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ASOs Against ATXN2 in Preclinical and Phase 1 Trials

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Trials for Cerebellar Ataxias

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease caused by DNA CAG repeat expansion. The mutation is in the coding 1st exon of the ATXN2 gene and results in an expanded polyglutamine (polyQ) domain. SCA2 is characterized by progressive ataxia and involves primarily Purkinje cells (PCs) but also other neurological systems. Some individuals with ATXN2 mutations can present as pure Parkinson or Lou Gehrig disease. Long normal ATXN2 alleles are risk alleles for amyotrophic lateral sclerosis. Comparison of mouse models expressing mutant ATXN2 (Pcp-tg-hATXN2-Q127; BAC-hATXN2-Q72) and Atxn2−/− mice clearly favors a predominant gain-of-function mechanism of repeat-expanded ATXN2 based on morphologic, transcriptomic, and slice physiology analyses. The lack of a neurodegenerative phenotype in Atxn2−/− mice led us to adopt a strategy of targeting wild-type and mutant ATXN2 with antisense oligonucleotides (ASOs). In two transgenic models, we were able to provide proof-of-principle data that targeting ATXN2 with intracerebroventricular injection of ASOs can slow progression of motor dysfunction. ASO treatment also improved expression levels of PC-specific proteins and PC firing frequencies in the acute cerebellar slice. An ASO targeting ATXN2 is currently in phase 1 human trials (BIIB105).

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Acknowledgments

I want to thank SCA2 patients, their spouses and partners, who often serve as caregivers, on several continents for their help with understanding SCA2. Special gratitude and recognition go to members of my laboratory over the last three decades for their intellectual and technical contributions.

Funding

This work was supported by grants R01NS33123, R56NS33123, RC4NS073009, UO1 NS103883, and R37NS033123 from the National Institutes of Neurological Disorders and Stroke.

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Authors and Affiliations

  1. Department of Neurology, University of Utah, Salt Lake City, UT, USA

    Stefan M. Pulst

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  1. Stefan M. Pulst
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Correspondence to Stefan M. Pulst .

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Editors and Affiliations

  1. Professor of Neurology, Shuang Ho Hospital, Taipei Medical University, Taipei, (Republic of China), Taiwan

    Bing-wen Soong

  2. Professor of Neuroanatomy, University of Mons and CHU-Charleroi, Charleroi, Belgium

    Mario Manto

  3. Paris Brain Institute, (Institut du Cerveau – ICM), CNRS INSERM, Sorbonne Université, APHP, Paris, France

    Alexis Brice

  4. Department of Neurology, Spencer Fox Eccles School of Medicine University of Utah, Salt Lake City, UT, USA

    Stefan M. Pulst

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Pulst, S.M. (2023). ASOs Against ATXN2 in Preclinical and Phase 1 Trials. In: Soong, Bw., Manto, M., Brice, A., Pulst, S.M. (eds) Trials for Cerebellar Ataxias. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-031-24345-5_15

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