Unlocking Huntington's Disease: DNA Repair Protein Could Hold Key To New Treatments

(Posted on Monday, February 24, 2025)

A new discovery offers hope for Huntington’s disease. This discovery provides hope that a DNA repair process may help slow or stop disease progression. Research has identified a critical DNA repair protein that drives the expansion of certain genetic sequences at the heart of Huntington’s disease. This breakthrough could lead to treatments that address the root cause of this devastating condition.

What Are CAG Repeats?

To understand Huntington’s disease, it’s essential to discuss what CAG repeats are. DNA, the blueprint of life, is made up of four chemical building blocks: adenine (A), cytosine (C), guanine (G), and thymine (T). These letters combine in specific sequences to form genes, which provide instructions for making proteins in our bodies. In the case of the huntingtin gene, a particular sequence of three letters—CAG—repeats multiple times in a row.

In healthy individuals, the number of CAG repeats is usually fewer than 27, which allows the gene to function normally. However, these sequences are inherently unstable and can expand over time. The number of repeats correlates with disease severity and age of onset. When the repeat count reaches 40 or more, it disrupts the gene’s ability to produce a functional protein. This malfunction ultimately leads to Huntington’s disease, causing symptoms such as movement difficulties, cognitive decline, and emotional instability.

Breakthrough Research and Therapeutic Implications

Mouse models have shown that targeting the DNA mismatch repair protein MSH3 can effectively halt or slow the expansion of CAG repeats. Research in Science Translational Medicine indicated that lower levels of the protein completely stopped repeat expansion in neurons derived from Huntington’s disease patients. Antisense oligonucleotides, synthetic molecules designed to bind to mRNA, can reduce protein levels and stabilize CAG repeats without interfering with other essential cellular functions.

Similarly, dual-siRNA therapies demonstrated dose-dependent reductions in repeat instability with minimal side effects. In mouse models, these siRNA therapies effectively reduced MSH3 activity. The results were promising, showing a significant decrease in repeat instability without major side effects. Instead of directly targeting the enzyme, which could disrupt other essential functions, scientists concentrated on silencing its messenger RNA, mRNA, thereby stopping its production.

One approach involves creating small-molecule inhibitors to block the activity of mismatch repair proteins, but no such compounds have been identified yet. Gene-editing technologies like CRISPR-Cas9 offer another promising option, as they can permanently reduce the expression of genes driving CAG repeat expansions. For example, CRISPR-Cas9 delivered via adeno-associated virus vectors has been shown to effectively disrupt the mutant HTT gene in mouse models, reducing toxic protein aggregates and improving motor function. However, systemic gene knockouts across the entire body carry risks, such as increased cancer susceptibility and disruption of essential cellular processes.

Others are exploring brain-specific knockouts using AAV vectors combined with neuron-specific promoters to mitigate these risks. These knockouts target affected regions like the striatum while sparing other tissues. Nanoparticles are also being investigated as an alternative delivery method to improve targeting and minimize immune responses. RNA-based approaches offer a safer and reversible way to suppress mutant HTT expression without permanently altering DNA. These strategies are still in development but represent significant possibilities for advancing Huntington’s disease treatments while minimizing potential side effects.

The Potential for Treating Other Diseases

The ability to inhibit somatic CAG repeat expansion could transform Huntington’s treatment by addressing the root genetic cause rather than merely alleviating symptoms. Additionally, this approach may extend to other trinucleotide repeat disorders caused by similar mechanisms.

For example, Spinocerebellar Ataxias, a group of inherited disorders, are caused by CAG repeat expansions in various genes. These expansions lead to difficulties with coordination and movement, often accompanied by other neurological symptoms. Another condition, known as Kennedy’s Disease or spinal and bulbar muscular atrophy, is linked to CAG repeat expansions, resulting in muscle weakness and hormonal imbalances.

Recent discoveries about how DNA repair processes drive CAG repeat expansions open up exciting possibilities for treating these disorders. By targeting the mechanisms that cause these repeats to grow, such as modulating DNA repair pathways or stabilizing the lengths of the repeats, we can delay the onset of symptoms or slow disease progression.

A Path Toward Hope

Identifying a driver of CAG repeat expansion represents a significant leap forward in understanding and treating Huntington’s disease. By targeting this protein or its associated pathways, researchers hope to slow or stop disease progression at its source. For those affected by Huntington’s and other repeat-expansion disorders, this discovery offers renewed hope—and a glimpse at a future where these conditions might finally be brought under control.

Back to Writings

Read Dr. Haseltine's latest piece with