Hirji, Nashila;
(2020)
Deep phenotyping and gene therapy in patients with achromatopsia.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Achromatopsia (ACHM) is an inherited cone photoreceptor dysfunction disorder. Disease-causing sequence variants in the CNGB3 gene account for approximately 40-50% of cases worldwide. There is currently no established cure, although gene-based interventions hold promise for the future. Herein, I investigate retinal structure and function in individuals with molecularly confirmed CNGB3-ACHM. I undertook the largest longitudinal study of retinal structure in ACHM to date, evaluating changes in spectral-domain optical coherence tomography (SD-OCT) parameters over time. The results supported the largely non-progressive nature of the condition, suggesting there may be a wide window for therapeutic intervention. Colour vision deficiency is a key feature of ACHM, and I demonstrated how the computerised low-vision version of the Cambridge Colour Test (lvvCCT) can assess colour vision in affected individuals. Furthermore, I have shown how this test may identify changes in colour discrimination post-intervention. I undertook the largest study characterizing nystagmus in ACHM to date, and subsequently demonstrated that the use of nystagmus as an endpoint in therapeutic trials may be of limited clinical significance. Subjects with ACHM have profound photoaversion which may impair mobility in bright environments. Herein, I have described my work to develop a navigational task to evaluate this, and report the results of the assessments I devised. ACHM impacts upon quality of life (QoL). I evaluated QoL in affected individuals using validated instruments and explored the correlation between QoL and objective tests of visual function. The results suggested that visual function and QoL should be looked at in conjunction when assessing patients, and raised the need for further development of potentially bespoke tools. Finally, I explored the use of magnetic resonance imaging (MRI) for evaluating changes in visual processing beyond the level of the retina, in affected individuals. Some of the data presented herein is from individuals participating in a natural history study of ACHM. These subjects provide a wealth of structural and functional information accumulated over time. I additionally present some baseline test results from individuals enrolled in a gene therapy trial for CNGB3-ACHM. Together, the findings from both cohorts provide important new insights into CNGB3-ACHM, which are directly relevant to interventional clinical trials for ACHM, and potentially other inherited retinal conditions.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Deep phenotyping and gene therapy in patients with achromatopsia |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10095838 |
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