Rare Disease - Drug Targets for Sanfilippo

Sanfilippo Syndrome is a paediatric lysosomal storage disorder that is commonly known as ‘childhood-onset dementia’, due to the severe cognitive impairment and neuronal loss associated with it. Children affected by this disorder experience symptoms such as hyperactivity, speech and hearing loss, sleep disturbances and motor impairment, all of which are followed by premature death around mid to late adolescence. While gene therapy has shown promising results in children diagnosed under the age of 2, most children are not diagnosed until 4 or 5 years of age. This highlights a critical need to identify new treatment options that could help manage symptoms, slow or stop disease progression and improve quality of life.

To begin to address this gap, the Laboratory for Human Neurophysiology and Genetics, led by Professor Cedric Bardy at SAHMRI and Flinders University, worked in collaboration with the SAGC. The aim was to understand the molecular changes underlying disease phenotypes and identify genetic targets for repurposed therapeutics. Using a human-derived neuronal model of Sanfilippo Syndrome along with state-of-the-art single-cell transcriptomic profiling, electrophysiology and machine learning, the team identified key phenotypes that may cause neurodegeneration.

As part of this, the SAGC created mRNA-seq libraries from single-nuclei extractions and sequenced these. Together, we have sequenced multiple patient lines and identified dysregulated genes and pathways that can be targeted with repurposed drugs. This has helped Cedric’s team to identify and validate therapeutic targets for Sanfilippo Syndrome, which they hope will fast-track to clinical trials and improve the quality of life for patients.

Prof Bardy’s recent publication reveals that patient-derived neurons in Sanfilippo Syndrome become trapped in a state of excitatory overdrive, disrupting critical homeostatic processes such as excitatory/inhibitory (E/I) synaptic balance early in disease progression.

This discovery provides valuable insight into how cognitive symptoms emerge—and opens new avenues for therapeutic screening and intervention.

📖 Read the full article in Nature Communications:  Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks | Nature Communications