Taking Control Of Your Diabetes® - The Podcast!

Hello and welcome to this edition of the Taking Control of Your Diabetes podcast. I am one of your hosts, Dr. Jeremy Pettus, joined as always by my good friend and colleague, Steve Edelman.
Now, if you're just tuning in, Steve and I are both endocrinologists. We both see patients with diabetes, have done research in diabetes, and we both have had type 1 diabetes since we were 15. Steve just got it about 20 years before me. We also work for Taking Control of Your Diabetes, the not-for-profit that Steve founded 30 years ago. We're going to have our 30th-anniversary party—what are we calling it? Fund-rager!—coming up to celebrate that on October 10th.
Alright. In this episode, we have a very unique topic, which is gene therapy and how it pertains to diabetes. Steve and I are going to set this up, but I wanted to lead with the punchline: we're going to go through what gene therapy is and what kind of diseases we're using it in, but we're going to get to a place where this is here and now for diabetes. Ultimately, we’ll be informing everybody how we can use gene therapy to have people's own bodies make insulin with a one-time therapy. So stay tuned, because that's where we're going to end up. By the end of this, you're going to be experts on this topic.
Steve and I were talking about how this is one of those rare topics in the diabetes world that nobody knows anything about—providers and patients included. When I was telling you about gene therapy a month ago, you kept calling it islet cells and things like that. So I've had to educate Steve a lot. So Steve, what's your background on this topic?
Well, my background is knowing you and hearing you speak about it and looking up the company online. But I just want to add that, you know, we hear a lot about how to prevent type 1 in people that have positive autoantibodies or what to do in the first 100 days after diagnosis when there are still some viable beta cells. But this doesn't matter. You could have diabetes for a hundred years and this therapy will still work for you. And that's exciting. That's nice 'cause finally, it's maybe something for you and me, you know, because people kind of forget about us.
Alright. So, this is literally the thing I'm most excited about, to be honest, especially in type 1 diabetes but in diabetes in general. So, without further ado, we have a very special guest joining us who is a true, true expert on this topic. He has done a lot in the gene therapy space. We have Dr. Fraser Wright. So, Fraser, say hi and introduce yourself.
Well, hello. Thank you, Jeremy and Steve. It's a real pleasure to be here. I'm Fraser Wright, a career gene therapist. I've been working in the field for over 30 years. I am a co-founder and the Chief Gene Therapy Officer at Kriya Therapeutics, for disclosure, and of course, we're very interested in type 1 diabetes and other prevalent diseases. My PhD is in biochemistry and immunology by original training. I got into the gene therapy space in the early '90s—the previous millennium. I’ve been working in this for quite a long time and have been involved with many gene therapy programs, especially using AAV. We're going to talk a little bit about adeno-associated virus vectors today, but also using the other major vector type, which is called lentiviruses. It's a different type that's used for other types of gene therapies as well.
A relevant highlight is that I've had both an academic and an industry background. I've had faculty positions at the University of Pennsylvania as well as at Stanford. In addition to co-founding Kriya, I was a co-founder at Spark Therapeutics, which brought forward the first gene therapy for a genetic disease that was licensed by the FDA and is distributed worldwide now for a form of blindness—not, of course, a prevalent disease.
Well, us diabetics, we're familiar with that word "blindness." You know, before you got here, Jeremy, I got to know Fraser. And Fraser plays the guitar, and he also does bouldering. You know what that is? That's when you pick up boulders and throw them at your enemies. So, I want to know, when you're bouldering, what kind of jeans do you wear?
I don't wear jeans.
Okay. Levi's, Jordache, or Lucky Brand?
He does it naked. He's fast.
Sometimes topless. Normally when we do our podcast, it's like, I don't know, the latest CGM, and we can jump right into it. Here, we've got to start from the beginning.
Totally. So, if you say "gene therapy" to people, their minds probably go in every direction. What is gene therapy in its simplest form?
Great. Well, just to go right back, I think many of us are familiar with protein therapeutics or polypeptide therapeutics, like insulin and monoclonal antibodies, which are made in factories in cells and then purified and administered as products. The concept with gene therapy is to go right back to the gene—the DNA gene from which those proteins are derived—and to put that gene into an individual. We could do in vivo gene therapy and put it directly into a person, or you can do something called ex vivo, which is different. I won't go into the details. But the big thing about this is that once you put a piece of DNA into an individual—and this is now validated with seven approved products using AAV in the United States to date—you have long-term expression. We call it "one and done." You put the gene in, target specific areas of the body, cells wherever it might be most relevant, and then have continuous expression of that gene, leading to the therapeutic protein being expressed on an ongoing basis. Of course, there's a lot of work to get the dose right and all that type of thing.
