Aykut Demirkol Interview Transcript

Bruce McCabe: Dr. Demirkol, thank you so much for making time to talk to us. I wanted to talk to you about the future of gene therapies and eye diseases today because of what you're doing here at Columbia University and we call it the Harkness Center, is that what we... Is that the correct pronunciation?

Dr Aykut Demirkol: Yes.

BM: I'd like to start very broad, can you tell us what's the dream, what... If everything comes to fruition over the next 20, 30 years, what could the world look like when it comes to treating eye diseases? How different could it be?

AD: It is a little bit different and difficult to say that, but if everything goes well in the future all the disease can be gone, so we are working in different genes, most of them are inherited retinal disease in here with Dr. Tsang and we have most of the projects about the CRISPR. So if the CRISPR is used, useful and if we are able to manage that in the future, many of the disease are not so.

BM: So every disease is potentially a target, it's not just one or two diseases, all of them are potential targets.

AD: It's also difficult to say that but most of the genetic disease are in target, but some of the disease not correlated with the only genetics because environmental changes, for example, foods or water or environmental issues also occur the disease.

BM: And that's, as I understand, is that part of the epigenetics process, the environmental factors can be passed through and affect the DNA that way? Or is that really separate, it's just a combination of environmental factors over here, genetic factors can add up to a disease?

AD: Yes, for example, if you have a genetic disease potential, you need double hit, one of them is your in gene, and if you get a second hit, you have the disease, for example, if you have a breast cancer gene, and if you use radioactive things and then it can be occur more potential. So it's not only affect the genes the disease, for example, we have a patient it's nearly the same genetic type, one of them is have the disease, but the other hasn't got – but they're all the same gene.

BM: And is it difficult to determine the proportionality of how much is genetic and how much is non-genetic?

AD: It's difficult to say that, but it's about the person's habits or personalities depends on most of them.

BM: Okay. Now two of the big targets I understand are retinitis pigmentosa and...

AD: Yes, our big target is retinitis pigmentosa.

BM: Is that the biggest one? Is that your first priority or the easiest pathway or what... What's... Where does that sit with the laboratory?

AD: It is easiest disease because you can manage the eye outside, and you can also solve the retina outside of the body so it can be easy to manage this disease.

BM: I see and so you do more of the work outside, so in-vitro, and then, is that right, is that what you mean?

AD: Yes, also we can make some subretinal injections and we can see the effect outside of the eye so we don't have any other procedures or surgeries.

BM: Got it.

AD: But if you have any kidney problem, you need to open the kidney, but we don't need to. [laughter] So you can see outside of the body the retina with some instruments or some lenses, you can see that, because of that, it's easy to manage this kind of disease in CRISPR or gene therapies.

BM: So how far have we got in the laboratory now with your research with retinitis pigmentosa? Where are we at in terms of developing therapies?

AD: Developing therapies are... There is two different approach, one of them is gene specific, it says, or we says gene editing or prime editing, and the other ones are not specific for the genes. It's according to metabolism. If you change the cell's metabolism it can be affect disease potential. For example some of the paper says retina use a lactate instead of glucose, if we produce a much more lactose lactate in retina cells it can be affect more effective, its effectiveness is increasing. So we have two approaches, one of them is targeting the genes and correct that gene, and the other one is make the cell more efficient to prevent other cells.

BM: And so would those two approaches potentially be used in combination with a patient?

AD: Not now, because we don't have so much options, so we have to then use the one way, for example, a metabolic approach we use only one gene or a vector and the other approach is the another way vectors so we don't use ...

BM: You don't use them in combination. I see.

AD: Maybe in future it can be, but not now.

BM: And the current experiments, are they in mice or what's the...

AD: It's depends on the project, most of them are mice or cell cultures. If they're successful, and then it can be used in humans, for example, as I said before RPE65 has a gene therapy now which is called... Can I say that? Luxturna can be used in this kind of patients. If I'm not misremember, there are six or seven patients says they got the treatment.

