Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment

Brennon O'Callaghan, Bente Hofstra, Hillary P. Handler, Holly B. Kordasiewicz, Tracy Cole, Lisa Duvick, Jillian Friedrich, Orion Rainwater, Praseuth Yang, Michael Benneyworth, Tessa Nichols-Meade, Wesley Heal, Rachel Ter Haar, Christine Henzler, Harry T. Orr

Research output: Contribution to journalArticlepeer-review


Spinocerebellar ataxia type 1 (SCA1) is a lethal, autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in the ATAXIN-1 (ATXN1) protein. Preclinical studies demonstrate the therapeutic efficacy of approaches that target and reduce Atxn1 expression in a non-allele-specific manner. However, studies using Atxn1−/− mice raise cautionary notes that therapeutic reductions of ATXN1 might lead to undesirable effects such as reduction in the activity of the tumor suppressor Capicua (CIC), activation of the protease β-secretase 1 (BACE1) and subsequent increased amyloidogenic cleavage of the amyloid precursor protein (APP), or a reduction in hippocampal neuronal precursor cells that would impact hippocampal function. Here, we tested whether an antisense oligonucleotide (ASO)-mediated reduction of Atxn1 produced unwanted effects involving BACE1, CIC activity, or reduction in hippocampal neuronal precursor cells. Notably, no effects on BACE1, CIC tumor suppressor function, or number of hippocampal neuronal precursor cells were found in mice subjected to a chronic in vivo ASO-mediated reduction of Atxn1. These data provide further support for targeted reductions of ATXN1 as a therapeutic approach for SCA1.

Original languageEnglish (US)
Pages (from-to)1006-1016
Number of pages11
JournalMolecular Therapy - Nucleic Acids
StatePublished - Sep 4 2020

Bibliographical note

Funding Information:
This work was supported by NIH/NINDS grant RO1 NS022920 , a National Ataxia Foundation Pioneer award, and a Wallin Neuroscience Discovery award to H.T.O. The authors thank the Biomedical Genomics Center and Mouse Phenotyping Core at the University of Minnesota.

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