The challenge:
SLC6A1 neurodevelopmental disorder is a rare genetic condition caused by mutations in the SLC6A1 gene, which encodes the GAT-1 (gamma-aminobutyric acid transporter 1) protein responsible for regulating gamma-aminobutyric acid (GABA), the brain’s primary calming neurotransmitter. When this system fails, the balance between excitatory and inhibitory brain activity is disrupted, leading to epilepsy and significant neurodevelopmental impairment.
The disorder is classified as an epileptic encephalopathy, meaning that ongoing seizures and abnormal brain activity contribute to progressive cognitive and developmental decline. Some individuals are also at risk of Sudden Unexpected Death in Epilepsy (SUDEP).
Sasha’s condition is caused by a splice-altering mutation, which disrupts how her genetic instructions are assembled, resulting in reduced levels of functional SLC6A1 protein. Her symptoms are severe and typical of the disorder, including:
- Epilepsy with absence seizures
- Intellectual disability
- Developmental delay and regression
- Complete loss of speech (non-verbal)
- Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD)
- Sensory dysregulation
- Insomnia
- Repetitive movement stereotypies (compulsive repetitive movements)
- Incontinence and constipation
As Sasha continues to lose developmental skills, time is critical. Early intervention offers the best opportunity to preserve her remaining abilities.
The solution:
Sasha could become the first individual to receive a personalised antisense oligonucleotide (ASO) therapy designed to correct the splicing defect caused by her SLC6A1 mutation.
ASOs are short, synthetic strands of RNA that bind to faulty genetic messages, acting like a molecular “patch.” Rather than altering DNA, they restore correct RNA splicing, enabling the body to produce a functional protein. This approach is precise, reversible, and highly targeted.
To ensure the therapy is both effective and safe, the project, led by Dr Laura Croft at the Queensland University of Technology, employs advanced patient-derived cellular and organoid models that closely replicate Sasha’s brain biology:
- The Phenomics Australia node, Australian Organoid Facility (AOF), has produced 60-day-old brain organoids, along with organoids derived from a CRISPR-edited isogenic control line in which the mutation has been corrected. These paired models provide a powerful system for directly comparing diseased and healthy tissue.
- In parallel, Patient-derived induced pluripotent stem cells (iPSCs) have been differentiated into neuronal precursor cells and astrocytes by StemCore. These cell types are essential for modelling neuronal signalling and GABA regulation in the human brain.
- These cellular and organoid platforms are used to screen and optimise candidate ASOs, allowing researchers to evaluate their ability to restore correct RNA splicing and functional SLC6A1 protein expression in a physiologically relevant context.
Laboratory studies have already demonstrated promising results, with candidate ASOs successfully restoring normal splicing in patient-derived cell models. The project is now progressing toward the final stages of preclinical safety testing required before clinical administration.
Importantly, more than 15% of disease-causing mutations across all genes are due to splicing errors, yet relatively few approved therapies currently address these defects. Sasha’s treatment represents a groundbreaking step toward filling this gap and may become the first personalised ASO therapy specifically designed to correct a splicing defect in the SLC6A1 gene in a living person.
The future:
While Sasha’s mutation is unique, the implications of her treatment are global. Her personalised ASO has the potential to:
- Demonstrate that splice-altering mutations are treatable using precision RNA therapeutics
- Establish a scalable model for personalised genetic therapies
- Accelerate treatment development for numerous rare diseases
- Shift the focus from symptom management to addressing root causes
Sasha’s case is more than a single patient story; it is a proof of concept for a new frontier in precision medicine.
Success will provide hope to countless families affected by rare genetic disorders and pave the way for future tailored treatments.
