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European Biopharmaceutical Review

Bridging the Gap

identifying a growing number of genes linked to rare diseases. While genetic testing provides great insight into the pathoetiology of such disorders, diagnostic discoveries rarely translate into improved therapies or, if they do, do so over the course of a drug development programme measured in years, if not decades. A poignant example of this therapy gap is epileptic encephalopathy (EE), which afflicts children with seizures starting at birth or soon thereafter. Developmental delay and autistic behaviours are prominent co-morbidities. A significant portion of these patients are refractory to antiepileptic drugs (1).

Historically, these children were diagnosed by seizure semiology and phenotype. However, nothing short of a genetic revolution has taken place in epilepsy over the last decade (2). As genetic testing has become more affordable and accessible, the sequencing of patients with EE has identified hundreds of pathogenic mutations, which are typically heterozygous, appear de novo in the patient and act in an autosomal dominant fashion. While genotype can now be used to supplement clinical phenotype for diagnostic accuracy, the prognosis remains dismal as therapies are typically lacking or only discovered through lengthy trial and error. As a means to bridge this therapy gap, an opportunity arises to combine Bridging the Gap A case study on epileptic encephalopathy highlights how the delay between gene discovery and its use to treat a disorder can be shortened by screening a library of repurposed drugs against a patient-specific mutation Dr Gregory R Stewart at Pairnomix www.samedanltd.com 53 personalised and precision medicine using repurposed drugs to rapidly translate therapeutic options back to patients in need. Closing the Gap To date, much of the research on epilepsy genetics has focused on genes encoding ion channels. Mutations in these proteins are directly associated with alterations in neuronal activity, which, with a high degree of mechanistic and clinical confidence, can be linked to the underlying evolution and propagation of seizures in the brain. For this reason, ion channel genes represent ideal targets for translational research. The first step towards performing a drug repurposing screen for a channelopathy is creating a cellular model bearing the mutation under study. Using site-directed mutagenesis and standard transfection techniques, the defective gene is introduced into cells in culture – typically Chinese hamster ovary or human embryonic kidney cells. Following successful transfection, the activity of the mutated protein is evaluated using electrophysiology, which allows for a direct readout on how the mutation alters activity through the affected ion channel. The rate and extent of channel opening and closing (measured as ion flow or conductance) is directly compared to cultures bearing the wild-type gene as a control.

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As Chief Scientific Officer, Dr Gregory R Stewart leads the scientific team at Pairnomix. He is responsible for developing the company’s scientific strategies, including its external research and drug repurposing offerings and internal development efforts. Gregory also oversees the execution of all research activities, including experimental design, research progress and delivery of findings. Prior to joining Pairnomix, he spent 20 years leading drug development efforts from the preclinical discovery phase to Phase 2 and 3 trials. He earned a PhD in neural sciences from Washington University in St Louis, US and a BSc in neuroscience from Texas Christian University, US.
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