A look at gene therapy for type 1 diabetes

Type 1 diabetes is a complex disease affecting millions of people across the world. Though insulin has been discovered as a treatment for patients, research is still being done to find additional and alternative methods to treat and perhaps cure type 1 diabetes. Hayley Wilson discusses how gene therapy is being used as one potential method of treatment. 

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.
 
In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.
 
If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

You can read our briefing on gene therapy and type 1 diabetes here.

If you have any questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: Welcome to 'Making science work for health', the PHG Foundation's podcast exploring developments in genomics and related emerging health technologies. The progress being made by teams of scientists and researchers around the world is gaining more interest and attention. Many of the latest advances feature genomics and omics related technologies. The field in which the PHG Foundation has more than 25 years of experience, helping policy makers get to grips with practical, on the ground delivery. 'Making science work for health' aims to look behind the hype and explain what new science means for patients, health professionals and members of society.

My name is Ofori Canacoo, part of the communications team at the PHG Foundation and host of 'Making science work for health'. For this episode we're talking about the use of gene therapy for type 1 diabetes. Type 1 diabetes is a complex disease affecting millions of people across the world. Though insulin has been discovered as a treatment for patients, research is still being done to find additional and alternative methods to treat and perhaps cure type 1 diabetes.

Dr. Hayley Wilson, Policy Analyst in Biomedical Science at the PHG Foundation, joins us to discuss how gene therapy is being explored as one potential method.

Hello Hayley. 

Hayley: Hi. 

Ofori: How are you? 

Hayley: I'm very well, thank you. 

Ofori: Good, good. So, we're here today to talk about gene therapy and type 1 diabetes. So, to start off with, could you give us a brief explanation of what gene therapy is?

Hayley: Sure, yeah, before it gets too technical. So, gene therapy, actually it's a pretty simple concept, so it's a bit of a catch all term, and that's for a group of genetic treatments that you can associate with altering or manipulating an individual's genetic code.

So, there's lots of different treatments, and there's lots of therapies that fall under this, and you can use it to treat a variety of often quite serious diseases. So, the simplest form of gene therapy actually just involves inserting healthy copies of genes to replace pathogenic ones. So those are the diseases... the genes that cause disease.

So, you can actually replace those and in many cases, you can reduce or remove the symptoms of that disease. So, we've had a lot of technological advances probably in the past couple of decades, and that allows us to edit genes in several different ways. So, you've got techniques such as things called CRISPR, which use enzymes that are designed to be molecular scissors almost, and they will precisely cut target areas of the genome, and then you can put in your new correct DNA to treat those genetic diseases.

There's also treatments such as oligonucleotide therapies where you introduce specific short pieces of DNA into target cells and that can silence pathogenic genes or it can reactivate genes that are not acting as they should or producing the proteins that they should. And then, in terms of type 1 diabetes, the most focus that we've had has been on the insertion of whole genes, or transcription factors.

Transcription factors are actually the proteins that control whether genes are turned off or turned on, whether they're expressing their products. And that can then restore the insulin production and insulin responsiveness in the body, and reduce or remove the need for people to manage their insulin supplementation by daily injections.

Ofori: Why then would there be such an interest in gene therapy? 

Hayley: Gene therapy is not actually a particularly new concept. It was probably proposed almost 50 years ago, but it has then had a real roller coaster of successes and problems, so a lot of highs and lows. The potential of a stable and lasting treatment that could be curative in a single treatment for a genetic disease has actually got a lot of considerable research attention for several decades. So, it was initially thought to be a treatment for what are called monogenic inherited diseases, so those are your diseases that are caused by a mutation in a single gene. But there's now many different therapy products available for acquired diseases, and it also includes specific cancers, which is really exciting.

Gene therapies are generally developed and successfully used in debilitating diseases that parents and clinicians have really long sought cures for. So, a couple of examples are gene therapies that can remove the need for blood transfusions in patients that have a particular type of sickle cell disease, but also in patients who have clotting problems as well.

So, there's a whole range of different use cases for gene therapy. 

Ofori: So, as we said, we're talking about gene therapy in connection with type 1 diabetes. So how might it be of benefit in the treatment of conditions such as type 1 diabetes? 

