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

Pauzuolyte, Valda; Patel, Aara; Wawrzynski, James R; Ingham, Neil J; Leong, Yeh Chwan; Karda, Rajvinder; Bitner-Glindzicz, Maria; ... Sowden, Jane C; + view all (2023) Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease. EMBO Molecular Medicine , Article e17393. 10.15252/emmm.202317393. (In press). Green open access

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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.

Type: Article
Title: Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.202317393
Publisher version: https://doi.org/10.15252/emmm.202317393
Language: English
Additional information: License: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: AAV9 gene therapy, Ndp, cochlea, retina, vascular
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Maternal and Fetal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10176240
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