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Explore a past NAF research grant awardee’s funded study, gaining scientific insights about their Ataxia research.

Dr. Hannah Shorrock will present the research, “A CAG expansion selective small molecule screen for multiple spinocerebellar ataxias.”

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Research Lay Summary: The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases. While SCAs can be caused by a variety of genetic mutations, a large sub-group are caused by CAG repeat expansion mutations in different genes. These CAG expansion SCAs include SCA types 1, 2, 3, 6, 7 and 12, all of which involve expression of expansion RNAs and some the expression of toxic polyglutamine proteins. There are currently no approved treatments for these diseases and preclinical therapy development mainly focuses on disease-specific approaches. The goal of my proposal is to screen and identify compounds that provide therapeutic efficacy across the family of SCAs caused by CAG repeat expansions. To accomplish this goal, I will generate a cell line that express both a tagged (CAG)60 repeat expansion and a no-repeat control transcript and screen small molecule libraries in this cell line to identify compounds that selectively reduce levels of the toxic (CAG)60 expansion transcripts. As the (CAG)60 expansion will not be in the genetic context of any specific SCA, this screen is designed to identify compounds that selectively target expanded CAG transcripts independent of the gene-specific sequences. Therefore, compounds that I identify are likely to have therapeutic potential against multiple SCAs. These candidate compounds along with selected compounds which show efficacy in other repeat expansion disorders will then be used to treat patient-derived cell lines from multiple SCAs to compare therapeutic efficacy and mechanism of action. I will assess the effect of treatment on the expression of CAG expansion RNAs, polyglutamine expansion proteins and downstream phenotypes specific to each SCA. This approach provides an exciting opportunity to not only understand common SCA pathogenic mechanisms but also to develop novel candidates that have therapeutic potential across multiple SCAs.