Hayley: So, in type 1 diabetes, the disease can actually be broken down into four stages which are slightly confusingly called "presymptomatic", "stage one", "stage two", and "stage three".

Now in the presymptomatic stage, a person may have been identified as having risk mutations for type 1 diabetes and they're at increased risk, but not definite risk, of developing the disease. In stage one, the patient has some beta cell damage and there are certain things happening as part of the autoimmune response and those beta cells are at risk.

In stage two, the damage is progressing quite significantly and those beta cells and their ability to produce insulin are being destroyed. And then once we get to stage three, we're actually at the point where 70-80% of those beta cells have been destroyed. The person can't really manage their own insulin internally, and they then have to start supplementing with external insulin injections and glucose monitoring.

So, despite the fact that insulin has been a mainstay lifesaving treatment for type 1 diabetes patients for just over 100 years now, it's just had its centenary, it's not without its problems. So, daily insulin management is really complicated and it's really onerous for those individuals. And even despite careful planning and monitoring, it's really hard to maintain acceptable blood glucose levels or blood sugar levels.

They require multiple daily finger-prick tests so they can monitor their blood glucose levels. Then there's several insulin injections that have to be planned around meals, the content of meals and the exercise and things that those people are going to be doing that day. But even in patients that really meticulously monitor and regulate their blood glucose levels, there's long term complications that can cause major cardiovascular disease, kidney disease, and it does shorten patients’ lifespan. So, patients also risk hypo and hyperglycaemic episodes. So, this is where the blood glucose levels either drop too low or they become too high, and that can cause serious problems, and actually in some cases it can be fatal.

So doing therapy to reduce or remove the requirement for insulin supplementation and give patients the ability to... or their body will be maintaining their blood glucose levels themselves would actually be really transformative for them. And it would also considerably reduce the burden on the health service because there's a lot involved in caring and looking after diabetic patients.

Ofori: So, could you take us through the concepts of the techniques of conversion, prevention and correction in the context of type 1 diabetes? 

Hayley: Sure. So, when I was researching gene therapy for type 1 diabetes, it's really complicated. It was a huge area. There's lots and lots of different things going on but I did start to notice kind of particular themes that were coming through and that was relating to the goals of the gene therapy to treat this disease.

So almost all the research in the area involves inserting whole genes or those transcription factors we mentioned into target cells and that's to try and cure the type 1 diabetes. But these different themes are reaching that point via different goals. So, I found that the most frequent method that was being investigated appeared to be to use gene therapy for the conversion of non-beta cells into beta-like cells.

So, the beta cells are the cells that are located in your islets of Langerhans in the pancreas, and they're the ones that produce insulin, and they manage the insulin, and they secrete it so that your blood glucose stays at a normal level. So, these are the cells that are destroyed during the development of type 1 diabetes, and unfortunately they're not the cell type that they can regenerate.

So, we need to find other ways of encouraging and manipulating insulin secretion. In many cases, researchers have inserted those transcription factors, the proteins that control gene expression into the target cells, and they especially often use alpha cells, which are another type of cell that are found in the pancreas, and they... their structure and their function is kind of similar to the beta cells, so they're the most promising different alternative cell types.

This then in theory leads to glucose responsiveness. So those cells sense the raise in blood glucose, say, for example, after a meal, and they then secrete insulin, and they can maintain those blood glucose levels, and that can be then done without insulin supplementation from the patient. 

So, another one of the themes that I identified was a little bit more tricky to determine, and sometimes it can be a little bit woolly around the edges is prevention. So, there's been a lot of prevention attempts using gene therapy and the part that we're preventing is that initial loss of beta cells and that occurs in the early presymptomatic stages of the disease. What the prevention theme is looking to do is to stop those beta cells being destroyed so people don't progress through those early stages into the final stage of type 1 diabetes.

This is really tricky though because of the different varied causes of the disease. But what researchers found is that if you overexpress certain factors associated with beta cell development, so, those transcription factors that are involved in initial beta cell differentiation and development in the early stages, and as they mature into functioning cells, you could potentially maintain those beta cell masses, and you could delay the onset of the disease, but research in that area is a little bit spotty.