So, I think people understand that we're delivering a gene that maybe the patient is deficient in to make some protein, like insulin. How do you do that? I know you need a virus. So, again, that's confusing to people. Is this virus a good thing or a bad thing? And how does that deliver these genes?
Yeah, the word "virus" is kind of scary for most people.
Absolutely. And the question is exactly why do we need to use a virus? So it's really a virus-derived vector. In fact, we don't use wild-type viruses. We engineer them extensively so that they become what are called vectors. A vector is kind of a delivery vehicle.
So you would say it's not infectious. This isn't something that's like people getting the flu or...
Not like venereal disease or anything. No, nothing. And if I could focus especially on AAV—adeno-associated virus. I mean, we've heard of adenovirus. This is not adenovirus. It's adeno-associated. It's a very harmless virus that's very common in the human population. As a matter of fact, if you go to daycare centers, wild-type AAV gets spread around to everybody, and it's not associated with any type of disease outcome or sickness.
But that's only the starting point. We actually take the guts—the natural DNA—out of the AAV through molecular biology techniques, tools that have been developed over the last 50 years. And we put in the gene that we want to express. So it's a viral vector expressing something that's going to be beneficial to a person. It is non-replicating. It doesn't spread; it doesn't amplify. It's very inert. And I think the key reason that we use a virus is because of efficiency. If you just inject a piece of DNA by whatever means into a body, it'll degrade very quickly. It's hard to get it where it needs to be. Viruses have evolved over the eons to be very efficient at doing this very thing for their own life cycle. So we're borrowing that life cycle efficiency of these naturally evolved viruses, picking a relatively harmless one, engineering it so it's harmless and expresses something therapeutic, and using that inherent efficiency of DNA delivery that is part of the nature of the virus.
That's really helpful. We're benefiting from Mother Nature creating this over millions of years, and that's what a virus does. It has to get into the cells and use our bodies to replicate. Here, instead of saying we want the virus to replicate, we're saying we want the specific thing inside of there—an insulin gene or whatever—to replicate. So, what does that look like? You said that you have helped develop some of these gene therapy products. Is there one shining example of a successful gene therapy that exists right now?
That's what I was going to ask too, so that we can relate what's going on to diabetes.
That's a great question. First of all, to put it in context, the idea of doing this viral vector-mediated gene therapy came up in the early '70s, a long time ago. This is when we started to understand the nature of the sequence of DNA and that we have molecular biology tools to cut and modify DNA. In the intervening time, there have been many different programs using viral vectors, and most recently using AAV. I'm so pleased to say that to date, now in 2025, there are seven approved gene therapies using AAV that have been approved by the FDA in the US and generally worldwide.
This is really exciting. To get that type of approval follows a long process of basic research, designing these vectors, doing an abundance of animal safety and efficacy studies, moving into early-phase clinical studies, and then advancing based on data into late-phase clinical studies, eventually preparing a package that would go to the FDA for approval. So it really represents a milestone that we have seven. I can say that I've been involved quite intimately with two of those seven. One for a form of blindness—it's a single gene defect leading to a form of blindness, it's quite rare—and also for hemophilia B, working with colleagues at Children's Hospital of Philadelphia, Katherine High and her group there. And then Jean Bennett, Kathy, and others for Luxturna, which is the product for the form of blindness.
Maybe walk us through that. I think everybody understands blindness. So, is this therapy restoring sight? How does this work? How is it administered? Let's say you have a patient in front of you—what's their journey like with this therapy?
It is a childhood disease. It is progressive. Typically, visual function deficits are apparent early in childhood in toddlers, and it progressively gets worse, typically leading to blindness—legal blindness probably in the teens and then progressive degradation. The disease is caused by a defect in the RPE65 gene, also known as Leber congenital amaurosis type 2.
The administration of this vector is really quite simple. It's very localized. It's called a subretinal injection. You know, I'm not a surgeon, but the idea is putting a needle under anesthesia just under the retina in the eye. This is done in both eyes, not at the same sitting.
