Updates in Gene Therapy | Congress 2023

Thank you Professor Kirik for dedicating your time to talk to us. I've learned through your talk, several strategies for gene therapy in movement disorders. Could you tell us what are the ones you think [00:01:00] are the most promising? 

[00:01:01] Prof. Deniz Kirik: Thank you so much, Sarah. It's nice to be with you. So the gene therapy landscape has evolved over the last few years.

Now we have approved therapies for a number of indications, including those in the brain and relevant for moment disorders. I think we're going to see this deepen and widen over the next period. And applications that we see in Parkinson's disease in Huntington's disease fields are both very exciting.

Several applications in a pipeline are going to change the way we approach gene therapy in this diseases. So I'm very excited about that. 

[00:01:34] Dr. Sarah Camargos: Perfect. We are too. One important issue is the distribution of the drug and the delivery systems are modifying.

 Could you tell us a little bit more about the new findings in the distribution? 

[00:01:47] Prof. Deniz Kirik: Exactly, so this is a very important point. There are a few things that as the field evolved over, you can say almost two decades, a few things have changed. We now have better manufacturing methods. For example, we [00:02:00] have many more viral capsid types that we can work with and they can be made into clinical grade vectors.

And through this we also acquired a new power, which is to distribute the virus that codes for the therapeutic genes through means that are different than what we thought before. So early applications required localized delivery in one part of the brain. The approaches that are being developed today actually approach the tissue from peripheral sites, so CSF, or even from the bloodstream, and try to get widespread transduction in the brain.

And this gives us an additional power, which we didn't have before. 

[00:02:38] Dr. Sarah Camargos: Perfect. And what about the dosage of such drugs? Could you explain a bit more? 

[00:02:46] Prof. Deniz Kirik: Yeah, so of course if you intend to make a small area in the brain produce a therapeutic molecule, you would need only a small amount of virus.

If instead you want to deliver it systemically, you would have to dose the individual with a [00:03:00] much higher viral load. And of course, the immune system would recognize that there is viruses circulating in the blood. So this introduces a challenge, right? The more peripheral and widespread the effects are, the higher the dose is.

The more likely we will face with some challenges that we need to understand, one of which is immunology immunological responses from the subject. The other one is targeting, so let's assume you wanna reach the brain. You introduce your therapeutic viruses in the blood, but you also have to make sure that it does not go to the liver, it does not go to the heart or affect other organs. Some therapeutic molecules can be widely distributed and be effective without side effects, whereas others really require restricted localized deliveries. So there will be solutions optimal for different therapeutic interventions.

[00:03:50] Sarah Camargos: Perfect. What do you think about the strategy of CRISPR/Cas9? 

[00:03:55] Deniz Kirik: Gene editing has become a tool that is very effective and [00:04:00] powerful in the laboratory. We use them in so many different settings, and we have now been able to do experiments we couldn't do before. In the translational space using this tool towards the therapeutic intervention in the clinic requires us to optimize and perfect some of its characteristics. So if you, for example, want to do a genetic correction for a blood disease and obtain a sample of the tissue that you wanna modify and do that in the lab, in a dish, select the right clones and then return it to the patient, you could have a safety due to the selection. In the brain we would directly apply this in vivo in the living subjects and so we cannot accept a situation where unknown number of events take place. So for that reason, I think we have to optimize and improve the methods. So that every editing event that happens in the brain is the intended one, and no other activity takes [00:05:00] place.

So this evolution requires some work in the laboratory, in my opinion. 

[00:05:04] Sarah Camargos: Yes, otherwise it would be an off target effect.

[00:05:07] Deniz Kirik: It could be on and off target effect, it could increase the risk factor. So we need to understand that better. 

[00:05:13] Sarah Camargos: Perfect, and do you have any provision for the future. Which ones are the most promising? 

[00:05:21] Deniz Kirik: Methodological point of view, if we start with that one, now we're discussing what is the therapeutic intervention? Where are we going to apply it? When do we want to start the treatment? The next thing we're going to do is to decide on the dosing, how much and how long, and that requires another technical advancement, which is to control the expression, duration, and level today.

All clinical trials as well as approved treatments. Are considered to be, and let's call it in quotation, uncontrollable, they will have a certain production of that therapeutic entity and that subject will experience that for several years as long as we have followed [00:06:00] them. But we won't be able to change that during the follow up period.

So I think one, let's call it the third iteration of gene therapy is going to incorporate this question about how much and how long. So that's where I expect some developments will take place. On the disease entities that we target, there are over 10,000 clinical trials across the globe, in all indications. 10% of them are in C N S. That is a lot of activity. Only a small portion of this happens inside the moment disorders field. And if we look then widespread, where is gene therapy going to have a big impact? I think one can say rare genetic disorders, they were the first ones that crossed the line.

We're going to then see this widening to more common diseases. I think brain still has an advantage because we have diseases for which we have no treatments and genetic interventions are known to be effective. So I see that we are going to be championing in the field [00:07:00] and it's going to kind of become an aspect which will then have a home in many disease indications beyond those that we discussed today, I'm sure we'll see many other conditions like Alzheimer's disease targeted with gene therapy. 

[00:07:15] Sarah Camargos: Perfect. I would like to be here to see everything and to interview you again. Thank you very much Professor Kirik. 

[00:07:22] Deniz Kirik: It will be my pleasure. 

Thank you.