SLC6A1 neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in SLC6A1, which encodes the GABA transporter GAT-1. Loss of GAT-1 function disrupts GABAergic neurotransmission and is associated with developmental delay, intellectual disability and epilepsy. For patients carrying ultra-rare variants, conventional drug development is unlikely to provide a mutation-specific therapeutic option. N-of-1 antisense oligonucleotide (ASO) development offers a potential pathway to address this therapeutic gap.
We are developing a personalised splice-modulating ASO for a patient harbouring a synonymous SLC6A1 variant, c.54C>T (p.Ser18=), associated with aberrant RNA splicing. Long-read RNA sequencing was used to characterise the resulting SLC6A1 transcript architecture and define the molecular defect. Candidate ASOs surrounding the aberrant splice event were designed and screened for their ability to restore productive SLC6A1 splicing and GAT-1 protein expression and restoration of GABA transport and neuronal activity. Lead candidates are being evaluated in patient-derived cellular models, including 2D neuronal cultures and 3D brain organoids. Molecular rescue is assessed through SLC6A1 transcript and GAT-1 protein expression, with functional studies examining restoration of GABA transport and neuronal activity.
This work establishes an end-to-end N-of-1 RNA therapeutic development strategy for SLC6A1 neurodevelopmental disorder, integrating patient genomics, long-read RNA analysis, rational ASO design and patient-derived neuronal models. Beyond the development of a personalised treatment for an individual patient, this approach provides a framework that could be extended to other ultra-rare neurological disorders caused by therapeutically addressable RNA-processing defects.