And this again is unfortunately something that people with diabetes are exposed to. A lot of the therapies are injected into the eye. Steve actually did a video of him getting an injection into his eye.
You always say it's odd, but it's not really painful.
Well, that was unusual, but it sounds like some type of torture, someone putting a needle in your eye, but it really is relatively painless. And if it's going to save your vision, go for it. It's not under the retina, but for retinopathy, they inject these medications into your eyeball, and it's supposed to help.
So in this case, they get the local injection, and I guess the earlier you catch it, the better?
Yes, it's better to catch it earlier. The vector expressing RPE65—that's the gene that is defective or missing in these patients—stabilizes within the cells that have been exposed to it in a critical area in the retina. Within probably two to four weeks, it starts to express, and you have this therapeutic protein, the correct version of it, start to express. This is a one-and-done procedure. I think we're up to 10-plus years now.
That's worth pausing on. When you say "one and done," it means a one-time injection of the vector in each eye. This is very different than taking insulin shots every couple of hours. We're very happy to have once-a-month therapies. Here is potentially lifelong. And in the case of the eye, I know this is nuanced, you don't need immunosuppression or any other long-term therapy. So it’s really quite a miraculous opportunity here. And it sounds like it's been effective.
It has been, and there have been multiple publications in journals like the New England Journal of Medicine. Long-term follow-up by the companies, Spark and Novartis, is ongoing. We’re coming up on 10 years showing continuous, ongoing benefit, which is remarkable. I always like to think, as a biochemist, about the microgram amounts of actual material that are going into the eye. It's very, very small, 1 to 10 micrograms of the DNA, having such a profound, life-changing impact.
I can maybe make a comment about what came up from some of the clinical trial subjects. Attending the advisory committee meeting for our application for FDA approval, some of the stories from patients were just... one of the young women who received it conveyed that she had given up on the idea of moving past high school and going to college. She was a very bright young woman, but this changed it for her. She was able to move forward to college. I think she got an engineering degree. It was a really heart-touching story, and some of the stories were bringing tears to our eyes as we were sitting up at the front. Really rather definitive, high-impact effects in these diseases.
You know, when I first met you maybe two years ago and I first heard about gene therapy, this is the world I put it in: these ultra-rare diseases. And it was helping these people, which is fantastic, but it couldn't be farther away from diabetes in my mind. So, what has happened that now we're talking about diabetes? Why can we start using this in more common diseases?
Yeah, and when you look at the eye condition you're talking about, it sounds like the earlier you intervene, the better. And maybe if someone's totally blind, it may not help them that much. That's so different in diabetes because we don't have any insulin. You can replace that at any time with this type of gene therapy, which I can see why it's so exciting and how you can affect so many people. The one-and-done nature and also the potential for superior, more real-time control, perhaps.
So, can he answer my question now?
Steve always likes to add a question to my question, which has nothing to do with it.
I was trying to get a word in edgewise.
So yeah, why common diseases? How did we get here?
Well, I'll go back to this first concept of gene therapy. Maybe part of the reason for the name is people were thinking of genetic diseases, more particularly monogenic diseases. That means diseases where a single gene defect caused a well-defined disease. You can think of hemophilia, you can think of Duchenne muscular dystrophy, you can think of these rare eye diseases. It's the most obvious case for gene therapy: one gene, and here we come with the gene, replace it in the right spot. In a sense, it was kind of the low-hanging fruit of the general strategic approach.
But I think we're at the point now where we have seven approved products. There have been hundreds of programs over the last 30 years, to be honest, and we've been doing a lot of learning. We're still learning, of course, but we've gotten to the point where we're getting successful, real medicines approved. And I think that really validates the strategy. It validates the fact that you can have long-term, multi-year, now approaching decade-plus expression in humans. You can say we've got animal data and it looks promising, but a year in a mouse, you can't really translate that directly into what's going to happen in humans.
So, I think the time has now come to take this validated therapeutic modality. It's a new paradigm. Like the recombinant protein therapeutic paradigm that has been so successful, I think we're emerging here with the gene therapy approach. If we understand the mechanisms—and with type 1 diabetes, we understand the mechanism, we know what's missing—if we have a strong mechanistic approach and we have the supporting data in animal models, then it just makes sense to move forward into prevalent diseases.
Well, maybe we should talk about type 1 more specifically now.
