Murray, SamanthaRussell, KNMelzer, TRGray, SJHeap, SJPalmer, DNMitchell, Nadia2021-05-192021-04-282021-062021-04-210014-483533930398 (pubmed)https://hdl.handle.net/10182/13814Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases primarily affecting children. A common feature across most NCLs is the progressive loss of vision. We performed intravitreal injections of self-complementary AAV9 vectors packaged with either ovine CLN5 or CLN6 into one eye of 3-month-old CLN5‾/‾ or CLN6‾/‾ animals, respectively. Electroretinography (ERG) was performed every month following treatment, and retinal histology was assessed post-mortem in the treated compared to untreated eye. In CLN5‾/‾ animals, ERG amplitudes were normalised in the treated eye whilst the untreated eye declined in a similar manner to CLN5 affected controls. In CLN6‾/‾ animals, ERG amplitudes in both eyes declined over time although the treated eye showed a slower decline. Post-mortem examination revealed significant attenuation of retinal atrophy and lysosomal storage body accumulation in the treated eye compared with the untreated eye in CLN5‾/‾ animals. This proof-of-concept study provides the first observation of efficacious intravitreal gene therapy in a large animal model of NCL. In particular, the single administration of AAV9-mediated intravitreal gene therapy can successfully ameliorate retinal deficits in CLN5‾/‾ sheep. Combining ocular gene therapy with brain-directed therapy presents a promising treatment strategy to be used in future sheep trials aiming to halt neurological and retinal disease in CLN5 Batten disease.12 pagesPrint-Electronicen© 2021 Elsevier Ltd. All rights reserved.neuronal ceroid lipofuscinosissheepintravitrealelectroretinographygene therapyAAV9CLN5CLN6RetinaAnimalsSheepDependovirusRetinal DegenerationDisease Models, AnimalGlial Fibrillary Acidic ProteinElectroretinographyGenetic VectorsFemaleLysosomal-Associated Membrane Protein 1Neuronal Ceroid-LipofuscinosesIntravitreal InjectionsGenetic TherapyLysosomal Membrane ProteinsJournal Article10.1016/j.exer.2021.1086001096-0007ANZSRC::3212 Ophthalmology and optometry