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International Parkinson and Movement Disorder Society
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Special Series: Update on therapies for Huntington's disease

May 06, 2024
In the latest installment of the Chorea Special Series, Dr. Ruth Walker interviews Prof. Sarah Tabrizi about the current state of therapies for Huntington’s disease, and what is coming down the pipeline.

[00:00:05] Dr. Ruth Walker: Hello, and welcome to the MDS podcast, the official podcast of the International Parkinson and Movement Disorders Society. I'm Professor Ruth Walker from the James J. Peters Veterans Affairs Medical Center in the Bronx and Mount Sinai School of Medicine in New York City, and I'm the guest editor for this special series on chorea.

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Today, I have the pleasure of interviewing Professor Sarah Tabrizi from the Huntington's Disease Center, Queens Square Institute of Neurology. and the UK Dementia Research Center. In London, UK. 

Professor Tabrizi will be telling us about the current state of therapies for Huntington's Disease and also hopefully what is in the pipeline.

[00:00:46] Prof. Sarah Tabrizi: Thank you so much, Ruth, for the opportunity to be here and looking forward to chatting.

[00:00:52] Dr. Ruth Walker: So, I'd like to start off if you could just tell us about the current state of management for Huntington's Disease.

[00:00:59] Prof. Sarah Tabrizi: So the [00:01:00] current state of management for Huntington's disease, unfortunately, hasn't changed significantly as we don't have any disease modifying therapies yet. So the current state of management for Huntington's disease is purely symptomatic and multidisciplinary in that the management focuses on the neurological symptoms, particularly the chorea, and we commonly use either tetrabenazine or valbenazine, which has just been recently licensed or neuroleptics, but chorea is actually not the main problem that patients often complain of.

It's, it's more likely to be the cognitive and psychiatric symptoms. And I would say that the psychiatric management of Huntington's. disease is probably the part that keeps the clinic most busy and our neuropsychiatrist is the busiest person in clinic. But the, the current state of management [00:02:00] really is, as it has been for many years, which is managing the chorea, managing the speech and swallowing problems, Managing the mobility and gait problems, advanced care planning, palliative care, genetics, because it's a familial disease.

And genetics and knowing other family members is always important. And reproductive options are, are a common discussion in management of HD and in the UK and I think in many places worldwide. Now, we, we follow up also regularly. individuals who are pre symptomatic gene carriers, as well as people who are symptomatic through all the stages of the disease.

[00:02:43] Dr. Ruth Walker: Great. Thank you. It's just obviously such an important factor that these are really multidisciplinary teams which ideally manage people with these really, you know, complex,

[00:02:54] Prof. Sarah Tabrizi: Absolutely, absolutely. Definitely a multidisciplinary team.

[00:02:58] Dr. Ruth Walker: So let's move [00:03:00] on to hopefully what's coming, you know, in the future. So what do you think are the most promising strategies for molecular therapies?

There's various different trials, clinical trials going on right now. What do you think is the most exciting?

[00:03:15] Prof. Sarah Tabrizi: I mean, Huntington's disease is a genetic disease. And when the gene was found in 1993, I think everyone thought that a therapy would be around the corner. But as in brain neurodegenerative diseases, it's much more challenging then first appeared even for a purely genetic movement disorder and dementia.

So I think the two most promising areas are Huntingtin lowering therapies and also targeting DNA repair. And I'll just briefly talk about both of them. So for Huntingtin lowering, there is very good preclinical evidence that if you lower either mutant Huntingtin or even total Huntingtin in animal models of the disease, you reverse symptoms of the disease.[00:04:00] 

And so the hypothesis behind Huntingtin lowering is strong. And but it's been challenging. The first trial with the antisense oligonucleotide, which read out in December 2017, which was the study I originally led. There was a lot of excitement because the study showed that we could lower the level of the mutant protein in CSF.

And that program went quickly to a stage, phase 3 trial with 791 participants, which was actually stopped early. In March 2021 by the Independent Data Safety Monitoring Board. And the data from that paper was from that study was recently published in December in the New England Journal of Medicine.

And the reasons for the trial being stopped was that the highest dose group were doing worse. than the placebo at the time point and the [00:05:00] IDMC had unblinded data. And I think the reasons for that are multifactorial was late stage of disease patients. The dose of the ASO was too high. It was lowering wild type Huntingtin as well.

And there was inflammation secondary to the ASO with enlargement of the ventricles. So it was multifactorial. A new trial is underway now with much lower doses, and this was based on a post hoc analysis which suggested people who were younger with earlier stage disease may benefit from the total Huntingtin antisense oligonucleotide tominercin.

