Journal Article

DZNE-2026-01107

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Single-nucleotide polymorphism-directed design of allele-specific antisense oligonucleotides for spinocerebellar ataxia type 3.

Helm, J. (First author)DZNE* ; Buena-Atienza, E. ; Sauter, C. M.DZNE* ; Wiora, L.DZNE* ; Kraft, M.DZNE* ; Schelling, Y.DZNE* ; Admard, J. ; Hübener-Schmid, J. ; Klockgether, T.DZNE* ; Synofzik, M.DZNE* ; de Almeida, L. P. ; Raposo, M. ; Giunti, P. ; Garcia-Moreno, H. ; Santana, M. M. ; Faber, J.DZNE* ; Hengel, H. ; Casadei, N. ; Schöls, L.DZNE* ; Hauser, S. (Last author)DZNE*

2026
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.adz2140

Abstract: Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease, the most common form of autosomal dominant cerebellar ataxia, is caused by a CAG repeat expansion in ATXN3. The mutant protein is prone to aggregation and exerts toxic gain-of-function effects, whereas the wild-type protein has important neuroprotective roles as a deubiquitinase. Current treatment strategies for SCA3 lack specificity for the mutant allele. Identifying genetic variants such as single-nucleotide polymorphisms (SNPs) in linkage with the pathogenic CAG expansion offers a promising avenue to develop allele-specific therapeutic interventions, like antisense oligonucleotides (ASOs). To address this, we conducted allele-specific, targeted, multiplexed nanopore sequencing on 79 patients with SCA3 from Germany, UK, and Portugal. We identified almost 200 polymorphisms and grouped them into three haplotype blocks on the basis of linkage disequilibrium. These SNPs were strongly associated with the CAG expansion. Genotypic modeling of our subcohorts indicated that targeting only two SNPs from different blocks could enable allele-specific treatment of the majority of European patients with SCA3. We evaluated 17 candidate ASOs targeting SNPs from different haplotype blocks. Seven of these ASOs caused allele-preferential reduction of more than 65%. A single ASO application in two SCA3 iPSC-derived cortical neurons (AX1, AX2) achieved up to 90% reduction of mutant ATXN3. Toxicity assessments together with RNA sequencing analyses in AX1 did not indicate evidence of toxicity or widespread transcriptional perturbations. These findings highlight that characterizing heterozygosity rates offers valuable opportunities for selective ASO therapies. Our proof-of-principle targeting with ASOs demonstrates the feasibility of haplotype-informed allele-specific silencing in ATXN3.

Keyword(s): Machado-Joseph Disease: genetics (MeSH) ; Machado-Joseph Disease: therapy (MeSH) ; Humans (MeSH) ; Polymorphism, Single Nucleotide: genetics (MeSH) ; Alleles (MeSH) ; Oligonucleotides, Antisense: genetics (MeSH) ; Oligonucleotides, Antisense: therapeutic use (MeSH) ; Haplotypes: genetics (MeSH) ; Ataxin-3: genetics (MeSH) ; Linkage Disequilibrium: genetics (MeSH) ; Animals (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Repressor Proteins (MeSH) ; Oligonucleotides, Antisense ; Ataxin-3 ; ATXN3 protein, human ; Repressor Proteins

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Contributing Institute(s):

1. Advanced cellular models of neurodegeneration (AG Hauser)
2. Parkinson Genetics (AG Gasser)
3. Patient Studies (Bonn) (Patient Studies (Bonn))
4. Clinical Research Coordination (Clinical Research (Bonn))
5. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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