Investigating the impact of small molecule SPT5 inhibition on somatic instability in Huntington disease

Project Overview

Huntington disease (HD) is a rare inherited condition that causes progressive damage to the brain, leading to problems with movement, thinking, and behaviour. It is caused by a genetic mutation in the HTT (or huntingtin) gene, where a short DNA sequence (called “CAG”) is repeated too many times. Although this mutation is present in every cell of the body, the disease mainly affects specific brain cells.
Importantly, the number of these CAG repeats can continue to grow over time in vulnerable brain cells—a process known as somatic expansion. This ongoing expansion is believed to worsen the disease and speed up its progression. At the same time, the mutant huntingtin protein produced by the faulty gene disrupts many normal cellular processes, contributing further to brain cell damage.
Recent research has identified a protein called SPT5 that helps control how genes are read and expressed in cells. In laboratory studies, blocking SPT5 reduced levels of the harmful huntingtin protein and improved disease-related changes in an animal model of HD. We propose that SPT5 may also play an important role in driving the harmful expansion of CAG repeats.
In this project, we will test whether blocking SPT5 can both reduce production of the mutant huntingtin protein and slow or stop the expansion of CAG repeats. We will study this using human cells derived from HD patients grown in the lab, alongside a well-established mouse model of the disease. We will also look for measurable changes in blood and cerebrospinal fluid that could serve as biomarkers to track treatment effects.
This research could lead to a new type of treatment for HD—one that targets both the root genetic problem and its harmful downstream effects—while also providing tools to measure whether the treatment is working in patients.

Partners and Donors

Brain Canada, Weizmann Canada, and the Weizmann Institute of Science