And now it's actually in a dose finding safety study in phase two. The other approaches with Huntingtin lowering, we've had a difficult time actually with wave had to allele selective. Targeting SNPs [00:06:00] and the, the first two trials were stopped early because there was no evidence of target engagement with the ASOs chosen.

And then Novartis started a small molecule Branaplam trial, which was a small molecule splicing modifier that had been in trials for, for spinal muscular atrophy and shown to lower Huntingtin. But that trial was actually stopped early. because neurofilament went up in plasma to very high levels and subjects developed a peripheral neuropathy, which was a known off target of these splicing modifiers, and so that study was stopped early.

There are, however, hopes on the horizon for Huntingtin lowering. There is a gene therapy trial sponsored by Unicure. which is injection of a micro RNA against exon one Huntington, which is intraparenchymal injection into the striatum with a long surgery. [00:07:00] But so far the clinical data up to 30 months, even though these are very small numbers of individuals, looks encouraging in that there looks as though there is a potential benefit in those treated versus historical control data.

So that's an ongoing study and I think is promising. And PTC therapeutics have another small molecule splicing modifier, that is currently in clinical trials and so far that data looks as though the study so far looks safe and that there's evidence of target engagement in blood and that's a small molecule and Alnylam have a lipid conjugated small interfering RNA that is about to enter clinical trials as well.

So Huntingtin lowering, I think, is still important. I think we have the challenges to do with wild type Huntingtin, which is important. Allele [00:08:00] selective approaches are difficult because it depends on there being the presence of a SNP on the mutant allele, which is only found in a percentage of the population.

Some allele selective approaches in development are approaches like looking at zinc finger proteins that switch off Huntingtin transcription and preclinically they look very exciting and that's something that I'm working on in the lab as well. And I think the Huntingtin lowering will be successful.

I'm not sure if lowering wild type Huntingtin as yet is going to show that it's safe, but the studies are ongoing. We're all trying to work hard on developing allele selective approaches. And I think the other area where there's a lot of excitement is DNA repair targeting. And what we have understood in the last five to ten years is that the CAG repeat expands during the lifetime of an individual in the brain.

So even though, You're born [00:09:00] with say, 42 repeats. The CAG repeat expands within the vulnerable regions. For example, in the striatum, particularly with CAGs up to the several hundreds having been found in post mortem tissue. And that's the, a term called somatic expansion. And we now know that genetic modifiers in the DNA repair pathways modify that somatic expansion and particularly MSH3, which we identified in 2017.

Is now, it's a mismatch repair gene encoding, a mismatch repair protein that appears to drive somatic expansion. And it looks like that if we can switch that off, we can slow somatic expansion. And that's in preclinical workup both in cell systems and in animal models. And a number of other genetic modifiers have been identified through the.

genetic modifier GWAS, and they're also being pursued. So targeting somatic expansion [00:10:00] is a very exciting area because it looks like the rate of your somatic CAG expansion in brain is what drives the brain. the rate of progression and onset. And that as the CAG gets longer, you produce a more toxic protein.

So it's, we want to treat both the somatic CAG expansion and lower the level of the toxic protein. So those are the two big areas for therapeutics. I

[00:10:29] Dr. Ruth Walker: That certainly makes sense. Suddenly, I know there's been a lot of recent work about the, the somatic expansion and trying to cut that back. And it certainly makes sense that if you can just get rid of the abnormally expanded CAG repeat track, that that would, certainly be a very good target. So, obviously, delivery these therapies is a major issue, you know, the brain seems to be really resistant to many things we want to do to it and you talked about like intrastriatal injections, I know a number of [00:11:00] these therapies have been delivered by monthly LPs and so, what are your thoughts about, the best way to get around these these delivery issues?

[00:11:10] Prof. Sarah Tabrizi: think that's a great question. Targeting the brain, delivery and distribution of molecules is our greatest challenge. And antisense oligonucleotides. Which we deliver intrathecally Do get to the brain, but they really have a cortical effect most of the lowering is in the cortex. And I think one of the reasons the Generation HD1 trial dose was chosen by Roche at a high dose was because they wanted to maximize getting as much as possible to the striatum, which we know is important in Huntington's disease, and that resulted in toxic side effects.

So delivery and distribution, I think, is our greatest challenge. And gene therapy, which is [00:12:00] direct intraparenchymal injection really targets the striatum and not the cortex. So we have this dilemma about delivery and distribution. And I think the biggest efforts in the field currently are to improve delivery of RNA therapeutics to reach more of an organ the size of the human brain, because many studies have done in mouse models, which have relatively tiny brains compared to our brains, and even in non human primates, which have much smaller brains than our brains.