And then finally we've got correction, where the goal here is to correct the blood glucose levels to an acceptable level using the gene therapy. And they're doing this by inserting an insulin gene into a target cell, which then is encouraged to produce insulin, and therefore you've got some control over your blood glucose.

This kind of sounds similar to the conversion theory, but the goal here is quite a lot more simplistic. With conversion, what you're trying to do is change those non-beta cells into ones that behave and look a bit more like beta cells. So, they develop a bit of their structure, they develop their functionality, like they can manage the insulin secretion, and they can respond appropriately.

Whereas in terms of correction, really what we're trying to do is to just purely to get those cells to produce some insulin, to reduce the blood glucose levels. So, they're doing... they are doing the same thing, but it's on a slightly more simplistic level. And again, that hasn't received as much attention as converting those non-beta cells into beta cells.

Ofori: Do any of these techniques appear more promising than others? 

Hayley: Well, I try not to be too negative on that, because a lot of these techniques do sound really promising. But gene therapy for type 1 diabetes has really progressed really, really slowly over the past two decades. And in all of the cases that I've mentioned previously, those conversion, correction, and prevention, all of that work's actually only being performed at the preclinical stage.

So, what that means is the investigations are being carried out only in vitro, so in laboratory using specific cell lines either from humans or mouse or rats and monkeys, or in vivo in animal models. So, they're inserting the genes into mice especially, but also rats. And sometimes we're using dogs as well. So, there's not actually any evidence that we've progressed to humans and there's no clinical trials registered for gene therapy and type one diabetes at the moment.

So, it's kind of a, a bit of a, an impasse in that there's, there's lots of research activity in this area at the preclinical stage, but we really haven't managed to make that leap across to human trials yet. Having said that, it seems that the conversion of non-beta cells into beta-like cells is probably the ones that's advanced furthest forward, and that's got the subject of the largest proportion of the research activity.

In fact, in the past five years, some researchers have managed to transplant certain transcription factors into alpha cells to get them to behave like beta cells, and then move those cells into diabetic mice, where the cells actually then produce insulin and reverse the diabetes in the mice, even after six months.

So that was one of the longer time periods of success there, but it's still very much in the animal model and cell line stage. 

Ofori: What are the general issues of gene therapy at the moment? 

Hayley: Well, there's several areas to consider in terms of gene therapy. And the... really the potential side effects are the big issues at the moment.

There have unfortunately been several deaths in gene therapy clinical trials in the early days, but then also quite recently in 2020 as well. And often, these deaths have been, or the adverse events that also happen, are related to severe autoimmune responses. And those responses are due to the viral vectors that are used to deliver the genes.

So what that means is, to transfer the genes to target cells, you need something to transport them in. So you need a vehicle to transport them in. And usually this happens in the form of a viral vector. So it's a virus that has had all of the infective material removed, anything nasty has been taken away, and then the genes or the transcription factors are placed into this empty virus.

This provides a stable transport mechanism, but unfortunately, even if you've stripped out all of the viral material, sometimes your body can recognize those cells as foreign and viral, and you can produce an immune response. As your body is designed to do, but unfortunately it's working against the gene therapy there, and that immune response can sometimes be fatal.

So there still needs to be quite a lot of work done to work out how the body responds, particularly when you've got serious diseases where people's body is already under a lot of stress, there's a lot going on, and then we're introducing viral vectors as well, so there's more work to be done there to determine how that affects us.

Another thing that we need to consider is the timelines. It can take a really, really long time to develop a safe and effective product after you've identified the potential target. So there is that initial burst of activity where you get an option, a potential target for gene therapy. But then following on from that, it can be quite a long-protracted timeline to get that into commercial use.

So the clinical trials have quite long follow up periods because you are manipulating genetic material, and that can actually also include a 15 year follow up in the United States if those delivery vectors, the viral vectors I mentioned, have properties that mean they can integrate into the person's own DNA. So we need to make sure that that's not going to cause any long term problems. 

So finally, I think one of the biggest factors and one of the biggest issues in developing gene therapy can be the cost, which can be absolutely enormous, meaning that the cost to the healthcare system or the patient themselves, that depends on what healthcare system they're in could really be a major barrier to implementation.

