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

• Published in: EMBO molecular medicine Vol. 15; no. 10; p. e17393
• Main Authors: Pauzuolyte, Valda, Patel, Aara, Wawrzynski, James R, Ingham, Neil J, Leong, Yeh Chwan, Karda, Rajvinder, Bitner‐Glindzicz, Maria, Berger, Wolfgang, Waddington, Simon N, Steel, Karen P, Sowden, Jane C
• Format: Journal Article
• Language: English
• Published: Frankfurt EMBO Press 11-10-2023; John Wiley and Sons Inc; Springer Nature
• Subjects: AAV9 gene therapy; Auditory system; Cochlea; Cytomegalovirus; Deafness; Ears & hearing; Electroretinograms; Gene therapy; Hair cells; Hearing loss; Hearing protection; Hereditary diseases; Inner ear; Ndp; NDP gene; Neonates; Norrie disease; Pathology; Plasmids; Point mutation; Proteins; Retina; Sensory deprivation; vascular; Young adults
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202317393

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.