And so the delivery to the human brain is the greatest challenge. And often doses are given, that are high to try and maximize brain penetration. It's also a challenge for small molecules, because even if it's an oral tablet, to get enough into the brain sometimes means that The periphery has a very high dose, as was seen by Branaplam and the peripheral neuropathy that occurred.[00:13:00] 

So I think delivery and distribution, I think we need better RNA therapeutics. We need better design with chemical bioconjugates and different lipid nanoparticles, for example, lipid conjugates. And I think we need better viral delivery, viral vectors that can, you know deliver to, to an organ the size of the human brain with shorter surgery times.

Because currently, surgery times are in excess of 12 hours to deliver to the striatum. And so, and there are promising approaches with intravenous viral delivery. And I think that's a way forward for the future. So I think exactly as you say, Ruth, I think our greatest challenge is not, not coming up with molecules.

It's how we deliver. To the human brain and its delivery and distribution, which I think is a challenge for all neurodegenerative diseases

[00:13:53] Dr. Ruth Walker: Yeah, and this is, I mean, this may be way, way off topic, I'm not sure. I remember seeing something about like [00:14:00] nanobubbles and disrupting the blood brain barrier 

[00:14:02] Prof. Sarah Tabrizi: So there is now in development, you which has been shown nicely by a number of neurosurgeons that you can ultrasound guided, produced tiny holes in the blood brain barrier and improved delivery across the blood brain barrier. And that's also something that's being developed.

Obviously that has to be managed with not disrupting the blood brain barrier too much because it's there for a good reason. So but that's right. Ultrasound approaches to disrupt the blood brain barrier. To open it to deliver molecules is an on going approach.. 

[00:14:36] Dr. Ruth Walker: And so, what do you tell someone, I mean, there's a lot of focus now on people who are technically pre motor symptomatic. And I know that kind of the more we look, the more we see , neuropsychological signs, very subtle motor signs before the frank motor manifestation where there's really, unequivocal chorea in people. So, actually, [00:15:00] let me just ask so what's the current thinking in terms of when, when do you make the diagnosis of Huntington's

[00:15:06] Prof. Sarah Tabrizi: it's a really good question because currently the diagnosis is, as you say, Ruth, is when they have clear motor signs. And that's relatively late. in the etiology of the disease. And one of the things that we did, I, I was chaired a working group with the Critical Path Institute for Huntington's disease, the Regulatory Science Consortium.

And we published in the Lancet Neurology in 2022, a new biological staging system for Huntington's disease that had support from both the FDA and more recently, the European Medicines Agency. And the biological staging system covers the whole lifetime of an individual with Huntington's disease.

So, it's actually got four stages, a bit like the cancer staging system. And [00:16:00] stage zero is the presence of the gene only. And so someone will be stage zero, potentially, if they have 42 repeats, there'll be stage zero from birth until maybe they're late twenties or early thirties. And then to enter stage one, there is a change in either your cordate or putamen volume, which is the landmark cutoff for stage one.

And that was calculated based on data from thousands of individuals and control individuals to look. for where the 5th percentile was for the cutoff. And if you were out with that, then you reached into stage one. 

So in stage one, you have nothing clinical to find.

But you have a biomarker of pathogenesis, which is a small change in the size of your chordate and putamen that is different from age and sex matched controls. And then to reach stage [00:17:00] two, that's when clinical symptoms come, and to reach stage two, you either have a change in your total motor score, where it reaches a total motor score of seven, Still very low Or a change in your symbol digit modality score test and those were the two landmarks that had the most powerful data And then stage two is what probably what we would call the old prodromal group because they have minimal motor signs or soft motor signs subtle cognitive problems and then HD integrated staging system stage 3 is when you have functional change, and that is one drop point in the total functional capacity.

And that's functional change, and that's divided into early, moderate, and late. So now clinical trials are now being done using this staging system at a much earlier time point. So most of the clinical [00:18:00] trials currently are in HDSS stage 2. which is in prodromal patients and we're doing a lot of work now to get to try and develop a framework to do trials in stage zero when people are in their late teens and twenties with nothing to find or in stage one when there's just a biomarker of pathogenesis.

And I've been leading a young adult study and we published the first paper a couple of years ago in the Lancet Neurology, and it was showing that individuals who were about 24 years before predicted onset pre symptomatic gene carriers, 24 years before predicted onset. Brain structure, function, CSF neurofilament, everything was normal.

They were identical to age matched controls. These individuals in their early 20s, and there was a lot of excitement about that data. Because it meant even [00:19:00] though you're born with the mutant Huntington gene, don't have a neurodegenerative process that's measurable from birth. And so 24 years before predicted onset, their CSF neurofilament was not significantly different from matched controls.