Yeah, let me start with my overview. When I first learned about this, a lot of this had been published in animals, and now it’s hopefully moving to clinical trials in humans in 2026. Using this idea, we all know that people with type 1 diabetes don't make insulin. We need to make that protein. So, they took rodent models, made them essentially type 1 diabetic, and were able to deliver this therapy.
The difference with this approach is that they're planning to do it in the muscle tissue. The good thing about insulin is that you can release it from pretty much anywhere. The muscle is very accessible. You can do these injections to put it in your leg, let's say. They've had really good data in terms of these animals not needing insulin and normalizing blood sugars. I don't know if it's "curing," because the disease of type 1 diabetes is still present, but these animals didn't need insulin. Then they moved on to dogs with multiple years of not needing insulin. They took these dogs that became type 1 diabetic—they were essentially in DKA, looked really unhealthy—and made them robust. There are these great videos of putting them on treadmills and them doing well. And now, some primate studies are again showing efficacy. This has been tested in as many animals as you honestly can test to show that this works.
So now here we are, on the cusp of doing this in people with type 1 diabetes. Broad strokes, it would be people like Steve and I, who don't make any insulin, doing this one-time procedure to get this vector into the muscle to have the muscle start acting kind of like a pancreas, secreting insulin. The hope is that it would at least reduce the amount of insulin you would have to take. And the ultimate goal would be to not need any insulin at all. What a cool concept with this "one and done" phrase that you're using, without the need for long-term immunosuppression. When we talk about curing type 1 diabetes, it's always been about needing islet cells and immunosuppression. This has nothing to do with islets; it's just putting the gene and the protein in a completely novel place. So, did I summarize the data well enough?
That's a great summary, Jeremy. And I would like to just call out Fatima Bosch, who developed this program some years ago and published the dog data. She's an academic based in Barcelona, Spain. So this has been through a number of different animal models. We've recapitulated many of the animal models as well. That seems to be a very robust outcome. So yeah, we're excited. That was a great summary.
Thank you. The first thing that comes to my mind is, it's going to be able to secrete insulin, something that we're missing. How do you make sure you don't secrete too much or too little insulin? I know a little bit of the answer, but it sounded complicated the first time I heard it. So that would be one question I think a lot of people would have.
Sure. We all know, of course, that insulin is a very potent molecule, and it's tightly regulated in us. The approach that has been demonstrated and that we're moving forward with isn't just a simple delivery of insulin. It may involve insulin and other enzymes that have a sensor function that can turn on or off the reduction of glucose, the glucose conversion into glycogen through phosphorylation. But it is a great point, and I would emphasize that the amounts of insulin expression that might be required locally are very, very low and, in terms of systemic insulin, would be considered very low. Nevertheless, because of the local effect, it would have a good impact on creating a strong glucose conversion machine to bring postprandial glucose down without going into a hypoglycemic state.
Yeah, that sounds like there’s some glucose sensing going on there.
Yeah, there's glucose sensing. Different versions of this might use insulin and another gene, like glucokinase, to help with regulating glucose. But that is the question: how do you get the dose right? That's where it might be, well, we could shoot for the moon and try to get everybody off of insulin, or you could come in with a lower dose that helps regulate glucose with fewer fluctuations and fewer boluses. I think about this as essentially eliminating DKA. If you could guarantee that somebody always had some amount of insulin on board, that's a big deal.
The other point I wanted to make is, yes, what if you do overdose? This was one of the first thoughts I had. Are you just going to be hypoglycemic all the time? There are ways to turn the genes off. You might have to do a local injection in that area with some substance to essentially damage the muscle tissue. But since it's such a small area that you're putting the genes into, it's not like you need to rip out a bunch of muscle tissue. But you can turn it off, and that's important.
Yeah, we've developed technology to be able to reverse out the transduction. And it's a good point about size, too. The number of cells that are converted as a fraction of your total muscle cells is really quite small. So this is a small biological sensor and glucose reduction pump, if I could put it that way. It's quite a localized effect that, yes, can be reversed.
Jeremy, you told me that they're going to put markers on where they inject the gene, then you can go back in and, like you said, make sure...
Yeah. No matter what, you're going to want to know where it is. So there are different ways you could think about how to do that. The other question that comes up a lot is, okay, this is in my muscle. What if I exercise? If it's in my legs, what happens if I go for a run or I bike? Is that going to make it secrete more insulin? Or is it going to damage the muscle tissue and turn things off? Obviously, this needs to be studied, but that's the main reason why they put these dogs on the treadmill and would run them to make sure that their blood sugars stayed normal. And they did. So, early signs show that hopefully you can still be able to do the normal things that you do and not damage the muscle to ruin your therapy, so to speak.
