Downregulation

2025-2027

This project is working on multiple fronts in Huntington's disease (HD).  It is investigating which oligonucleotide therapeutics might be most effective for treatment, and exploring CRISPR gene editing options for a lasting solution.

Specifically, we are looking to:

Develop a novel long-read DNA phasing assay for (HD, to enable accurate assignment of naturally occuring sequence variations that could be explited therapetuically.

Explore using CRISPR genome editing to target the expanded CAG repeat in HD iPSC-derived striatal neurons.

Test various allele-selective ASOs and siRNAs for mutant HTT in iPSC-derived neuronal cultures and assess downstream effects on disease pathology, including nuclear HTT aggregation, HTT1a production, DNA damage markers, and somatic expansion of the CAG repeat.

Evaluate the reversal of transcriptional dysregulation phenotypes in the oligo-treated iPSC-derived neuronal cultures after intervention.

Test lead compounds in brain organoid models and assess effects on pathobiology, including HTT distribution and aggregation, neurofilament light (NfL) and further toxicity measures.