2025 HDBuzz Prize: When Good Huntingtin Goes Missing: A Step Toward Designing Safe HD Treatments

A new study has shed light on the role of the regular huntingtin protein in the brain. For years, researchers have known that the faulty expanded huntingtin protein drives Huntington’s disease (HD), but this new study shows why the regular version matters for brain health. By lowering regular huntingtin (HTT) in brain cells, scientists discovered hidden changes inside nerve cells that might help explain why some past HD drug trials may have run into trouble. Far from being discouraging, these findings give researchers a clearer roadmap for designing future therapies that are safer and more precise. Let’s take a closer look.

The Role of Huntingtin in Huntington’s Disease 

HD is caused by a change in a single gene called HTT. People with HD have a DNA “stutter,” a repeated stretch of the letters C-A-G, that is much longer than usual. Since everyone inherits two copies of each gene, one from their biological mom and one from their biological dad, people with HD typically carry one expanded HTT gene and one regular copy. This means that their cells produce two versions of the huntingtin protein: a faulty, expanded form that drives the disease and a regular form that supports brain health.

The Promise and Challenge of Huntingtin-Lowering

Most of the treatments currently being tested for HD in clinical trials aim to lower huntingtin protein (HTT) levels. The goal is to reduce the toxic expanded huntingtin protein, but many of these approaches also reduce the regular version. 

In recent years, potential HTT-lowering therapies have faced challenges in clinical trials, with some not working as expected or raising safety concerns. There are many reasons why this may have happened, but one possible explanation is that reducing too much of the regular HTT protein could be harmful. 

This has led scientists to ask an important question: what happens if too much regular HTT protein is lost? By understanding this, researchers can design safer trials and develop drugs that target the expanded form while sparing the healthy one.

In this new study, the researchers began to answer this by lowering expanded huntingtin in a type of brain cell, the nerve cell that transmits signals, and uncovered hidden changes that may explain why some past drug trials ran into trouble. Far from being discouraging, these findings offer a clearer roadmap for designing HD therapies that are safer and more precise.

Why Study the Hippocampus

Most research on regular HTT has looked at the developing brain, where regular HTT is essential, or at the striatum, the region that helps control movement and is most affected in HD. But most drugs circulate throughout the whole brain, not just one area. To better understand how lowering regular HTT affects overall brain health, scientists in this study turned to the hippocampus, a region of the brain that plays a central role in learning and memory.

How the Study Was Done

The researchers began by lowering regular HTT in nerve cells from a mouse hippocampus which were grown in a dish. To do this, they used a tool called siRNA, which works like a genetic “off switch” by telling cells to stop making a chosen protein. This allowed them to reduce regular HTT in a precise and controlled way.

After treatment, the researchers used special markers to label different parts of the nerve cells and then looked at them with microscopes. These microscopes can zoom in so closely that scientists can see all the intricate details of the nerve cells, including the synapses where nerve cells connect and communicate, and chromatin, the DNA-and-protein bundles that package up all our genetic material and help control whether genes are switched on or off. The team tracked how the structure of nerve cells changed as regular HTT levels dropped.

The researchers also created a mouse model to replicate the experiment and confirm the results. This step is important because findings in simple systems, such as cells grown in a dish, do not always translate to the complexity of a whole brain and body. In these mice, regular HTT was specifically removed from the hippocampus using a harmless virus that delivered a molecular switch that tells certain genes to turn off. In this case, the switch was designed to shut down the gene that makes regular HTT.

The Wiring Looks Pretty Normal

When the researchers looked at the wiring between nerve cells in these mice, they found that these structures remained mostly unchanged with less regular HTT around. That means reducing regular HTT levels did not immediately seem to disrupt how nerve cells connect to each other.

The Nucleus Reveals the Answer

The big changes were hidden deeper inside the cell. When the researchers looked at the nucleus, the control center where DNA is stored, they saw clear effects. After regular HTT was reduced, the nuclei grew larger compared to the nuclei of untreated cells.

Even more importantly, DNA in these nerve cells became less tightly packaged, making it harder for the cell to manage which genes were active.

The researchers also looked at proteins and chemical tags that help control whether genes are switched on or off. When regular HTT was lowered, their levels shifted from their usual balance. Together, these changes suggested the nucleus was less stable, even though the wiring of the nerve cells looked fine.

What This Means for the HD Community

At first, the idea that reducing regular huntingtin can affect the stability of nerve cells in the striatum might sound worrying. But in fact, these insights are good news for the HD community. For the first time, researchers know one of the possible reasons why some huntingtin-lowering drugs may have faced problems in earlier trials. Knowing this means the next generation of drugs can hopefully be designed to avoid those pitfalls. Instead of trial and error, scientists now have a roadmap showing what they should try to target and what to protect.

Importantly, this study lowered regular HTT by much more than what current drugs being tested are designed to do. In cells, levels dropped by about 86%. In comparison, clinical trials usually aim for a 30–50% reduction of regular HTT. The changes seen in this study potentially reflect what happens when the amount of HTT is lowered too far, giving researchers a clearer sense of the safe range to target.

This research also shows that not all changes are obvious at the surface. While the wiring between nerve cells looked normal, the nucleus revealed the hidden stresses that might come from lowering regular HTT. That insight gives scientists a powerful tool to check whether new drugs are safe before they move to larger trials.

A Step Closer to Safe and Effective Therapies

For families, the message is hopeful: every study, even those that uncover challenges, helps sharpen the path towards effective treatments. By understanding how regular HTT supports brain health, researchers can better design drugs that lower the harmful expanded HTT while minimizing effects on regular HTT.

Science is a step-by-step process. What we know today is built from the lessons of yesterday, and this study adds an important piece to the HD puzzle. With each discovery, the picture becomes clearer, and the future of safe and effective therapies comes into sharper focus.

Summary

• Huntington’s disease is caused by expanded huntingtin (HTT), but regular HTT is essential.
• Reducing regular HTT in hippocampal nerve cells left synapses intact but disrupted the nucleus, with looser DNA and weaker gene “off switches.”
• These results help explain one of the possible reasons why some huntingtin-lowering drug trials didn’t work as we had hoped
• Most importantly, they show the path forward: new drugs should take into consideration how much of the expanded HTT and regular HTT are reduced and find a balance that supports healthy brain function.

Learn more

“Huntingtin reduction results in altered nuclear structure and heterochromatic instability.” (Open access).

Meet this 2025 HDBuzz Writing Competition Winner

Gravity Guignard is in her final year of an Honours Bachelor of Science at Trinity College, University of Toronto, specializing in Fundamental Genetics. She conducts research in Dr. Derek van der Kooy’s laboratory, where she studies the development of neural stem cells.

This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.