Researchers used genetic data from 79 people with spinocerebellar ataxia type 3 to design allele-specific antisense oligonucleotides. One candidate lowered mutant ATXN3 by up to 90% in two patient-derived cortical-neuron lines.
Spinocerebellar ataxia type 3 (SCA3) is caused by a CAG-repeat expansion in ATXN3. An international academic team analyzed genetic variants linked to the expanded allele in 79 patients from Germany, the United Kingdom and Portugal. The researchers found almost 200 polymorphisms organized into three haplotype blocks and used those data to design 17 antisense oligonucleotides (ASOs) intended to reduce the mutant transcript while sparing the normal copy.
Seven candidate ASOs produced more than 65% allele-preferential reduction in the reported assays. A single application of one candidate to two SCA3 cortical-neuron lines derived from induced pluripotent stem cells (iPSCs) lowered mutant ATXN3 by up to 90%. Toxicity assays and RNA sequencing in one line did not reveal evidence of toxicity or widespread transcriptional changes under the tested conditions.
A four-platform comparison combined lipid imaging, liver-function measurements, expression profiling and CYP assays. Lipid accumulation did not uniformly reduce drug metabolism, and differences depended on the model and donor.
A 512-compound screen in patient-derived motor neurons identified resveratrol tetramers with neuroprotective activity. Follow-up work covered 14 iPSC lines and linked protection to changes in neuronal excitability.
