Dr. W. van Roon-Mom
Developing a SCA1 therapy targeting the ataxin-1 protein in a patient-specific neuronal cell model
The goal of this project is to develop three different strategies to reduce toxicity of the polyglutamine expanded ataxin-1 protein that causes spinocerebellar ataxia type 1(SCA1), a neurological condition that leads to progressive disturbances of coordination, balance, speech and swallowing, and to loss of independence and early death. SCA1 is an autosomal dominant disorder caused by an expansion of a CAG repeat in the ataxin-1 gene and mRNA that results in an expanded polylgutamine repeat in the ataxin-1 protein. This protein with an expanded polyglutamine stretch aggregates in the brain, and these protein aggregates are considered a pathological hallmark of the disease.
We hypothesize that by prolonged lowering of mutant ataxin-1 toxicity, we can halt or reverse the disease progress in SCA1 patients. We will reduce toxicity by designing different antisense oligonucleotides (AONs) that specifically target the disease-causing ataxin-1 mRNA, resulting in either reduced expression of the ataxin-1 protein, or in a modified ataxin-1 protein lacking the polyglutamine expansion. At the end of this project, we will select the two most promising therapeutic strategies for further development.