Poster abstracts
Poster number 173 submitted by Anasemon Botros
Using Antisense Oligonucleotides to Induce Exon 10 Skipping as a Potential Therapeutic Treatment for Spinocerebellar Ataxia Type 3 (SCA3)
Anasemon Botros (Biology and Lewis University)
Abstract:
SCA3 (Machado Joseph Disease) is a neurodegenerative disease caused by excessive glutamine (polyglutamine) in the Ataxin-3 protein which is due to an expansion of the CAG codon in exon 10 of the ATXN3 gene. A healthy individual can have as many as 44 CAG repeats. Symptoms of the disease begin to appear at 45 plus CAG repeats. The excess polyglutamine causes the protein to aggregate and leads to neuronal death, resulting in symptoms ranging from impaired motor functions to death. Currently, there is no cure for the disease. A therapeutic method is being tested via exon 10 skipping of the ATXN3 gene which would result in the removal of the CAG repeat while leaving the binding domain and C-terminus of the protein intact. To determine if this is a viable therapeutic method, C. elegans with the endogenous Ataxin-3 gene knocked out, were used to assess lifespan and movement to determine if the truncated protein was detrimental. Results showed that the truncated protein improves lifespan over the mutant protein with the polyglutamine repeat without altering motor function. To develop a therapeutic to be used in patients, Antisense oligonucleotides (ASOs) were tested on several target sequences to induce exon 10 exclusion during splicing. Various chemical modifications to the ribose backbones, such as 2’MOE and phosphorothioate modifications were compared to determine the most efficient chemistry.
Keywords: CAG, SCA3, Ataxin-3