While it is still important to study HTT as a drug target, we emphasize the power of human genetics in drug development. Thanks to lab members (Lucy Namuli, Alana Slike and Mason Hollebeke) for their valuable contributions! Looking forward to sharing follow up studies shortly
Our results lend support for targeting mismatch repair genes (e.g. PMS1 MSH3) and somatic repeat instability in HD. A new McCarroll Lab paper (HD single cell expression/HTT CAG sizing) shows that HTT toxicity occurs late, while somatic expansion is constant www.cell.com/cell/fulltex...
Aggregating total evidence revealed that the mismatch repair gene PMS1 ranked favourably across all the features that we studied, while HTT (where therapeutic knockdown is being extensively studied) appears to be a theoretically riskier drug target
Although all have human genetic evidence (associated with ⬆️ clinical trial success) for modifying HD AOO, we studied new genetic features associated with clinical trial failure (genetic constraint, interactions & broad expression). HTT performed poorly www.nature.com/articles/s41...
We assessed which human traits and diseases are associated with HD modifiers. Some DNA repair genes are linked to cancer, potentially increasing Tx risk. Beyond DDR, we demonstrated that certain 'toxicity driver' HD modifiers were connected to pathological aggregates in GWAS
First, we wanted to emphasize the cross-repeat expansion disorder relevance of HD genetic modifiers. Top HD AOO GWAS variants show similar effect sizes in another RED XDP (CCCTCT repeat). Developing a successful HD modifier therapeutic may also be relevant for other REDs (n=>60)
GWAS has made progress in identifying genetic factors (e.g., MMR/DDR 💣🧬genes) contributing to the age of onset (AOO) in HD outside of CAG repeat length. Our study used diverse human genomic information to prioritize these genes for therapeutic research
I am excited to use my first post on this platform to share the results of a new study from the lab!
Genomic characterization of Huntington’s disease genetic modifiers informs drug target tractability
Available in Brain Communications academic.oup.com/braincomms/a...
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@galenwright.bsky.social and I are looking for someone to join our team!
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