Posters

To date, treatments of neurological, neuropsychiatric and neurodevelopmental disorders have focused on symptom suppression rather than the correction of pathological brain network dysfunction. Epilepsy remains one of the most prevalent neurological diseases, affecting 1% of people globally, of whom 30% remain non-responsive to current treatments. Therapies primarily focus on symptom management (i.e. seizure control), rather than addressing the inherent brain network dysfunction. Thus, the question whether one can interrogate and treat the pathological brain network dysfunction at the heart of epilepsy arises. The Lignani lab has developed a tool, which provides a platform to test the hypothesis that a transient therapeutic intervention is able to reset the pathological brain to a ‘ground state’. This novel tool is an activity-dependent promoter-driven (ADPD) gene therapy, which upregulates the endogenous Kcna1 gene. In vivo studies demonstrated the efficacy of this tool in modifying neuronal excitability, restoring physiological activity in pathological neurons, acting only when overt pathological activity is present. The next question remains: what transcriptional changes are underpinning this pathological rescue? To answer this, I am applying single cell and spatial transcriptomic tools to quantify transcriptional changes at single cell level, in situ. This data will reveal key pathways which are remodeled in the disease state, and which pathways are being rescued by the therapeutic tool. We can pair global transcriptome information with longitudinal electrocorticography recordings to disentangle genetic drivers of seizure pathology. Preliminary RNA sequencing data points to inflammation and synaptic plasticity changes being primary drivers of epileptogenesis in pre-clinical models.

Huntington’s disease (HD) is a monogenic, CAG repeat expansion disorder presenting with cognitive, psychiatric and movement problems. Alleles of >35 CAG repeats are pathogenic. CAG repeats expand in somatic cells, particularly striatal medium-spiny neurons during a gene carrier’s lifetime. HD is slowly progressive, driven by CAG expansion in these cells which eventually leads to neuronal dysfunction and cell death manifesting as clinical motor symptom onset after decades. Inheriting a larger CAG expansion causes earlier symptom onset as the repeat accelerates toward the toxic threshold more quickly. Genetic anticipation, earlier symptom onset in successive generations, is a central HD characteristic that is due to germline CAG expansion, which occurs predominantly during paternal transmission. Previous studies investigating sperm DNA showed CAG length variability in the sperm population using capillary electrophoresis. Next-generation sequencing methods are yet to be employed to investigate CAG sequence composition and variants to reliably quantify and understand germline CAG variation. This study aims to characterise CAG variability in sperm and the contribution of paternal age, inherited CAG and genetic modifiers to the rate of CAG expansion. The study involves the prospective collection of blood and semen samples from male HD mutation carriers. Five sites across the UK are now recruiting with 112 participants consented and 97 men having provided a semen sample. A protocol for remote semen collection and sperm-specific DNA extraction has been established to collect samples and to isolate germline DNA. Data will be presented comparing different sperm DNA extraction methods and capillary electrophoresis versus MiSeq sequencing.