And We measured many different things. It was a, this cohort is deeply phenotyped and we've just finished the five year follow up of the cohort. So we know that if we treat potentially in stage zero, we might be able to prevent the disease ever occurring. And we're, and part of the journey in this is to work with the regulators on showing that something potentially works in HDSS stage two.

And then taking it further back. So I'm very excited about that area. So people who have a new positive predictive test for Huntington's disease, I always explain to them there's a huge opportunity to be involved in research, particularly also through the enrolled HD database registry study, which has got over [00:20:00] 20, 000 people worldwide.

And that eventually. We will be doing trials in stage 0 and 1 as well as stage 2. And trials are still ongoing in stage 3, and people with early functional deficits. So, there's a huge amount of research going on. So, Huntington's disease is a terrible disease. It's a terrible disease of families, as you know.

But there's a massive interest and passion about finding therapies. And I've just come back from the HD Therapeutics Conference that was in Palm Springs, where we spent a week discussing all of the different approaches to treat Huntington's disease. Mostly preclinical, but it's we will have something.

I, I'm absolutely passionate about it and I'm sure we will. And I think the new staging system gives us the regulatory framework to treat earlier, because as you say, the clinical diagnosis, is when they've got obvious motor signs. And actually that's quite [00:21:00] late in the course of the disease.

So the earlier I think we can treat, the more chance we have of rescuing this brain disease.

[00:21:09] Dr. Ruth Walker: So exciting to hear that there's so much going on. I think, I just want to make one comment about the staging system is that unlike the, the UPDRS where it's kind of like the same parameters as you move from one stage to the next, you've got like a bunch of different parameters for each 

which is a little unusual, but you know, whatever works. It's really good that you kind of have, you'll have the window of opportunity in

[00:21:35] Prof. Sarah Tabrizi: It's a research staging system because we wanted to have a regulatory framework that would allow us to treat earlier in the course of the disease. And so, In clinical practice, we still use the previous Cholson and Phan TFC staging, but that's the time they've got functional decline.

And so but in clinical practice, we [00:22:00] still make a clinical diagnosis when they've got clear motor signs. But I think with the new staging system, more people getting recruited to trials earlier with prodromal symptoms with total motor scores of eight and nine, which is still quite low. So there's, I think, and there's been a huge uptake from that group of individuals.

So I think the, The HD integrated staging system, although it was designed purely for research, is, I think, will impact clinical practice as well, because there would be the opportunity to get involved in research, people are, are more comfortable with saying they are prodromal, for example.

[00:22:44] Dr. Ruth Walker: So just to put you on the spot, what do you think the timeframe is to an effective cure?

[00:22:49] Prof. Sarah Tabrizi: Yeah. I always tell my patients that it, I promise before I retire. So I hope we have something that shows [00:23:00] benefit within the next five years. And I would hope In the next five to eight years, we will be doing a stage zero prevention trial. I know those timelines seem long, but I think it's because the drug development pipeline is slow.

I'm hoping one of the therapies that are in development at the moment it might be sooner. But I think some of the therapies that are targeting to switch off CAG, repeat somatic expansion, or to switch off the Huntington gene transcription. I think they're really exciting, but I think they're going to take longer to get to the clinic because we have to develop biomarkers of target engagement and so on.

So I think that's probably realistic timelines, hopefully shorter. Hopefully something, we'll have positive news in the next few years.

[00:23:53] Dr. Ruth Walker: Yeah. We certainly know from all of the work, the research looking for cures for any neurodegenerative disease from [00:24:00] Alzheimer's, Parkinson's, I mean, I, I think it was like in the nineties that Michael J. Fox said there will be a cure for Parkinson's in like 10 years.

And, here we are 30 years down the road. So we know that these diseases are challenging, but.

[00:24:15] Prof. Sarah Tabrizi: Lots going on. So reasons for optimism.

[00:24:19] Dr. Ruth Walker: absolutely great. And hopefully you will be able to retire at some point. All right, well, that's great. So, thank you so much, Sarah. Really interesting catching up with you.

It's, very potentially exciting field in this really horrible disease and, and hopefully with some potential for, extension to other, trinucleotide repeat diseases and also to other, neurogenetic degenerative diseases. So,

[00:24:46] Prof. Sarah Tabrizi: Thank you.

[00:24:48] Dr. Ruth Walker: Thank you. [00:25:00] 

Special thank you to:

Prof. Sarah J Tabrizi MD FRCP PhD FMedSci 
Huntington’s Disease Centre and Department of Neurodegenerative Disease 
UCL Queen Square Institute of Neurology & UK Dementia Research Institute, at UCL 

Dr. Ruth Walker 

James J. Peters Veterans Affairs Medical Center in the Bronx and Mount Sinai School of Medicine

New York City, NY, USA

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