we’re surrounded by people who are doing CRISPR, they’re doing gene therapy, they’re doing splice modulators, they’re doing different types of genetic-based approaches to treat people with Huntington’s disease. I could never have imagined that it would’ve exploded in the way that it did over the last 10 years. It’s just incredible.

And so it kind of gives me so much hope that I don’t think I can even imagine, in many ways, what is going to happen in the next 10 years to come. But what I can tell you is the investment is there at that level of the discovery. We’re in this kind of exponential growth curve, and it’s going to be really exciting to watch what people do.

Manjula Selvarajah: When we look at the future and we see all of this promise, how do we define cures here? Like, what would be considered a cure?

Rachel Harding: For people of different diseases, that could potentially be a bit of a loaded question. You know, you can genetically have Huntington’s but not actually get outward symptoms until you’re middle aged. So you know, at what point do you become a patient? And I think that’s an ethical and logistical and logical question that I think not everyone has the same answer to. But I think a cure for many people would be, you know, in the case of Huntington’s would be like removing the genetic change that means that someone has Huntington’s throughout their body. And that is, again, an ethical quandary about whether that is appropriate or whether that’s real. And so I think that’s something that, moving into the future with different gene therapies and you know, DNA editing approaches, there’s not only the difficult science, the difficult clinical trials, difficult regulatory and commercial processes, there’s also a lot of ethical questions that we’ve got to really sit down and think about. Where are we happy to take this to and what are the end points that we decide are or are not appropriate?

We’ve already seen this with CRISPR-based approaches where, you know, there were children born in China who had received CRISPR editing and that was received with very mixed reviews around the world. And so these are discussions I think we really need to have. And again, you know, sorry to harp on, but I think this is not something that will be the same for every disease.

I know for many people having your identity as being from a Huntington’s family is actually very important for a lot of people. That’s part of who they are and how they live their lives. And as much as they want treatments, there are also studies that show that people with Huntington’s actually have genetic benefit in some way. That there’s a reason that this mutation has persisted through evolution. So we have to be cautious in how we approach this. But nonetheless, I think everyone is hopeful of the ways that these kind of interventions could lead to reduced suffering, so that people have all the best options available to themselves and their families in their lifetimes.

Manjula Selvarajah: Rachel, thank you so much. It’s been such a pleasure speaking with you.

Rachel Harding: Thank you. Manjula.

Solve for X is brought to you by MaRS. This episode was produced by Ellen Payne Smith. Lara Torvi, Sana Maqbool and Sarah Liss are the associate producers. Mack Swain composed the theme song and all the music in this episode. Gab Harpelle is our mix engineer. Jason McBride is our senior editor. Kathryn Hayward is our executive producer. I’m your host, Manjula Selvarajah. Thank you for listening in.

llustration by Kelvin Li; Image source: iStock