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A novel therapeutic approach for the treatment of SCA3

Written by Larissa Nitschke Edited by Dr. Gülin Öz

Researchers in the Netherlands uncover a new way to treat SCA3

Upon receiving a conclusive diagnosis of Spinocerebellar Ataxia (SCA), hundreds of questions can appear in a patient’s mind: What is Spinocerebellar Ataxia? Why am I affected? How will my symptoms progress? What is the ultimate prognosis? Thankfully, years of research have enabled us to answer many of these questions for patients affected by Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph Disease. Still, the most important question a patient could ask – How can I be healthy again? – has remained unanswered.

SCA3 is the most common form of Spinocerebellar Ataxia worldwide. It is passed down from generation to generation in affected families. Initial symptoms typically appear around midlife, but cases of much earlier and much later onset have been reported. At first, problems with movement coordination are the most noticeable, leading to an increase in stumbles and falls. At later stages, speech difficulties, muscle stiffness, and sleeping problems appear, leaving the patient fatigued during the day. The symptoms worsen over the course of 10 to 20 years, at which point affected individuals typically succumb to the disease. As with other SCAs, current options for SCA3 treatment are mainly limited to symptom management rather than treating the direct cause of the disease.

Artist’s representation of DNA. Photo from Pixabay.

The genetic cause of SCA3 is the presence of excess copies of the DNA building blocks cytosine (C), adenine (A), and guanine (G) in the Ataxin-3 gene (Atxn3). Scientists refer to this type of mutation as an expansion of a triplet repeat, since the C, A, and G copies appear as sets of back-to-back CAGs. Because the CAG triplet is responsible for coding the amino acid glutamine (Gln or Q) in the Ataxin-3 protein, the repeat expansion results in an elongated glutamine (polyQ) tract. This faulty protein accumulates in cells and causes toxicity in specific regions of the brain. Since the 1994 discovery that SCA3 is caused by a polyQ expansion in Atxn3, scientists and physicians all over the world have been humbled by the question of how to help patients affected with SCA3. One specific angle of research has focused on the removal of the toxic protein altogether. However, one downside of this approach is that it would also cause the loss of normal Atxn3 function in patients. Atxn3 is critical for the degradation of unwanted proteins, which is necessary for the healthy functioning of all our body’s cells. It normally binds to little marks on proteins called ubiquitin chains (which tag proteins for removal), then cleaves these chains to facilitate the entry of proteins into the cell’s destruction machinery. Since treatment will need to be sustained over the span of a patient’s lifetime, the complete removal of Atxn3 might be harmful.

To overcome this issue, a research group in the Netherlands, in collaboration with Ionis Pharmaceuticals, sought a new way to remove only the polyQ tract from the Atxn3 protein – leaving the remaining protein and its function intact. In a cell culture system, the group used molecules known as antisense oligonucleotides (AONs; also called ASOs) that bind to selected regions in the RNA precursor of the Atxn3 protein. When the AON binds the precursor RNA, it prevents the inclusion of the polyQ expanded region into the Atxn3 protein that is built based on the RNA code. The resulting protein retains its ability to bind and cleave ubiquitin chains, but does not have the expanded polyQ repeat.

Upon demonstrating the functionality of the shortened protein in cell culture, the researchers further tested the effectiveness of AONs in a living organism. To do so, they injected the AONs into the brains of mice. AON injection achieved distribution throughout the entire brain and had no toxic effect on the animals. The shortened Atxn3 protein was observed for over two and a half months in the brains of treated mice, indicating that the AON molecule was quite stable. To test the impact on SCA3 disease development, the researchers repeated this experiment in an SCA3 mouse model. These mice have mutations similar to those seen in human patients, which result in expanded Atxn3 proteins that form toxic aggregates in the brain. Treatment with AONs reduced the amount of Atxn3 aggregates in these mice, validating its potential as a therapeutic agent for SCA3.

The clinical use of AONs appears promising so far. Clinical trials using AONs to treat children affected with spinal muscular atrophy (SMA) showed good tolerability, as well as a significant improvement in motor function. The AONs were detectable for multiple months in the cerebrospinal fluid of SMA patients, suggesting that infrequent injections could also be feasible as a treatment for SCA3. Given that SCA3 often runs in families, AON therapy could even start before the onset of symptoms in patients with a family history of the disease. This would increase the chances of delaying disease onset and slowing its progression – possibly even stopping it completely. Future studies will be needed to confirm that AON treatment can not only reduce the toxic Atxn3 aggregates, but also mitigate the main disease symptoms of motor incoordination and early lethality.

Taken together, the data in this study confirm the potential use of AONs as a therapeutic approach for SCA3. While removal of Atxn3 in the mouse appears to have no major side effects, it is so far unknown whether long-term removal can be tolerated in humans. The use of AONs could bypass this concern by only removing the expanded polyQ tract from the protein, leaving the remainder functionally intact. While these results are promising, the researchers will still need to confirm that the AON treatment can indeed improve symptoms in animal models of SCA3 and, ultimately, in patients.

Key Terms

DNA: Deoxyribonucleic acid; the molecule that carries the genetic code.

Gene: A unit of heredity made up of DNA; fully or partially controls the development of specific traits.

Mutation: A permanent alteration in DNA.

RNA: Ribonucleic acid; the molecules that carry information from DNA to the machinery that produces proteins.

AONs/ASOs: Antisense oligonucleotides; short DNA or RNA molecules that can bind to specific sequences in the RNA

Conflict of Interest Statement

The authors and editor declare no conflict of interest. Dr. van Roon-Mom, the senior author of the article reviewed, is a contributor to SCAsource. They were not involved in the writing or editing of this piece.

Citation of Article Reviewed

Toonen LJA, Rigo F, van Attikum H, van Roon-Mom WMC. Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice. Mol Ther Neucleic Acids. 2017. 15;8:232-242. (

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