Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model ( Ndp tm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease. image Norrie disease is a genetic condition causing blindness and progressive deafness. Successful AAV‐mediated gene augmentation therapy in a mouse model showed that the Norrie phenotype is responsive to treatment after the onset of degeneration, preventing further progression of hearing loss. Injection of AAV9 NDP gene therapy in neonatal Ndp ‐KO mice prevented retinal dysfunction and hearing loss in adult mice and rescued retinal and cochlea vasculature abnormalities. Treatment of older Ndp ‐KO mice also preserved hearing by preventing the loss of sensory hair cells in the cochlea. RNAseq analyses showed that dysregulated gene expression patterns in the Ndp ‐KO cochlea were normalised by AAV9 NDP gene therapy.