Updates in Huntington's Disease | Congress 2026

Samuel Kim: Thanks for the invitation.

Eduardo de Pablo Fernandez: So we are talking about advances in Huntington's disease, and the first question is about the pathobiology of Parkinson's and the recent advances in our understanding on the genetic mechanisms.

We have had the discovery of somatic repeat expansions [00:01:00] and also the role of DNA repair genes as modifiers of the genetic information. So, can you give us a brief summary of the advances in this field?

Samuel Kim: Sure.

I think everyone recognizes there are modifiers that modify the huntingtin's gene expression and

for a long time, we weren't sure what these modifiers were. Now, with Huntington's disease, the CAG repeat count does explain some of the reasons, mainly in terms of the age of onset.

The CAG repeat count explains about 70% of the variance about the age of onset. And so there's always a mystery in terms of why someone with the same CAG repeat count presents late versus early. With the recent expansion in the knowledge of the pathogenesis, especially with the somatic CAG repeat expansion, I think that this goes a long way in explaining some of the variance that we're seeing in people.

And so [00:02:00] this is a potential target that we can look into to modify the disease progression. So far we've been looking at modifying the  huntingtin gene, and lowering the huntingtin protein has been the main target. But so far we haven't translated the reduction in protein level in CSF to actual efficacy in people.

Potentially with this new discovery of somatic CAG mutation, we can look into another method of modifying the disease process.

Eduardo de Pablo Fernandez: And we will talk a bit more about that later. But my understanding is that the old concept of Huntington's disease, seen as related to the accumulation of the mutant huntingtin, now it's a bit more of a dynamic DNA disease where repair genes and somatic expansions can modify the expression.

If we move now to the field of diagnostics or biomarkers to monitor disease. A few years back the [00:03:00] international agreement to provide the integrated staging system provided a pathway to monitor disease from a clinical and also biological perspective.

But there has been advances recently in other biomarkers, such as neurofilament light chain the ability to also quantify mutant huntingtin in CSF, and also the detection of the somatic expansions that we discussed before in blood. How do you feel like these biomarkers can complement the staging system, and how close are we to measure acutely disease activity before the symptoms manifest?

Samuel Kim: I think these biomarkers are mainly used in the research setting. These biomarkers allow us to measure whether the disease activity that we're trying to treat, whatever target we're trying to treat, whether that treatment actually engages the target. So far we've been trying to reduce the huntingtin protein level by directly measuring mutant huntingtin protein level in [00:04:00] CSF and NfL, and we can look into whether there's target engagement. So that helps us in terms of measuring are we achieving what we're trying to achieve, and does that actually translate into efficacy?

Eduardo de Pablo Fernandez: This is one of the difficulties of performing clinical trials in a population where we don't have any clinical monitoring reliable to detect disease activity. So if we move a bit towards therapeutics, you mentioned the previous efforts to reduce mutant huntingtin, and tominersen was the the main clinical trial about this that showed a bit disappointing results. What do you think about these types of therapies? Do you think this is the end of the road or where do you see the field moving forward in that area?

Samuel Kim: I think there's still ongoing research looking into lowering  huntingtin protein. There's plenty of trials still in progress and , I believe, upcoming. And so this story is not quite dead, if you want to put it that way. But [00:05:00] yeah, we've had a number of trials that have come to a dead end, and some of the studies have shown promise, and yet we haven't come up with anything to actually release to the public to say that there are treatments that are now available after years of trying.

It is certainly very disappointing, but it's not the end of the road, I believe.

Eduardo de Pablo Fernandez: Excellent. And yeah, we will be looking forward to more news in that field. You also mentioned potential therapeutic targets with somatic expansions, and also we have a new kid on the block with suppression of huntingtin expression. And there was an interesting and promising study with gene therapy delivered using AAV virus.

What are your views on the results of this and these potential therapeutic opportunities?

Samuel Kim: In terms of AMT-130 I think last year, in 2025, there was a lot of interest in this study because it released the data saying there was clinical efficacy in slowing the composite UHDRS decline in people who had this therapy. The [00:06:00] unfortunate side of this story is that there was no placebo that they compared it to.

They compared the data against an external matched cohort from Enroll-HD. And it's not really a placebo-controlled trial, so we cannot really make definite conclusions from that study. I think that recently they released some further data from the, I think, 48 month result, and that showed there was some reduction in the composite UHDRS, but not as much as what we saw in the 36 month data.

And the result wasn't statistically significant. So yeah, this story, it's still to be seen where this lands. I think in the US there was an application for, I think they call it BLA, biologic license application, I believe. So yeah, if it gets released, then perhaps this will be rolled out in the clinic, and we'll be able to gain some [00:07:00] more data as to whether it's actually effective or not.

This story is still unfolding as we speak, I guess.

Eduardo de Pablo Fernandez: Yeah. As you mentioned, there is limited information about this trial, and there are certainly some limitations, but it's promising to see that there is some biological signal there. Thank you very much for joining us today and give us this overview about the advances on Huntington's disease.

Thank you very much, Samuel. 

Samuel Kim: Thanks so much.

Eduardo de Pablo Fernandez: Thank you.