Research Project

Personalized gene editing approach for the treatment of Spinocerebellar Ataxia type 1 (SCA1) 

Principal researchers: Dr Francesca Salvatori, University of Ferrara (Italy) 

Scientific Summary  

Spinocerebellar ataxia type 1 (SCA1) is a dominant ataxia, caused by an abnormal trinucleotide CAG repeat expansion in the ataxin-1 (ATXN1) gene, which produces the ataxin-1 protein. In this project, the researchers aim to develop a patient-specific gene editing approach, to selectively inactivate the mutated allele and thus prevent the production of the toxic ataxin-1 protein. They will use the CRISPR/Cas9 system to cut the mutated allele at specific sites. 

To discriminate the mutated ATXN1 allele from the non-mutated one, they will identify and exploit single nucleotide polymorphisms (SNPs). Small guide RNAs (sgRNAs) will be designed to recognise the mutated allele, and will enable specific silencing of the production of the toxic ataxin-1 protein. 

In order to determine the efficiency of the technique, the research group uses Western Blotting. However, they have been unable to identify an ataxin-1 antibody able to correctly label the healthy and mutated ataxin-1 protein. The grant from Ataxia UK will enable the group to purchase a custom antibody in order to carry out these experiments. 

This strategy will be developed for individuals and validated on fibroblasts taken from the individual, before being tested in vivo. 

Lay Summary  

Spinocerebellar ataxia type 1 (SCA1) is a genetic ataxia, caused by a mutation in the ataxin-1 (ATXN1) gene. This mutation causes the ataxin-1 protein to become toxic, eventually leading to the symptoms of SCA1. In this project, the researchers aim to develop a gene editing approach to prevent the mutated gene from producing the toxic ataxin-1 protein. 

People with SCA1 have one mutated ATXN1 gene, and one healthy ATXN1 gene. To discriminate the mutated ATXN1 gene from the non-mutated (healthy) one, the researchers will identify and exploit small changes in the genes called single nucleotide polymorphisms (SNPs). Identifying these small differences will allow them to selectively recognise the mutated gene, and will allow them to specifically prevent production of the toxic ataxin-1 protein. 

In order to determine how well this technique is working, the research group uses an experiment called Western Blotting. This requires a label (called an antibody) which is able to attach to the ataxin-1 protein. However, they have been so far unable to identify an ataxin-1 antibody able to correctly label the ataxin-1 protein. The grant from Ataxia UK will enable the group to purchase a custom antibody in order to carry out these experiments. 

This strategy will be developed for individuals, and tested on cells taken from people with SCA1, before being tested in animal models. 

For more support or information please contact:  
Ataxia UK, 12 Broadbent Close, London, N6 5JW 
Website: www.ataxia.org.uk.   
Helpline: 0800 995 6037 Tel: +44 (0)20 7582 1444   
Email: helpline@ataxia.org.uk.