AAV9-mediated NGLY1 gene replacement suppresses non-epileptic convulsions in Ngly1-/- rats

N-glycanase 1 (NGLY1) deficiency is a rare autosomal-recessive neurological disorder characterized by neurological dysfunction and so far, has no effective therapy. A systemic Ngly1^-/- rat model recapitulates many patient symptoms, including developmental delay, motor and cognitive deficits. Here we carried out further detailed phenotypic analyses for the Ngly1^-/- rats, with particular focus on those easily translatable to patients’ symptoms, i.e. sleep disturbances, EEG abnormalities and convulsive behaviors. EEG/EMG recordings revealed fragmented sleep and frequent spontaneous epileptiform discharges in Ngly1^-/- rats. Continuous video-EEG monitoring confirmed a high incidence of convulsive events with/without epileptic discharge. At three weeks of age, Ngly1^-/- rats received a single intracerebroventricular injection of AAV9-hNGLY1. We then examined whether central nervous system-targeted gene therapy using an adeno-associated virus serotype 9 carrying human NGLY1 (AAV9-hNGLY1) can rescue those phenotypes