Toms, M;
Dubis, AM;
De Vrieze, E;
Tracey-White, D;
Mitsios, A;
Hayes, M;
Broekman, S;
... Moosajee, M; + view all
(2020)
Clinical and preclinical therapeutic outcome metrics for USH2A-related disease.
Human Molecular Genetics
10.1093/hmg/ddaa004.
(In press).
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Abstract
USH2A variants are the most common cause of Usher syndrome type 2, characterised by congenital sensorineural hearing loss and retinitis pigmentosa (RP), and also contribute to autosomal recessive non-syndromic RP. Several treatment strategies are under development, however sensitive clinical trial endpoint metrics to determine therapeutic efficacy have not been identified. In the present study, we have performed longitudinal retrospective examination of the retinal and auditory symptoms in (i) 56 biallelic molecularly-confirmed USH2A patients and (ii) ush2a mutant zebrafish to identify metrics for the evaluation of future clinical trials and rapid preclinical screening studies. The patient cohort showed a statistically significant correlation between age and both rate of constriction for the ellipsoid zone length and hyperautofluorescent outer retinal ring area. Visual acuity and pure tone audiograms are not suitable outcome measures. Retinal examination of the novel ush2au507 zebrafish mutant revealed a slowly progressive degeneration of predominantly rods, accompanied by rhodopsin and blue cone opsin mislocalisation from 6–12 months of age with lysosome-like structures observed in the photoreceptors. This was further evaluated in the ush2armc zebrafish model, which revealed similar changes in photopigment mislocalisation with elevated autophagy levels at 6 days post fertilisation indicating a more severe genotype-phenotype correlation, and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease.
| Type: | Article |
|---|---|
| Title: | Clinical and preclinical therapeutic outcome metrics for USH2A-related disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddaa004 |
| Publisher version: | https://doi.org/10.1093/hmg/ddaa004 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | phenotype, audiometry, pure-tone, autophagy, retinal cone, constriction procedure, fertilization, genotype, sensorineural hearing loss, lysosomes, opsin, photoreceptors, retinitis pigmentosa, rhodopsin, rod photoreceptors, visual acuity, zebrafish, treatment outcome, autosomal recessive inheritance, usher syndrome, outcome measures, tissue degeneration, retinal examination |
| 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10092833 |
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