And that wraps the #HDTC2026 meeting! As always, we’re floored by the novelty and diversity of ideas moving us closer to treatments for HD. Summary articles will follow, so stay tuned!
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Claudia has applied a bottom-up approach to connect very rare symptomatic observations with new genetic causes. She is also applying meta-analyses that combine findings from multiple studies for an even richer collection of “big data.” #HDTC2026
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To overcome this challenge, there are ongoing efforts to diversify these databases with participation from folks who come from all over the world. Hopefully this means that moving forward, gene-health connection research can be more inclusive. #HDTC2026
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This kind of analysis is only made possible because of the tens of thousands of folks who participate in data collection efforts. However, these databases are dominated by people of European ancestry, which means these trends might not hold true for people from other backgrounds. #HDTC2026
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Claudia and her powerhouse team have applied their analysis to see how well they are able to predict different diseases based on data signatures alone. They have had success with multiple myeloma, a type of blood cancer, and are expanding their approach to other diseases, including HD. #HDTC2026
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Instead of considering proteins in isolation, they are looking at many readouts - genetics, proteomics, and other data, all in combination. This is called a multi-omics approach. Using AI tools, they can pull out patterns too complicated to spot with regular statistical approaches. #HDTC2026
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Claudia shows us a huge dataset where most diseases do not have signals in their protein signatures that track robustly with disease - this is disappointing, but there are other datasets to consider. #HDTC2026
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One of the biggest and best databases to study the gene-health connection is the UK Biobank. Big pharmaceutical companies and academic scientists have been analysing data to try and find links. The problem is that biology is blooming complex so the trends are not easily found. #HDTC2026
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Science for the last ~10 years has been in its “big data” phase, which science calls “omics”. We have tons of data which clever scientists like Claudia are trawling through with cool computing tools to look for trends and patterns to better understand diseases, and maybe develop new drugs. #HDTC2026
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Claudia reinforces the fact that new tools are allowing us to connect genetics with human health measures and symptoms on a large scale and like never before. This can help us diagnose diseases and predict their course. #HDTC2026
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The next talk is from Claudia Landenberg, who has positions in both London and Berlin. Her work uses large-scale data on both the molecular and clinical level to understand the effects of genetics on cells and organs in different diseases. #HDTC2026
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The next talk is from Claudia Landenberg, who has positions in both London and Berlin. Her work uses large-scale data on both the molecular and clinical level to understand the effects of genetics on cells and organs in different diseases. #HDTC2026
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They also worked in partnership with Veronica Brito’s lab, who gave a talk earlier this conference. This system worked in her lab’s models too - they could see repair in some blood cells. This suggests that blood samples from people with HD could be used to track somatic expansion. #HDTC2026
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This is an interesting new way to measure DNA damage repair. One takeaway is that there are many more successful repair events than events where repair goes awry to lengthen CAG repeats. Good to know that biology works most of the time! #HDTC2026
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The HTT gene repair signal was impacted by blocking these genes known to impact HD, but the other repair hot spots were not affected. #HDTC2026
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Next they looked to see how this EdU signal might change if different DNA repair machinery components were blocked, like MSH2, MSH3, MSH6 and PMS1 (all known to affect age of HD symptom onset. #HDTC2026
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They looked to see where else EdU was added into the genome during repair, finding good signal in repair hot spots and suggesting the new approach was working well. Paolo's team are now confident they can see where repair is occurring, and therefore infer where expansion has happened. #HDTC2026
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This experiment was a success! They could see the EdU but only in the HTT gene of cells which model HD, and not in healthy cells. The signal became more obvious in the HD cell models with longer and longer CAG numbers. #HDTC2026
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In a proof-of-concept experiment, the scientists feed a special type of DNA letter to the neurons, called EdU (pronounced E-D-U), which they can measure as it is used to fill in these gaps in the expansion bubbles in the HTT gene. #HDTC2026
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Mismatches, the bubble-outs in the DNA that often occur with expanded CAGs, are repaired with new DNA letters to fill in the gaps they create. Paolo suggests that we can infer somatic expansion by looking out for this newly synthesised DNA in the cell. #HDTC2026
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A lot of our understanding of somatic expansion comes from post-mortem brain samples. But we can’t take brain samples in a clinical trial to test if a drug can alter somatic expansion! We need ways to monitor somatic instability in living things, ideally not too invasively. #HDTC2026
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While somatic expansion has been a hot topic in HD research, Paolo points out that there are a few bottlenecks in advancing this finding toward drug development. #HDTC2026
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Up next is Paolo Beuzer from CHDI. He’ll be sharing work he’s been doing with several collaborators on a new assay that can help with studying somatic expansion in HD. #HDTC2026
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We'll be back after a quick break for the last three talks of the #HDTC2026 Conference.
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This is all possible because new genetic sequencing methods can pick up things that were previously missed! #HDTC2026
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He can also use these new methods of genome sequencing to discover new types of triplet repeats, and to infer new structural variants - previously unknown, large genetic changes - that could be causing both rare or common diseases in specific populations. #HDTC2026
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Evan’s analyses revealed that there are some people who have HD-length CAG repeats (40+), but they do not have symptoms and do not have a family history of HD. It might be interesting to study why these folks are so resilient to symptoms! #HDTC2026
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One source of his data is a US-based research program called All of Us, which recruited an extremely diverse group of Americans for inclusive genetics and medical records research. The researchers sought out diversity in racial, socioeconomic, geographic, and rare disease groups. #HDTC2026
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He can use detailed sequencing data to work backwards and identify genetic repeats that represent risk factors for common diseases like heart failure, which can then offer biological explanations and new therapeutic targets. #HDTC2026
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They can use this wealth of data to zoom out and look at structural variants (big genetic changes) and how they differ by geography and racial background. A huge percentage of genetic changes are big ones like deletions and expansions (like we see with HD). #HDTC2026
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