Pauzuolyte, Valda;
(2022)
Hearing Loss in Norrie Disease and AAV-mediated Gene Therapy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Norrie disease (ND) is a rare X-linked recessive disorder, caused by mutations in the Norrie Disease Pseudoglioma (NDP) gene, encoding norrin, a small, secreted β-catenin agonist. ND manifests as congenital blindness and progressive hearing loss, with possible cognitive impairment and peripheral vascular disease. Hearing loss starts around adolescence, severely disrupting the quality of life of already blind ND patients. No curative treatment currently exists. Previous studies indicate the cochlea as the major site of lesion, with both vasculature and sensory hair cells affected in advanced stages. This thesis aims to elucidate the primary pathology in the cochlea and to investigate the potential for treatment. Ndp-KO mice (Berger et al, 1996), which are known to recapitulate ND-specific vision and hearing loss were used as an animal model. A histological and functional timeline study of the cochlea between P2 and 2 months of age demonstrated the primary and progressive pathology in cochlear vasculature, barrier, perivascular cells and reduction of endocochlear potential, necessary for the function and survival of the sound receptors, hair cells. This was followed by degeneration of the outer hair cells (OHC) and coincided with a decline in hearing, manifesting as increased DPOAE (measure of OHC function) and ABR (measure of hearing) thresholds. To test the possibility of gene therapy, a tagged human NDP cDNA under a ubiquitous CAG promoter in AAV9 vector was designed and delivered intravenously. A full rescue of hearing, tissue readouts and downstream gene expression was achieved by neonatal treatment. Later treatment, before or after the OHC degeneration, was shown to improve the hair cell survival, gene expression and hearing. In summary, this study determined the vascular and hair cell defects leading to hearing loss in Ndp-KO mice and demonstrated the responsiveness of the phenotype to gene therapy throughout different stages of the disease.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Hearing Loss in Norrie Disease and AAV-mediated Gene Therapy |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL 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 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10157562 |
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