Sundaram, V; (2014) Gene therapy for inherited retinal diseases. Doctoral thesis , UCL (University College London).

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Abstract

Inherited retinal diseases include a number of disorders which typically affect photoreceptor/retinal pigment epithelial function, and can lead to severe visual impairment. Advances in molecular genetics have allowed the identification of many of the genes responsible for particular conditions, and progress in viral gene transfer technology has enabled the replacement of specific genes into the retina. The first human clinical trial of gene therapy for inherited retinal disease was carried out at Moorfields Eye Hospital and UCL Institute of Ophthalmology, involving 12 patients with RPE65 deficiency - an early-onset retinal dystrophy. The results from this trial are described and provide evidence for the safe administration of viral vectors in the eye, and also demonstrate improvements in retinal function in a number of patients. However, the extent and duration of the response did not match that observed in prior animal studies, suggesting improvements in gene expression level may be required in humans. In addition, consideration for future involvement of the foveal region is highlighted, since retinal thinning was observed in a number of patients following subretinal delivery. Achromatopsia is an inherited disorder of congenitally absent cone photoreceptor function. Gene replacement therapy in animal models of achromatopsia has shown evidence of restored cone function, suggesting that this condition may be an appropriate target for gene therapy in humans. Recent studies have suggested that achromatopsia is a progressive condition with deterioration in cone structure with age, implying that the window of opportunity for therapeutic intervention may be narrow. In this study of retinal structure and function (in preparation for a gene therapy trial) in 40 patients with achromatopsia, an age-associated deterioration in cone structure was not identified, suggesting that the age range for potential intervention is wider than recently suggested, and prospective patients should be assessed on an individual basis, irrespective of age.

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