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So first of all, since you've been you just gave your lecture at the MDS-ES workshop, I would ask you to start by giving us a brief overview of the topics you covered in your lecture.
[00:00:41] Prof. Olivier Rascol: Oh, the topic was covering gene therapy and cell transplantation. This is a hot topic, but that has been explored for now 40 years, starting from very basic, I would say, naive approaches like transplanting cells [00:01:00] from the adrenal medulla into the brain. But that was the initial concept, and that has been developed further with a huge improvement in technical approach in producing better cells from embryonic cells or stem cells to treat and compensate for the deficit of dopamine production into the striatum and improve the symptoms of the patient, or not using cells, but transferring the gene of different transmitters or growth factors, which makes sense for managing patients with Parkinson's disease and improving their condition using viral vectors.
[00:01:40] Prof. Tiago Outeiro: You've been involved in the development of most therapeutic strategies for PD. You have a huge experience in the field. Where do you see the greatest chances for success are? Is it gene therapy, cell therapy, or still pharmacological approaches?
[00:01:57] Prof. Olivier Rascol: Well, it depends what you mean by [00:02:00] greater chance. If it is to have positive results, then the more innovative you are, the less the chance to get a final positive outcome are, because it's more risky. But this is more what we are looking for and needing. So from gene therapy, there is already evidence that this approach can improve the symptoms of the patient.
The question is in which condition we can treat the patient with this approach in a way which will be sufficiently efficacious to compete and overcome the limitation of the existing drugs with good enough safety to expose the patient. And I think we still need a long way to improve the vectors to test the patient on the long term, and to identify the best target and the best population. For cell therapy, it's probably the same [00:03:00] thing. Technologically now there are ways to produce, in a high quality manufacturing way, cells to be transplanted, which are not anymore related to be, you know dissected from fetal tissues, which pose ethical issues, for example.
Again, we need further studies, longer follow up, to be sure that this is going to be efficacious on the long term and that it's going to be safe. Most of the materials are allogenic. They require immunosuppression. To which extent this is safe on the long term, and that must be balanced by the efficacy.
If it's extremely efficacious, then you can take the risk. On the other hand, cell therapy, which might be autologous, might not require such immunosuppressant co-treatment. But still the data in men are extremely scarce, and we have to wait until we get [00:04:00] more experience.
[00:04:02] Prof. Tiago Outeiro: And given your experience and knowledge in the field, do you think it's reasonable to expect that one day we might be able to find something that stops disease progression?
[00:04:12] Prof. Olivier Rascol: Yes, not necessarily from biotherapy or not gene therapy or cell therapy. I think that we have some evidence for the first time in the last few years that there are some molecular steps in the cascade driving neuronal deaths that can be modified with a positive outcome in patients. Because for the last 30 years, we had good theoretical targets, but we failed to demonstrate any benefit in humans.
But for example, when you look at insulin resistance mechanisms, there has been a four years ago the paper by the London's group, showing that there might be a reprotected effect. And the French network [00:05:00] that I'm chairing has recently is going to publishing another positive study with another GLP 1 agonist, which is the drug that are influencing these insulin resistant mechanism, showing that the progression over time in patient with Parkinson's disease can be significantly reduced as compared to placebo.
So, as opposed to a few years ago, where we were just looking at decades of disappointments, I think we are now opening a new area where the targets are better. Maybe the animal model is a little bit more predictive. This is still a matter of debate. But where we have finally, in repurposing approaches, but maybe also with novel medication, the chance to positively reduce the worsening of Parkinson's disease over time.
And then on the long term, maybe like for cancer or infectious disease, [00:06:00] combining different molecules, targeting a different level of the cascade, we will be more efficacious. And of course, ultimately, that might lead to the fact that if we can detect the patient at risk before the onset of the symptoms, that could move to primary prevention.
But I think this is still a bit of science fiction. It will take a number of years before we reach this step. But, if immunotherapy on alpha-synuclein is beneficial in some patients, If targeting that kinase inhibitors in other population of patients, because there are genetic reasons to believe that this is a meaningful mechanism in them, plus a generic effect like insulin resistance that could apply to across these different personalized approach — it might be in the future, yes, that we will be finally, hopefully stopping this progression, but at least significantly slowing it down.
[00:06:54] Prof. Tiago Outeiro: Are you more confident now as we seem to be developing tools that [00:07:00] may help make a decision and classifying specific types of disease that this will help and speed up progress in this area?
[00:07:09] Prof. Olivier Rascol: I think it will. I think this, we have example of successful achievements in other disease, including neurodegenerative disorder like Alzheimer's disease or multiple sclerosis. We are still in the infancy. And I think we should be cautious because there are still technological aspects that I'm not sure, I'm not a specialist in the field, but I'm not sure how hundred percent reliable they are, and reproducible.
And B, they can be markers, and that can help in screening the population for better outcome and selecting better responders, but before we can use this as a surrogate endpoint, and like in MS with MRI or other disease, there is still a long way to go. And I don't know if this will be a biological fluid marker, or if it will [00:08:00] be a neuroimaging marker, or something else, or maybe all of them combined together.
[00:08:06] Prof. Tiago Outeiro: Thank you so much, Olivier. Is there anything else you would like to highlight in the context of this workshop and your participation?
[00:08:13] Prof. Olivier Rascol: Oh, I think I learned a lot of things in this workshop. One of the message I take home back is you know, discussing with people who are good professionals with expertises in all of these biological aspects of alpha-synuclein, it emphasizes how our our understanding of all these mechanisms is still in the infancy. And it reinforced my feeling that at the moment, this is very exciting, but let's not be too overenthusiastic prematurely, even on, you know, just painting our staging or diagnosis on and putting all our eggs in the same basket.
[00:08:57] Prof. Tiago Outeiro: Yeah, I think that's good advice. Thank you so much. [00:09:00] It was a pleasure.
[00:09:00] Prof. Olivier Rascol: It was a pleasure for me too. Thank you.
[00:09:02] Prof. Tiago Outeiro: So we've just interviewed professor Olivier Rascol on the occasion of the MDS-ES workshop on diagnostic and progression biomarkers in Parkinson's disease and atypical parkinsonism in Padua, Italy.
So I thank you all for listening, and I invite you to join us in our upcoming podcasts.