Aboshiha, JN; (2016) Deep phenotyping of inherited retinal disease in preparation for and guidance of gene therapy intervention. Doctoral thesis , UCL (University College London).

Abstract

Deep phenotyping is used to examine inherited retinal eye disease in preparation for anticipated human gene therapy. New light is shed on the existing dichotomy in the literature regarding rod photoreceptor function in achromatopsia (ACHM), suggesting that the location and size of the stimulus used to test such function is critical. The first prospective longitudinal study of ACHM to be published suggests that any progression in ACHM is likely to be slow and subtle, both structurally and functionally. A relationship is demonstrated in ACHM between rod structure, as assessed by adaptive optics (AO) imaging, and function, where increasing ‘rod area’ correlates with lower sensitivity. AO imaging is used to serially assess groups of ACHM cone photoreceptors over time, demonstrating no change in cone densities within the measurement error derived herein. AO derived cone reflectivity profiles in ACHM are shown to broadly mirror the functional findings of detailed psychophysical assessments, where those subjects with more ‘normal’ reflectivity profiles demonstrate evidence of cone function, whilst those with ‘worse’ reflectivity profiles do not. Rarer genotypes of ACHM are further examined by AO imaging and psychophysical methods, and for one such genotype (PDE6C) a novel and distinguishing AO reflectivity profile is suggested. Photoaversion in ACHM is explored, and found, for the first time, to be the most significant symptom for a substantial proportion of patients. A novel subjective photoaversion measurement technique is developed and demonstrates fidelity with more invasive existing testing paradigms. An objective measurement technique is also refined for use in ACHM. Detailed psychophysical testing of ACHM subjects is shown to reveal an incomplete phenotype where conventional clinical tests failed to do so. Finally, young children with AIPL1 Leber congenital amaurosis are shown, for the first time, to have preserved foveal outer retinal structure, which may offer a therapeutic window for gene therapy.

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