Developing novel gene therapy technology for treatment of glycine encephalopathy (360G-Wellcome-210774_Z_18_Z)

We aim to develop a novel therapy for NKH that provides lifelong restoration of GCS enzyme activity in patient liver after a single intravenous injection. Current NKH therapies involve repeat administration of short-lived compounds, such as sodium benzoate and dextromethorphan, that cause disruption to a patient's life and do not adequately improve their neurological symptoms. Our LV-based gene therapy will provide lifelong management of a patient's circulating glycine levels, potentially rescuing neurodevelopment without the need for repeated therapeutic interventions. LV based therapies are optimal for neonatal liver therapy as these vectors integrate into patient genomes, thus providing lifelong gene restoration. At GOS-ICH, we have developed LTR1, a novel LV vector that has been engineered for enhanced safety and efficacy (Vink et al., 2017). Leading on from this grant, we intend to progress this LTR1-based NKH gene therapy into a first-in-human clinical trial at Great Ormond Street Hospital (GOSH), which would constitute the first clinical application of a liver-directed LV therapy for a paediatric, early-onset metabolic disorder. Successful outcome from this trial would also show proof- of-concept for similar metabolic diseases, such as argininosuccinic aciduria (ASA) and ornithine transcarbamylase deficiency (OTCD), for which collaborators are currently developing gene therapy treatments at GOSH.