So we really don't have a lot of information on gene therapy and type 1 diabetes costs because we just haven't progressed past that preclinical stage yet. So just to give an example, the first gene therapy product that was available in the UK outside of a clinical trial cost £2.8 million for that…for that therapy.

And it's not really a comparable cost because this drug was designed for one patient based on their own cells. But it does kind of give an idea of some of the costs involved and I think the thing to consider here is the burden of type 1 diabetes patients could actually make the cost really quite prohibitive. So that is probably one of the biggest issues I think. 

Ofori: Are there any barriers that are more specific to the progression of gene therapy in type 1 diabetes? 

Hayley: So, when we're looking specifically about type 1 diabetes, one of the big questions is the length of effect. Type 1 diabetes is a lifelong condition and what you want from a genetic therapy is something that's going to go with you for the rest of your life.

So, as we've mentioned before, some researchers have managed to achieve insulin production and secretion beyond six months. But still only in that preclinical stage and then there's other studies that have unfortunately reported a return to the hyperglycaemia. So, subjects have lost that blood glucose control. But then there's also studies that will stop monitoring the blood glucose levels after several months. So, it's really difficult to interpret the effect length in human patients from this preclinical data. 

So, another thing that we need to consider is the alternative to insulin supplementation. Now insulin supplementation does have its problems, particularly in accurately replicating that fine scale glucose control that is achieved by insulin produced by the body. But it's quick acting, it's straightforward, and it's convenient, and it provides that rapid blood glucose control that we need. Which means for an alternative that sets a really high threshold for success. So that new intervention or that new treatment must have a comparable level of clinical utility and it must be as safe as insulin is and it also has a relevant cost versus benefit ratio that actually means that it's feasible to implement into the healthcare system.

So finally, it's really important to try and not oversimplify this problem. So, gene therapy is a pretty complex and technical procedure, but actually it's a relatively straightforward concept. We are introducing a healthy gene to replace a pathogenic one, and that, for example, sometimes will result in the restored production of a protein, and we end up with a reduction or removal of the symptoms of a genetic disease.

So, you can see this quite successfully in treatments for muscular dystrophies, where genetic mutation results in the absence of a protein, which helps to keep the body's muscle cells intact. So, the absence of this protein results in severe muscle weakness, and eventually it will cause life threatening cardiac and respiratory problems.

And unfortunately patients with muscular dystrophies will often succumb to the illness in their 20s and 30s. So, there's a new drug that's been released which will replace this mutated gene, restarts the production of the protein needed for the muscle cells, and reduces the symptoms of the disease. But in the case of type 1 diabetes, the beta cell destruction is not usually caused just by one gene, there are a whole host of different causes of the disease.

And repairing the damage done by that autoimmune attack on the beta cells is not really as simple as just restarting the production of a protein. You need an insulin management system which monitors and responds to blood glucose along with a proper storage mechanism and all of these things are lost when those beta cells are destroyed and they can't regenerate.

So, all these different causes and the multiple risk alleles that have been identified produce a really complex pathophysiology that doesn't actually respond that well to a single gene insertion. 

Ofori: So, is gene therapy the only or main form of intervention being explored for type 1 diabetes?

Hayley: Interestingly, no actually. Novel therapeutics for type 1 diabetes is a really big area of research at the moment, so there's been some really big recent advances that hold a lot of potential to impact the lives of those with type 1 diabetes. And gene therapy is not top of the list. 

