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Non-Ketotic Hyperglycinemia is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. Severe NKH presents in neonates with hypotonia, apnea and seizures and affected infants display profound developmental delay and complex epilepsy. NKH is an autosomal recessive condition, and the majority of affected individuals carry mutations in GLDC (glycine decarboxylase). Current treatments for NKH are not effective or curative. NKH is inherited as a monogenic condition with known genetic causation and is therefore potentially amenable to gene therapy. An AAV9-based gene therapy vector was designed to target sites of GCS activity in liver and brain. Using a ubiquitous promoter to drive expression of a GFP reporter, administration of vector at neonatal stages by intra-venous and/or intra-cerebroventricular route was confirmed to result in transduction of both liver and brain. Using the same capsid and promoter with transgenes to express mouse or human GLDC, vectors were then tested in a GLDC-deficient mouse model, that recapitulates key features of NKH including elevated plasma glycine concentration, accumulation of glycine in liver and brain tissues, and suppression of folate one-carbon metabolism and related metabolites. Neonatal administration of vector achieved reinstatement of GLDC mRNA and protein expression in GLDC-deficient mice. Treated GLDC-deficient mice showed significant lowering of plasma glycine, confirming functionality of vector expressed protein. AAV9-GLDC treatment also led to lowering of …