A new study led by researchers at University College London explored a promising new way to potentially slow down Huntington disease (HD) by reducing the levels of a key DNA repair protein, called MSH3. Using antisense oligonucleotides (ASOs)—a type of genetic therapy that targets RNA—the researchers successfully stopped C-A-G repeat expansions in lab-grown brain cells derived from people with HD. Their findings highlight a potential treatment approach that could help delay onset of symptoms and progression of HD.

How Expanding C-A-G Repeats May Drive HD

HD is a genetic brain disorder caused by an expansion of C-A-G repeats in the huntingtin (HTT) gene. Everyone inherits two copies of the HTT gene, one copy from each of their parents. While everyone has some C-A-G repeats in their two HTT genes copies, people with HD inherit a copy HTT with too many C-A-Gs.

Research has shown that in certain brain cells, particularly medium spiny neurons - the cells most affected in HD - these C-A-G repeats can continue to grow over time in a process called somatic expansion.

Many scientists believe that this ongoing C-A-G expansion in specific brain cells plays a role in determining when symptoms first emerge. Because of this, researchers have been exploring ways to slow or stop somatic expansion in hopes of delaying the onset of symptoms and slowing how fast the disease progresses.

What Can We Learn About Drug Targets From Genetic Studies?

Large genetic studies of people with HD have linked certain genes responsible for proofreading the genetic code, including MSH3, to the age at which symptoms first appear. Normally, MSH3 helps fix small mistakes in the genetic code, but in HD, it can actually promote repeat expansion, causing CAG repeats to get bigger and bigger.

Other genetic studies in people with HD also suggest that lowering MSH3 could be a promising treatment. Interestingly, a small natural genetic hiccup in the MSH3 gene, which causes people to produce slightly less MSH3, has been linked to slower disease progression, less CAG repeat expansion, and a delay of about one year in symptom onset in people with HD who have this variant.

Other types of genetic variations of MSH3 that lead to even bigger reductions of MSH3 levels have been associated with delaying HD symptoms by more than 10 years. Because MSH3 is not essential for survival and most people born with lower levels of it generally live normal lives, MSH3 has emerged as a promising drug target for HD.

A Genetic Approach to Reducing MSH3

In this study, researchers tested whether drugs designed to lower levels of the MSH3 protein could slow C-A-G repeat expansion. To do this, they used ASOs, which are short synthetic DNA-like molecules designed to bind to the MSH3 message in the cell and prevent the production of MSH3 protein, causing the levels of this protein to drop.

In dishes in the lab, the researchers grew medium spiny neurons, a type of brain cell found in the striatum - the area most affected in HD. These cells were dosed with the ASO, which led to a strong reduction in MSH3 levels. The effect the scientists saw was dose-dependent, meaning that the more ASO they added, the more the levels of MSH3 were lowered in these cells.

MSH3 Lowering Puts The Brakes On C-A-G Repeat Expansion

Importantly, the study found that lowering MSH3 stopped C-A-G repeat expansions in these neurons. In fact, the more MSH3 was reduced, the more the expansion process slowed down. At very high levels of MSH3 lowering, the CAG repeats not only stopped expanding but even began to shrink. This is a very exciting finding because it suggests that drugs lowering MSH3 might be able to reverse some of the genetic changes that occur in HD, which could be very beneficial.

To explore how this therapy might work in living organisms, the researchers developed a special mouse model that carries the human MSH3 gene. This was essential because the ASO being tested specifically targets the human version of MSH3, so the model needed to accurately reflect the drug’s intended future target - MSH3 in people.

They injected the ASO directly into the brains of these mice and found that MSH3 levels were successfully reduced across multiple brain regions, including the striatum - the area most affected in HD. This means that the drug was able to effectively spread out in the mouse brain, getting into brain cells in many different regions. Most importantly, the ASO was well tolerated, showing no signs of toxicity in these mice related to lowering MSH3.

What This Means for HD Research and Future Treatments

These findings provide strong evidence that targeting MSH3 with ASOs could be a safe and effective way to slow, stop, or even reverse C-A-G repeat expansions in HD. By preventing these repeats from growing, this strategy could potentially delay the onset of symptoms and slow disease progression.

Several biotech companies, including Rgenta Therapeutics, LoQus23, Latus Bio, and Harness Therapeutics, are now working on therapies to target somatic expansion in HD, and MSH3 targeting ASOs could be an important addition to these efforts. We expect to hear more from many of these companies later in the year at the Huntington Study Group meeting, which will be held in Nashville, Tennessee in October this year.

While this study was done in lab-grown neurons and mice, the next step would be to test this approach in human clinical trials to determine whether it could be a viable treatment option for people with HD. Stay tuned for more updates as this research progresses!