Antisense oligonucleotides to KIF1A polymorphisms expand targets and rescue patient-derived neurons in vitro.

Dominant negative pathogenic variants in KIF1A result in an allelically heterogeneous neurodegenerative condition that manifests as a variable clinical phenotype including seizures, cognitive deficits, optic nerve atrophy, spasticity, and peripheral neuropathy. One potential therapeutic strategy is allele-specific knockdown of pathogenic transcripts. However, targeting the over 100 known unique pathogenic variants is challenging. Alternatively, different pathogenic KIF1A variants in multiple patients can be knocked down by targeting shared common polymorphisms with antisense oligonucleotides, provided that the pathogenic variants are in cis with the targeted polymorphisms. Here, we use long-read sequencing data from fifty-six individuals to phase for polymorphisms. We identify four common polymorphisms that, if targetable, would make it possible for 54 of these individuals to receive antisense oligonucleotide therapy. Using patient-derived glutamatergic neurons, we characterize and quantify a cell-autonomous phenotype, dendrite neurite outgrowth length. In vitro we further demonstrate that antisense oligonucleotide-mediated knockdown of the pathogenic transcript rescues the dendrite neurite outgrowth phenotype in neurons from a patient with the P305L variant.