CLN1 disease is caused by deficiency of the lysosomal enzyme Palmitoyl Protein Thioesterase (PPT1), and is theoretically amenable to enzyme replacement therapy (ERT) or gene therapy to replace the missing PPT1 enzyme. We have previously shown partial efficacy of ERT in both PPT1 deficient mice (Ppt1-/-) and a CRISPR/Cas 9 generated CLN1 R151X sheep model. In mice, adeno-associated viral (AAV) mediated gene therapy is comparatively more effective than ERT, significantly prolonging the lifespan of Ppt1-/- mice. In order to scale up this approach in a larger brain we devised a strategy to deliver gene therapy to CLN1 R151X sheep. We first constructed an AAV9 vector expressing sheep PPT1 (AAV9-shPPT1) and delivered this intracerebroventricularly (ICV) to neonatal Ppt1-/- mice. This AAV9-shPPT1 vector transduced neurons and astrocytes throughout the Ppt1-/- mouse CNS, extending down to the lumbar spinal cord. At normal disease end stage AAV9-shPPT1 treated Ppt1-/- mice displayed near complete prevention of disease-associated neuropathology and behavior. We next delivered this vector ICV to 4-month-old CLN1 R151X sheep at 1E13 vg/sheep (low dose), and progressively monitored their behavior and neurological performance, and performed both structural and MRS-spectroscopy. At sacrifice at normal disease endstage at 18 months, compared to untreated homozygous CLN1 R151X sheep, low dose AAV9-shPPT1 treated CLN1 R151X sheep displayed partial preservation of MRI brain volume relative to untreated controls, a partially preserved ratio of creatine/N-acetyl aspartate (NAA) (a marker of neuron health) via MRS spectroscopy, and evidence for prevention of CNS neuropathology. A second cohort of CLN1 R151X sheep have also been treated at a higher dose of 2E13 vg/sheep and are currently being monitored for efficacy. Collectively, our data so far provide initial evidence for the efficacy of AAV-mediated gene therapy in this genetically accurate large animal model of CLN1 disease.