Reducing DNA repair protein levels to target root cause of Huntington’s disease microbiologystudy

Researchers from the Huntington’s Disease Center, UCL Queen Square Institute of Neurology, and UK DRI at UCL have taken major steps forward in advancing MSH3-targeting therapies for Huntington’s disease (HD). Their study is published in Science Translational Medicine.

Using an HD patient-derived neuronal model, their paper defines the level of MSH3 lowering required to suppress CAG repeat accumulation and demonstrate the safety of this approach, while also introducing a mouse model with humanized MSH3 to evaluate future treatments in vivo. These achievements lay an important foundation for clinical trials targeting the genetic cause of the disease.

Huntington’s disease is a genetic condition caused by an unusually long DNA sequence (CAG) in the huntingtin gene. In individuals with HD, this already extended sequence of CAGs continues to get longer throughout life until reaching a threshold when it becomes toxic to cells, leading to the progressive loss of brain cells. This degeneration results in uncontrollable movements, cognitive decline, and psychiatric symptoms.

Although there are currently no disease-modifying therapies available for HD, multiple genome-wide association studies (GWAS) conducted over the past decade have uncovered new opportunities for therapeutic intervention. These studies have consistently highlighted the role of DNA repair in influencing the age of onset and disease progression.

Among the DNA repair genes identified, MSH3 has emerged as a particularly promising therapeutic target. MSH3, a key component of the mismatch repair system, recognizes and attempts to repair unusual structures formed by the CAG repeat tract in the huntingtin gene. However, this process inadvertently worsens the disease by further lengthening the CAG repeat tract, accelerating cellular toxicity and brain cell death.

To determine the level of MSH3 lowering required to have a meaningful impact on CAG repeat expansion, the research team used a neuronal model generated from patient stem cells. Donated by the family of a young girl with juvenile Huntington’s disease, these cells are one of the few patient lines that demonstrate CAG expansion over a reasonable experimental timeframe (in this case, measured over 15 weeks).

The stem cells were developed into neurons from the striatum, the brain region primarily impacted by Huntington’s disease, making the model relevant to disease conditions. These neurons were then treated with an antisense oligonucleotide (ASO) that binds to MSH3 mRNA, reducing its expression, and changes in CAG repeat expansion were measured over time with varying levels of MSH3 suppression.

In addition to showing promising effects on reducing CAG repeat expansion, the researchers also highlighted the potential safety of MSH3 lowering in these neuronal cells. Using RNA sequencing, they found that reducing MSH3 levels had no detectable impact on DNA repair pathways or cancer signaling.

To support future testing of MSH3-targeting therapies, the team also developed a mouse model with humanized MSH3, enabling preclinical evaluation of the efficacy and safety of future MSH3-targeting molecules.

These results provide valuable information for future clinical trials aimed at developing disease-modifying treatments for Huntington’s disease.

This promising strategy could slow or halt Huntington’s disease progression at the root of its genetic cause. “Targeting MSH3 is exciting not only because it’s directly involved in the CAG repeat expansion, but also because genetic studies suggest that loss of MSH3 function is relatively well-tolerated in humans,” said corresponding author, Professor Sarah Tabrizi.

“Our findings emphasize the potential for MSH3 suppression as a safe and effective way to delay Huntington’s disease.”