I'd be worried when you and I play Twister and sometimes we get in a wrestling match. I don't want to mess up my jeans.
Cheats!
Well, I do have to say that I saw some of your music videos, and boy, that's a lot of exercise.
It is. We're moving and shaking.
So again, I think we're taking people through a lot here, but leaving them with the fact that this initial study will be going on in 2026. A lot of times when we talk about things, it's kind of this, "Well, maybe one day." Steve and I always make the joke of, when you were diagnosed, Steve, how long did they tell you it'd be for a cure?
Fifteen years.
Yeah. Me, 15 years. And you tell somebody now, 15 years. This is actually happening essentially now. It obviously takes years to go through the whole clinical trial process to get approval. But if everything went well, you're looking at sometime before 2030, which for somebody living with type 1 diabetes, that's here. We've been promised so much for so long. I'm not saying we're promising this, but this is the speed that it could potentially happen, right?
That's fair. We now have experience developing gene therapies based on AAV. So, that's a reasonable estimate. Again, we can't promise any specific dates. It really is pending the clinical trial performance and negotiations with the regulatory authorities, of course. But I would say it's on the horizon, and a reasonable time horizon.
And it has been proven in seven other diseases. Exactly. So it's not like the very first one ever.
Yeah. I just love this because Steve and I have so many meetings about what we should talk about. And there's the usual prongs: technology updates, new medications, lifestyle interventions, diet, exercise, and then maybe some of these curative things, which have usually been islet cell transplants. Here's something that people probably didn't even know about—a whole other column of research. This mechanism can be used for many different things. If you have type 2 diabetes, there could be other hormones that are used. Maybe it's insulin with something else. This is just going to become a new modality. Just like you can take a pill, you can take a once-a-week shot, or you can get your gene therapy. I think it's not that distant of a future that we could be there with these metabolic diseases.
This might be the first patient program explaining this gene therapy that I've ever heard of. I think you need to give me, Fraser, a PhD in gene therapy after listening to all this for the last 30 minutes.
MD, PhD sounds good.
Yeah, no, it sounds great.
I think it's nice to think of the complementarity of the approaches that we have. As a first approximation, this could substantially progress control and meet unmet needs and maybe compliance issues in T1D. Maybe down the road, we could talk about even more substantial things.
I think you're right. And these things work together, right? Maybe you get to a point where you get your gene therapy and you're on a pump, but you don't need to bolus or something like that. It modulates it. So there are all kinds of areas of success. Obviously, we always want to keep our eye on the prize of not needing insulin, but we've got a lot of ways in between that could be a win. We'll see.
My thought is just leaving people with hopefully some hope. Be excited about it. Fraser mentioned in the beginning that he works for Kriya Therapeutics. You can always Google it, look up their website, and see exactly what they've got going on.
Spell that. K-R-I-Y-A, right?
Yes, Kriya Therapeutics. It's a Sanskrit word that means "energy." My fellow co-founder, Shankar Ramaswamy—I think his wife suggested that this might be a good name. Shankar, forgive me if I've got that wrong. But it's Kriya Therapeutics, exactly.
Any closing comments or thoughts you have?
Well, thank you. I would say, thank you for all the work you've done in this field. You're a pioneer. I mean, to bring back someone's vision is incredible for a small number of people, but to bring back insulin for millions of people, that's a big deal.
Thank you for that.
Well, thank you, Steve. I appreciate that. I must say, I've been very lucky in my career. I followed my nose in many regards. I like science, and I'm a career scientist. That's my passion. I just have to acknowledge the many great individuals who have really advanced gene therapy to date as well—on the medical side, on the basic science side, on the vector design, manufacturing, and characterization. There are so many strands that lead into this. I've played a part. I've been lucky to have been involved, too, because it's been such a fulfilling...
You are humble. We're very lucky to have you. I mean, how many people are there that have launched a gene therapy? Not many, and we got one of them here with us today. So, really appreciate it.
I hope you guys enjoyed listening to this. Honestly, this is one of the podcasts I think I've learned the most from, and I continue to learn about this area. I hope you guys found this enjoyable. Please be sure to like, subscribe, follow, and share these things. Your comments are all actually very meaningful.