Shota Shibata, MD, PhD
Research Fellow, Massachusetts General Hospital, Dr. Ricardo Mouro Pinto
Clinically accessible biomarker for CAG somatic instability in Huntington’s disease
Huntington’s disease is caused by an expanded DNA sequence in the HTT gene, and this sequence continues to lengthen in certain cells over a person’s lifetime. Growing evidence suggests that this ongoing “somatic expansion” may play a major role in when symptoms begin and how quickly they progress, which is why several companies are now developing therapies aimed at slowing or stopping this process. The challenge is that we currently have no reliable way to measure somatic expansion in living people. Existing methods underestimate the longest and most relevant expansions, and the tissues that show the biggest changes are located deep in the brain and cannot be sampled in routine clinical care. Dr. Shibata’s project tackles both limitations. His team will test whether cells collected through a simple outpatient procedure can act as a useful window into the genetic changes that occur in the brain. In parallel, they will build a next-generation measurement method that tags each DNA molecule with a unique “barcode,” allowing the true length of expanded sequences to be captured without the distortion that affects current assays. The approach also incorporates a strategy that groups DNA molecules together to dramatically increase sequencing speed and reduce cost, which is essential for future clinical use. If successful, this work would deliver the first practical tool for tracking somatic expansion in living patients. That would give researchers a clear way to test whether emerging therapies are affecting this key genetic process, enabling faster, more decisive clinical trials and supporting the development of treatments that aim to slow disease progression at its root.
