Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons
Stefan Hauser, Jacob Helm, Melanie Kraft, Milena Korneck, Jeannette Hübener‐Schmid, Lüdger Schöls
Abstract
that is present in most SCA3 patients. We found ASOmut4 to reduce levels of mutant ataxin-3 by 80% after 10 days while leaving expression of wild-type ataxin-3 largely unaffected. In a long-term study we proved this effect to last for about 4 weeks after a single treatment without signs of neurotoxicity. This study provides proof of principle that allele-specific lowering of poly(Q)-expanded ataxin-3 by selective ASOs is feasible and long lasting, with sparing of wild-type ataxin-3 expression in a human cell culture model that is genetically identical to SCA3 patients.
Topics & Concepts
Spinocerebellar ataxiaMutantMachado–Joseph diseaseWild typeBiologyDownregulation and upregulationMutationAtaxiaCell biologyGeneticsMolecular biologyGeneNeuroscienceGenetic Neurodegenerative DiseasesDNA Repair MechanismsCRISPR and Genetic Engineering