BM: When did that start? Is that just the last couple of years or...

AD: I think two years ago.

BM: Two years ago. Yeah. So we're in the very beginnings...

AD: Yes.

BM: Of this process and we'll be watching those six or seven patients I guess over the next few years to see what the results are like or do we have an early indication of...

AD: I don't know the exact position. But it's a long way. Because if we firstly create a gene or guide RNA to targeting the gene and we test them, the safety, efficacy and other things in the cells and the mouse after that if it's can be successful, we do the trials in humans.

BM: Yep. Yeah. So when I read the press releases for the or Dr. Tsang's comments publicly, it sounds like you're very optimistic for the long term that you'll have a range of tools...Which will turn to therapies. It's really just a matter of time and hard work I guess and trials...Would that be fair or do you see any substantial gaps in the science where we're not certain?

AD: We need time firstly because it's not done like a magic. So we need time. Also we have some guess or hypothesis but sometimes it doesn't work.

BM: Yes. [laughter]

AD: So if everything is goes, we need time, also we need scientific methods or machines. For example, when you are in a cave, you need a tool to make the circle or wheel. If you make the wheel and then you need some other tools. So it's cause developing, developing, developing.

BM: Yeah.

AD: So we need some developments.

BM: So it's trial and error, and then you're discovering new problems as you go that...

AD: Yes.

BM: You've got to solve and go from there. Now the other one is that comes up a lot and it's obviously very debilitating is macular degeneration. So where are we at with that? What kind of experiments are going on?

AD: I don't have so much idea...

BM: Okay.

AD: Because we are working in retinitis pigmentosa but when we work in this area, the other colleagues are working this kind of things. So I think they have some improvements, but I don't know exactly what's ongoing.

BM: Are there particular diseases which like RP lend themselves to experimentation? Are there other early targets for you that you'd say, would that be next for us to go after?

AD: I didn't understand the question...

BM: Well, if we look at all the possible diseases or maladies of the eye, are there others that stand out as being easier targets from a science point of view?

AD: Yes, the recessive genetic diseases are the most popular. Because there is two couple of gene strain, so DNA strain. Recessive ones has only one couple, only one target. So it's been more easy to manage that. So the next target or next easy targets are recessive genetic disorders.

BM: Just looking at the future, when these therapies do mature as they probably will, and to not really off the shelf therapies, but therapies that are routinely used, it's within I guess the hospital context, isn't it mostly? So there, it'd be a patient going in for an operation. I use the term gene surgery now. I've seen that term being used. It sounds like you go in, have the therapy, perhaps the hospital stay is a matter of days. I'm not sure. I'm trying to paint a picture of what the experience might look like in future for having say RP therapy to.

AD: Nowadays it's not so easy because first of all you need to enroll the trials, and if you are eligible to do this test or these trials, and then we do several tests before the treatment because we are need to understand you are eligible and you need to these therapies. After that, we do the injection or therapy use the therapeutic on you. After that we need to understand its safety and efficacy. So you have to came here several times.

BM: Right.

AD: It's depends on the study but every month or maybe every three or three, two months. You came here and check the test. After that, I think two or three years later it can be occur in your retina.

BM: Then that's the time it takes to grow enough cells? Two or three.

AD: Not to grow enough cells but it's time to regenerate or it's time to integrate the AAV vector in your retina cells and it's like a … It's passed one cell and another cell and other cell. So it takes time.

BM: Interesting. That's... I did not know that at all, in my head. I'm thinking of oncology and CAR T-cell therapies, which are all about very fast processes of adapting immunotherapies to attack the wrong type of cells and get rid of them really quickly, sometimes in a matter of days. But you are talking about a different process. We're talking about starting a growing process, I guess, at the back of the retina.

AD: Yes. Because retina cells are not reproduction. So there is some cells and there isn't any reproduction.

BM: Okay.

AD: We involve these cells, but for example, blood cells are reproduction. If you correct one cell, it's reproduce the other ones. But in retina cells doesn't reproduce, the main problem is that. If the retina cells is died, it's died.

