From Genetic Error to Promising Treatments
The most common dominant hereditary ataxia, SCA3, progressively robs coordination, but science is fighting back with groundbreaking strategies.
Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is a progressive neurodegenerative disorder that affects movement and coordination. It is the most common form of autosomal dominant inherited ataxia worldwide4 . For affected individuals, simple tasks like walking, speaking, and swallowing become increasingly difficult.
This article explores the fascinating scientific journey to understand SCA3—from the fundamental genetic mistake that causes it to the latest experimental therapies that aim to silence or even correct this error. We will delve into the proteins that malfunction, the neurons that degenerate, and the innovative tools researchers are using to design a future free from this disease.
At its core, SCA3 is a monogenic disease, meaning it is caused by an error in a single gene. This gene, called ATXN3, is located on chromosome 14 and provides the instructions for making the ataxin-3 protein4 9 .
The specific error is a "stutter" in the DNA sequence—an expansion of a CAG trinucleotide repeat in the ATXN3 gene4 . In healthy individuals, this CAG sequence repeats between 12 and 44 times2 . In those with SCA3, the sequence is expanded, typically between 60 to 87 repeats2 .
Since CAG is the genetic code for the amino acid glutamine (abbreviated as "Q"), this expansion results in the production of an ataxin-3 protein with an abnormally long polyglutamine (polyQ) tract4 . This simple molecular change has devastating consequences for the nervous system.
The normal ataxin-3 protein is a deubiquitinating enzyme, meaning it helps manage the cell's process of tagging and recycling other unwanted or damaged proteins8 . It is essential for maintaining protein homeostasis, a delicate balance crucial for neuronal health7 .
The polyQ-expanded mutant ataxin-3, however, takes on a toxic gain of function4 . It becomes misfolded and prone to clumping together inside neurons, forming toxic aggregates7 . These aggregates predominantly accumulate in critical brain regions like the cerebellum, brainstem, and spinal cord, disrupting cellular functions and ultimately leading to neuronal death7 .
Genetic Anticipation: The disease exhibits genetic anticipation, meaning the CAG repeat can expand further when passed to the next generation, often leading to an earlier age of onset in children than in their parents7 .
CAG Repeats: 12-44
Normal ataxin-3 protein with proper function
CAG Repeats: 60-87
Mutant ataxin-3 protein with toxic polyQ tract
While many therapeutic strategies aim to reduce the toxic protein, a groundbreaking approach seeks to fix the problem at its source—the DNA. A 2025 study published in Gene Therapy explored a sophisticated "ablate-and-replace" strategy using the CRISPR-Cas9 gene-editing system8 .
The researchers faced a challenge: simply destroying the mutant ATXN3 gene could also eliminate the essential functions of the normal protein. Their ingenious solution was a two-part strategy:
Use a self-inactivating CRISPR-Cas9 system (KamiCas9) to cut and disrupt the mutant ATXN3 gene in the cerebellum, halting the production of the toxic protein.
Introduce a healthy, replacement gene—a naturally occurring, CRISPR-resistant paralog of ATXN3 called ATXN3L—to take over the vital functions of the original protein8 .
This approach is suitable for all SCA3 patients, regardless of their specific genetic background.
They packaged the KamiCas9 gene-editing machinery and the ATXN3L replacement gene into adeno-associated viruses (AAVs), which act as molecular delivery trucks.
They injected these AAVs directly into the cerebellum of the SCA3 mice, targeting the deep cerebellar nuclei, a region critically affected in the disease.
Two months post-injection, they analyzed the mouse brains to measure editing efficiency, ATXN3L expression, and the health of cerebellar neurons.
