Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder inherited in an autosomal dominant manner that leads to various symptoms including progressive cerebellar ataxia and vision loss. Similar to other SCA types, SCA7 is a polyglutamine (polyQ) disorder and is caused by a CAG expansion in exon 3 of the Ataxin-7 (ATXN7) gene. Control individuals carry 4-17 CAG repeats while this is expanded to 34-460 CAG repeats in individuals with SCA7. Generally, longer CAG repeats are associated with earlier onset of disease and more severe symptoms. SCA7 is a rare disorder with a prevalence of less than 1 per 100,000 individuals. At the moment there is no molecular therapy that can block or delay disease progression in patients.
The Ataxin-7 protein is a subunit of the Spt3-Taf9-Ada-Gcn5 acetyltransferase (STAGA) complex, which is involved in chromatin remodeling. The expanded Ataxin-7 protein alters this activity, resulting in a disrupted transcription regulation. The exact disease mechanisms involved in disease progression are still not completely understood. As the expanded CAG repeat in ATXN7 is the causative genetic mutation in patients, restoring or inhibiting the pathogenic ATXN7 mRNA transcript may offer a promising therapeutic strategy.
The main goals of SCA7 research in the Neuro-D lab:
- Generating SCA7 patient-derived induced pluripotent stem cell (iPSC) lines. These cell lines can be differentiated towards neuronal cell types (2D cell culture) and brain organoids (3D cell culture). These patient-derived cell cultures can be used to further study the disease mechanism and to test new therapeutic compounds.
- Develop and screen new RNA therapies, mostly antisense oligonucleotides, that can restore or block the mutant SCA7 mRNA transcript.