AD: Got it.

AD: Or, we try to manage before they died. And when we correct one cell, it's correct the other cell, and then it goes like that.

BM: So help me understand that mechanism of correcting one cell, and then it corrects the next cell, the adjacent cell. How does that happen in a biological terms?

AD: Not like that, but we give the AAV vector to subretina. And AAV vector goes to one cell and correct this cell. If we correct one cell, it prevent the other cells because if your neighbor is died, the next cell is affecting that one. So if your neighbor doesn't die and live and it's prevent your cell and the other cell. And it's goes like that.

BM: Wow. Okay.

AD: But not reproduction.

BM: [laughter] Okay. That's very different to what I imagined. Thank you for that. Yeah. Very interesting. So just getting back to the present day, what does the lab look like? How many people are here? Give us a sense of the partnerships and the effort here.

AD: In our lab, Dr. Tsang's Lab, I think we have 12 people. And also there's some PhD students, post-doc researchers and all of them, I think 12. So, we are working different projects. As I said before, we have two different approaches. And some teams working in metabolism way and the other ones are working in gene therapy or gene editing. And we have more than 10 projects now. And working that.

BM: And what about your personal journey? You are Turkish by background, is that right?

AD: Yes.

BM: And so your undergrad and your initial graduate studies were in Turkey?

AD: Yes. I'm from Turkey and I'm graduating medical school nearly 15 years ago. And after that, I go to the residency for ophthalmology. And I graduated I think 10 years ago.

BM: And was there a particular interest in or particular reason for your interest in ophthalmology as a pathway?

AD: I like, how can I say, engineering. Before, when I'm a childhood, I want to be a engineer, but I took the other way and I became a doctor, and then I decided I can do engineering and doctor in this field.

BM: Combine them? Bioengineering?

AD: Combine Bioengineering. And also my wife is genetic doctor also. And so in Turkey we have maybe you know, Turkish populations have so many consanguineous marriages so we have many, this kind of patients. After my wife is graduate genetic doctor's field, I sent my patients to her, to genetic diagnosis. After that, it's came to here.

BM: Fascinating.

AD: It's different [laughter].

BM: Yeah. No, it's interesting story. Has anybody inspired you in particular, because this is hard work, it requires a lot of innovation, you know, in this journey of study and development for yourself, anyone in particular inspired you?

AD: Maybe Dr. Tsang because I followed him before I came here. He has many awards and many projects in this field. And also maybe you know the two years ago Nobel's goes to the CRISPR-Cas9. So it's inspired me and I'm here.

BM: Jennifer Doudna and Emmanuelle Charpentier.

AD: Yes.

BM: Incredibly inspiring.

AD: Yes. It's a big improvement in this field. Because you have to change the genes. Also it's developing so fast. For example, first time like a pen and pencil, you write the genes, now we typewriter use, Maybe in future, it can be of course computers [laughter] and it's developing and developing.

BM: So lastly, given that I'm presenting to audiences of lay people all over the world, ordinary people, any particular things they should be watching for or any advice you'd give them as to where they can monitor progress? I mean the science journals are very difficult for people. I guess it's just a matter of monitoring the news. But what would you be doing if you wanted to monitor progress?

AD: In ordinary people it's can be difficult. Because if you don't read the publishing papers and scientific papers, it's difficult. Maybe you can see in newspapers or news but sometimes it can be not so true. So it's difficult to say...

BM: It's very difficult to read the science magazines or whatever. So, look, I think that's about wraps up from an interview point of view. Thank you Dr. Demirkol, it has been a privilege for me and it's such an important area. There are so many people that are completely debilitated by eye diseases in both RP and AMD. So any progress we make here is really important. It will change so many lives so.

AD: Yes, if you change one life, it change a lot...

BM: Definitely.

AD: Hopefully for their own family or their neighborhood.

BM: Indeed.

AD: Yes.

BM: Thank you.

AD: You're welcome.

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