Indu Subramanian, MD: Hi, everyone. Welcome to Medscape. We're so excited to have Professor Alfonso Fasano, who is a very animated friend and colleague of mine. He is dual appointed as a professor of neurology at the University of Toronto, and he is also a professor of neurology at Humanitas University in Milan, Italy.
He's taken the time out of his busy life to join me. My name is Indu Subramanian. I'm a neurologist at UCLA. Welcome, Alfonso.
Alfonso Fasano, MD, PhD: Thank you for having me. A pleasure to do this once again with you, Indu.
Subramanian: I had the pleasure of briefly seeing you at the Movement Disorders Society. I think there's a number of clinical highlights and a number of basic science highlights. Alfonso will be picking his favorites. Perhaps I'll hand it off to you, Alfonso.
DNA, Diagnostics, and a Huntington “Breakthrough”
Fasano: We'll start with maybe diagnostics and understanding of diseases. There's been a large amount of interest in the next generation of DNA testing, particularly dose-sequencing reads, which is probably going to help us understand diseases that are genetically based. But in the past, we simply could not really detect any mutation.
This applies not just to well-known genes that could not be detected when mutated in the past, but also new mechanisms and new genes, or intronic variants, that could not be seen in the past. Clearly, we're expanding our understanding of DNA, and this has a clear translation into clinical practice because many conditions —think about late-onset ataxia — now have the possibility to be diagnosed once and for all. For many patients, this will certainly be the starting point of understanding what's going on, but also looking into new treatments.
Maybe connected to this, a large amount of interest has been devoted to precision medicine. As we know, precision medicine is based on the assumption that understanding the biological mechanisms of a disease, particularly DNA in this example, is certainly needed for discovery of treatments that are not just symptomatic in nature, as often we have in neurology, but they're actually going to be disease modifiers.
A compound called AMT-130 is actually a gene therapy that's being used in Huntington disease. This has been a breakthrough for many of us because it's the first time that we actually see significant improvement in Huntington disease, with an approach that is not just going after the gene and protein entity in this case, but it's going after the mutated allele.
It's probably going to be a breakthrough that will have lessons for other conditions because the idea is not to reduce an expression of proteins in general, but just the one that is mutated — and in this case, acquiring a gain of function.
Parkinson’s Disease-Modifying Therapy
I'm going now into my third highlight. There's been a plenary session on the therapeutics of Parkinson's, particularly in the disease-modifying space. Historically, there's been a large amount of interest in reducing the synuclein levels. The pathology of Parkinson's disease, at least in the vast majority of cases, has to do with the aggregation of synuclein.
Some people argue that this is just a bystander that has nothing to do with the pathogenesis of the disease. In any case, it's a great model to start with and seeing whether reducing the aggregation of synuclein can reduce the progression of the disease. There are many reasons why this has not happened so far.
There may be some signal that reducing the aggregates of synuclein can reduce the progression of Parkinson's, especially in post hoc analysis when looking at a particular type of disease, a more aggressive disease. This is just the beginning of a new era with a new approach, and again, the experience that we gain with Alzheimer's, but also with Huntington disease, with a more specific tailored approach to the mutated allele or the pathological protein, if you will, might be the next step. And it might be the reason why we haven't seen a clear benefit so far.
REM Sleep Behavior Disorder
In terms of other highlights from the conference, I'm thinking of the award for the best research paper. There has been a paper focused on what's going on biologically in people with idiopathic REM sleep behavioral disorder.
RBD, or REM sleep behavioral disorder, always comes from some neurodegenerative processes going on in the brain — most of the time, a synucleinopathy. The concept of idiopathic RBD per se doesn't really exist. It depends how long you see these patients for because the longer you follow them, the more you recognize that this is just the prodromal phase of something else, namely Parkinson's or Lewy body disease.
Understanding why some people convert into one of these conditions while others don't is crucial in understanding not just the biology of Parkinson's, but also the protective mechanism or compensatory mechanism that the brain puts in place.
This particular research paper Iooked into the role of inflammatory changes in the brain, particularly deactivated microglia, which is, I think, a best paradigm for us to understand how genetic predisposition and other individual predispositions really connect with the environment in a very complex interplay. This is where the inflammatory mechanism comes into play. One that has been discussed often over the past years is the microbiota.
Maybe that's a connection, and that's the one triggering inflammatory reactions in predisposed individuals, as some animal studies have shown. Looking at microglia deactivated in RBD patients before they convert is certainly a step forward in understanding what's that trigger that enhances the neurodegenerative processes, so that the patient transitions from the classic isolated RBD to a more complex condition like Parkinson's disease.
Focused Ultrasound
Other highlights, more in the therapeutic space, that I can think of are related to the focused ultrasound field. There's been a large amount of interest in MRI-guided focused ultrasound and there have been some posters and also discussions in sessions on the new target for Parkinson's disease, which is the so-called PTT, which stands for pallidothalamic tract. Now it's approved by the FDA for unilateral and staged bilateral lesioning.
What we know so far is that this is an easy target to some extent because it's more central in the brain. Therefore, a focused approach — with ultrasound coming from all around the skull — makes total sense for a very central target. So it’s easy to lesion, and the lesion of this part of the brain seems to be good for improving dyskinesia as well as tremor. There is also some effect on rigidity and perhaps bradykinesia. This is certainly a step forward, considering the classic thalamic procedures as the very first approved treatment for Parkinson's.
Pallidotomy has been approved in the recent past. The pallidum is more lateral, so it's not easy to target and to lesion in many patients. PTT seems to be a good compromise because of the central location anatomically.
Stem Cells
Talking about therapeutic intervention, another highlight from the conference is stem cell trials. In 2025, we have seen three important papers published. There were twoback to back in an issue of Nature, and I was involved in one of them. There was one more recently in Cell from Korea.
One approach is using human embryonic stem cells, part of the so-called “floor plate protocols,” meaning that these are homogeneous populations of cells taken from embryos, but then engineered, multiplied, and purified so that they can be used on a large group of patients. It's no longer taken from an embryo one by one for each individual patient. Actually, for a single patient, you need more than one embryo historically. Instead, these are cells that are basically cultivated in vitro and can be implanted in a more safe and standardized fashion. This has been the Korean experience, with similar experience in collaborations with Boston and New York.
It’s a similar approach, cell wise, from a different company. Overall, the safety profile is quite reassuring, so no evidence of graft-induced dyskinesia or tumor proliferation. There was possibly some signal of improvement, especially comparing the people receiving a high dose of cells compared to the low dose of cells, which might be considered as a proxy of a placebo if you want, although we need better studies that are placebo controlled or even sham surgery controlled.
The third approach, also published in Nature this year, was done in Kyoto. This is using iPS cells, so induced pluripotent cells. This is really a breakthrough in the history of medicine because we can reprogram cells back to anything. Taking, for example, the skin of a patient, we can make these cells produce dopamine. This has a big advantage, which is the immunotolerance of the transplant because these are cells with the same HLA (human leukocyte antigen), so there's no need for immunosuppressants, which are still needed for the other trials that I described so far.
This is another phase 1/phase 2 study, so these are very preliminary data. It’s exciting and has been presented, but we certainly need studies with a larger group of people with sham surgery because unfortunately placebo plays a major role in any condition, and particularly in Parkinson's disease. These are more or less the highlights that I can think of. It has been certainly a great event in a beautiful location.
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.