So islets cell transplantation is subject to quite intense research activity at the moment, probably the most out of all of these novel procedures. And what this does is replaces the destroyed beta cells by transplanting healthy islets from deceased donors. So those islets are actually really, really fragile and you also need really high volumes for the transplant to be successful. So that this actually means you need two to three deceased donors, usually for two infusions over the therapy course. But unfortunately donor pancreases are in very, very short supply, coupled with the fact that you need multiple pancreases. So I was quite surprised about this, and this treatment's actually been available on the NHS since 2008. But it is reserved for patients who have serious problems in detecting very low blood glucose. They have regular episodes of hypoglycaemia, and which can be fatal. And in the United States a new treatment has just been released, which is the first donor derived pancreatic islet cell therapy for US patients and you have that by an intravenous infusion. So again, this is reserved for those with ongoing hypoglycaemia problems, so they really, really struggle to control their blood glucose despite intensive management, and they're often having these dangerous low blood glucose episodes. So, it's important to remember though that. These cases don't actually give you freedom from insulin. So, the individual now also has to take immunosuppressive medication to prevent rejection of the islet cells, and they probably still need to top up with insulin anyway. There's quite a few ventures underway to develop devices that would encapsulate and protect those islet cells and to try and improve their survival and reduce the number of transfusions you need. And really exciting is that recently a transplant of stem cells that were reprogrammed into islet cells have reversed a patient's diabetes to the point that she. You need any insulin, insulin supplementation anymore. So there are some really positive avenues being investigated and some really exciting developments there. 

So another major area of research for type 1 diabetes has been immunotherapy. Researchers have been investigating lots of different ways to use immunotherapy to protect those beta cells and prevent that initial autoimmune attack so that we don't destroy the beta cells. And this has not really been without its hurdles as to prevent the autoimmune attack early intervention is key. So as we've mentioned how there's a set of stages for the progression of Type 1 diabetes. Those stages until we get to the asymptomatic point are long and they're silent and once we get to 70-80% of beta cells being destroyed, that's when you get symptomatic type 1 diabetes. And unfortunately once a patient is symptomatic, it's usually a bit too late to save those cells and we’re now into the territory of insulin supplementation. 

So, there's been a new drug recently approved that actually uses immunotherapy to prevent patients from moving from stage 2 diabetes, where the beta cell damage is occurring, but they're not fully symptomatic, to stage 3, which is the symptomatic stage. And in clinical trials, this treatment actually delayed that progression from stage 2 to stage 3 by up to three years in high-risk individuals. And it interestingly worked better the younger the patient was. So this isn't actually a cure and it's not preventing type 1 diabetes completely, but it does provide those additional years of disease freedom so. A young person can kind of get to grips with how they're going to manage their condition once it develops, and it also will reduce the impact of those disease associated side of. And the impact upon the health service is also lessened by a number of years as well. So that's a really exciting development and that's just been approved in America.

Ofori: As things stand would you say there's a future for gene therapy in type 1 diabetes? 

Hayley: Well, the honest answer is that I'm not sure at this stage.

There's been a lot of research in the area for a number of decades, but as I've mentioned before, there's not really a lot of progress that's been made past those preclinical stages, so there's not really a lot for us to work with. Developing gene therapies can actually take a really long time. So, there could be work in the pipeline that we don't know about yet.

We might be just experiencing delays that are caused by the COVID-19 pandemic and this may have lengthened those research timelines, so maybe there's going to be some publications coming out in the next few years. But there's also efforts to see if gene therapies can be applied to diseases with multiple genetic causes. But again, that's very, very early days. The concept makes sense, and applying it to type 1 diabetes also does, you know, make a certain amount of sense. But type 1 diabetes is a really extremely complex disease. So, we may be at the point where we're trying to fit a square peg into a round hole. 

There's actually quite a few areas where the research has progressed significantly further and is doing really well. So, we've got the immunotherapy and the islet cell transplantation and there's also some really exciting stem cell work happening. So, these commercial successes, plus the release of those approved treatments is probably going to drive further interest and research in those areas rather than in gene therapy, where we've not managed to make the same amount of progress.

I wonder that as genomic medicine and other omics biology progresses, we might actually find a place for gene therapy in type one diabetes. But I think at the moment it really does kind of risk being eclipsed by those more successful techniques. 

Ofori: Okay. I think that's a fairly poignant place to end this episode. So, Haley, I would just like to say thank you very much for coming on to talk to us and hopefully we'll have you on again soon to talk about something else. 

Hayley: Yeah, no problem. Really enjoyed it. Thank you.

Ofori: And that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description. You can also find additional information on our website, phgfoundation.org. And if you have any further questions about the topic, then you can email us at intelligence@phgfoundation.org. Thank you for listening. And we look forward to bringing you a new topic in the next episode.