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

Abstract

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 (Ndptm1Wbrg ), 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.

• Authors: Valda Pauzuolyte, Aara Patel, James R Wawrzynski, Neil J Ingham, Yeh Chwan Leong, Rajvinder Karda, Maria Bitner-Glindzicz, Wolfgang Berger, Simon N Waddington, Karen P Steel, Jane C Sowden
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 15 Issue 10 Pg. e17393 (Oct 11 2023) ISSN: 1757-4684 [Electronic] England
• PMID: 37642150 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.