The experiment yielded promising results, summarized in the table below.
| Measurement | Result in "Ablate" Group | Result in "Ablate-and-Replace" Group | Significance |
|---|---|---|---|
| Gene Editing Efficiency | 55% ± 18% of ATXN3 genes edited in the cerebellum | Similar high editing efficiency achieved | Demonstrates the technique can robustly reach and alter the target gene in the affected brain region8 . |
| Cerebellar Neuron Markers | Improved markers of neuronal health | Improved markers of neuronal health | Suggests that the strategy can mitigate the neurodegenerative effects of mutant ATXN38 . |
| Replacement Gene Expression | Not Applicable | Successful expression of the healthy ATXN3L protein | Confirms that the replacement gene can be delivered and produce functional protein in the brain8 . |
Proof of Principle: This study provides a crucial proof of principle that a one-time, permanent gene-editing treatment for SCA3 is a realistic future possibility. By not only removing the toxic gene but also providing a healthy substitute, this strategy aims to preserve essential cellular functions, potentially offering a safer and more comprehensive therapeutic outcome8 .
The fight against SCA3 relies on a sophisticated arsenal of research tools. The table below details some of the essential reagents and their functions.
| Research Reagent | Function in SCA3 Research |
|---|---|
| Adeno-Associated Viruses (AAVs) | Used as gene delivery vehicles to transport therapeutic genes (e.g., CRISPR machinery, ATXN3L) directly into the brain8 . |
| CRISPR-Cas9 Systems (e.g., KamiCas9) | Gene-editing "scissors" that allow researchers to make precise cuts in the DNA of the ATXN3 gene to disrupt or correct it8 . |
| Antisense Oligonucleotides (ASOs/AONs) | Synthetic short DNA/RNA molecules designed to bind to ATXN3 RNA, preventing the production of the mutant protein5 . |
| SCA3 Transgenic Mouse Models (e.g., MJD84.2) | Animals genetically engineered to carry the human mutant ATXN3 gene, used to study disease progression and test therapies8 . |
| Plasma Neurofilament Light Chain (NfL) | A biomarker measured in blood that indicates neurodegeneration; levels rise years before symptoms appear, making it useful for tracking disease progression and treatment response3 . |
Adeno-associated viruses (AAVs) are engineered to deliver therapeutic genes to specific cells in the brain. They are modified to be non-pathogenic and can target neurons affected in SCA3.
The CRISPR-Cas9 system acts like molecular scissors that can cut DNA at precise locations. In SCA3 research, it's used to target and disrupt the mutant ATXN3 gene.
The gene-editing strategy is just one of several exciting avenues being explored. The therapeutic pipeline for SCA3 is rapidly diversifying, with multiple candidates at different stages of development.
| Therapy / Candidate | Mechanism | Latest Reported Stage |
|---|---|---|
| Troriluzole (BHV-4157) | Modulates glutamate signaling in the brain to improve ataxia symptoms5 . | Under FDA review5 |
| VO-659 (Vico Therapeutics) | Antisense oligonucleotide (ASO) that targets the mutant ATXN3 mRNA to reduce toxic protein5 . | Clinical trials initiated3 5 |
| Cure Rare Disease ASO | Antisense oligonucleotide designed to reduce mutant ATXN3 protein5 . | Preclinical development5 |
| Stemchymal | Mesenchymal stem cell therapy aiming to reduce inflammation and repair tissue5 . | Investigational therapy5 |
| Ablate-and-Replace Gene Editing | Permanently disrupts mutant ATXN3 gene and replaces its function8 . | Preclinical proof-of-concept8 |
The progress doesn't stop there. Other strategies being investigated in labs include:
Drugs that enhance protein clearance pathways to help cells remove toxic aggregates4 .
Compounds that improve mitochondrial function to support neuronal energy needs4 .
Agents that modulate histone acetylation to correct errors in gene transcription4 .
The journey to understand and conquer Spinocerebellar Ataxia Type 3 has been a remarkable demonstration of scientific progress. From identifying a single genetic misspelling to now developing complex tools like gene editors and molecular scalpels to correct it, research has moved at an accelerating pace.
Aided by advanced techniques like long-read genome sequencing7 .
Like neurofilament light chain (NfL) to monitor disease progression and treatment efficacy3 .
From symptomatic treatments to disease-modifying ASOs and potentially curative gene therapies.
Future Outlook: While challenges remain, the collective efforts of the global research community are steadily transforming SCA3 from a relentlessly progressive disorder into a treatable, and perhaps one day, preventable condition.