Dr Sandra Macedo-Ribiero of the University of Porto, Portugal, has shared results from her project co-funded by Ataxia UK, ‘NanoSCA3: Development of brain-targeted nanobodies for application in spinocerebellar ataxia type 3 therapy’. Read more about the project here.
SCA3 is caused by a defect in a gene, which causes a protein, called ataxin-3, to become sticky and clump together. These toxic clumps are called protein aggregates. They cause damage to cells, and stop the cells from functioning properly, eventually leading to the symptoms of SCA3. Researchers believe the removal of these toxic aggregates could be a treatment for SCA3. This team in Portugal has some preliminary results to show that they can decrease the ataxin-3 toxic aggregates in cells using specific nanobodies they created.
Nanobodies are small parts of antibodies – a component of our immune system – that can be made in the lab. Like antibodies, nanobodies help to destroy harmful matter found in the body. They have shown promise as a therapy in a number of neurodegenerative disorders. Specific nanobodies are needed for specific conditions, and the research team have developed some for SCA3, which target the ataxin-3 protein aggregates.
The researchers previously identified a collection of nanobodies that can bind to ataxin-3. In this project, they tested the effects of these nanobodies, and showed that one of them could bind to multiple different sites on the ataxin-3 protein and interfere with its aggregation. Using a widely recognized fly model of SCA3, they saw that this specific nanobody could improve motor impairment associated with SCA3. However, the neuroprotective effect on motor function is not maintained over time, a feature they observed for other modulators of ataxin-3 aggregation, such as the molecular tweezer, CLR01, that also delayed symptom onset in a SCA3 mouse model. In the next steps, the team will move on to testing the effects of this nanobody in human cell models.
These nanobodies need to be modified to increase their safety, reduce side effects and increase the likelihood of them reaching the brain. They also need to be tested in further experiments, before eventually being tested in a clinical treatment trial in people with SCA3. The team are working on new variants of this nanobody aiming to improve their selectivity for the ataxin-3 protein. They will also test additional nanobody variants for how well they can be administered to the brain.
Should this therapy ultimately be successful, then it has the potential to be modified to work across other ataxias caused by protein aggregates, such as SCA1, SCA2, SCA6, SCA7, SCA17 and Dentatorubral-pallidouysian atrophy (DRPLA).
Work as part of this project was presented at the 2023 Euro-ataxia conference. You can watch the recording here (starting from 8 minutes 54 seconds).
This project has also been co-funded with other ataxia organisations across Europe, including Plataforma R+SCAs, AISA (Associazione Italiana per la lotta alle Sindromi Atassiche), ACAH (Catalan Association of Hereditary Ataxias) and the Swedish SCA network.
The researchers have recently published a paper on targeting ataxin-3 protein aggregation in cell and animal models of SCA3 using the CLR01 nanobody. Look out for a summary of this paper on our website.
