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EHDN 2022 | Biomarkers for therapeutic development in Huntington’s disease

Huntington’s disease (HD) is caused by abnormal expansion of CAG repeats in the Huntingtin (HTT) gene, which gives rise to mutant HTT (mHTT) protein, as well as smaller toxic mHTT fragments through splicing and post-translational modification processes. Accordingly, disease modifying strategies in HD are predominantly focused on HTT lowering. Lauren Byrne, PhD, UCL Queen Square Institute of Neurology, London, UK, discusses the importance of developing HD biomarkers for assessing the impact of therapeutic interventions. Advances in ultrasensitive immunoassays have enabled the measurement of HTT in cerebrospinal fluid (CSF) to demonstrate target engagement in clinical trials of HTT-lowering investigational agents. However, these CSF measures cannot provide information on the distribution of HTT lowering throughout the brain. Current studies are working to develop mHTT-PET tracers to enable visualization of mHTT in specific regions throughout the brain. Dr Byrne also comments on efforts to develop markers of somatic instability. Thought to have an impact on age-of-onset and disease progression, measures of somatic instability in patients over time could be very valuable in future clinical trials. This interview took place during the European Huntington’s Disease Network 2022 Plenary Meeting.

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Transcript (edited for clarity)

For Huntington’s disease, there’s a big push, therapeutically, to target the huntingtin protein and try and lower it. Huntingtin protein being the cause of what goes wrong in all cases of Huntington’s disease. So for those kind of trials, we need ways to actually measure that those drugs are doing what they’re supposed to do. And to do this, we can use things like the immunoassays, which combine to huntingtin in the cerebrospinal fluid of patients...

For Huntington’s disease, there’s a big push, therapeutically, to target the huntingtin protein and try and lower it. Huntingtin protein being the cause of what goes wrong in all cases of Huntington’s disease. So for those kind of trials, we need ways to actually measure that those drugs are doing what they’re supposed to do. And to do this, we can use things like the immunoassays, which combine to huntingtin in the cerebrospinal fluid of patients.

That’s been really important so far to show target engagement for different therapies. But it doesn’t tell us about where in the brain these drugs may be targeting and if they’re lowering huntingtin across the whole brain or in certain regions. As all of these different drug therapies have different approaches and different targets, in terms of they could be intrathecal ASOs or they could be gene therapies that target the center of the midbrain. That’s a huge unmet need, I think, in the field, and one of the reasons why I invited Aline Delva to give an update on the huntingtin PET MRI study called iMAGEmHTT. This is one of the first radiotracers that have been targeting the mutant huntingtin protein in the brain. So it’s exciting to see where that is, in terms of clinical development. But that, I think, is a huge unmet need for huntingtin lowering programs.

One thing that didn’t come up during the session, or my session at least, was the ability to look at somatic instability in patients in their lives. Somatic instability is this idea that the huntingtin gene mutation, which is a CAG repeat expansion, although everybody has a allele that they get measured when they get the genetic test, what researchers have found in different tissue in the body, and in particular tissues that are very impacted in Huntington’s disease like the striatum, there are much higher repeats. And it links to some of the findings in the genome-wide association studies, which have shown hits in genes that are involved in DNA maintenance and repair, as well as new findings that have shown that if the actual sequence of the polyglutamine stretch in the huntingtin gene is slightly different, where you can have CAA insertions or CAGs, but it’s still polyglutamine, that can have a huge impact on age of onset.

There’s a story coming out from all these different findings that this might be really important in disease progression, but we currently can’t measure this in patients over time because we can’t really biopsy of the brain and the tissue where the larger expansions are happening. If we could find a method as a biomarker to measure that, that will be hugely important for the future of upcoming trials and new gene candidates that are hopefully targeting this.

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